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Ehmke-H; Persson-PB; Just-A; Nafz-B;
Seyfarth-M; Hackenthal-E;
Kirchheim-HR
Physiological concentrations of ANP exert a dual regulatory
influence on renin release in conscious dogs.
Am-J-Physiol. 1992 Sep; 263(3 Pt 2): R529-36
The influence of physiological increments in circulating atrial
natriuretic peptide (ANP) on renin release was determined in conscious
dogs. Renin stimulus-response curves (RSRCs) were obtained by
controlled reductions of renal perfusion pressure (RPP) under control
conditions and during intrarenal or intravenous ANP infusions. Under
all experimental conditions, the RSRCs were characterized by a plateau,
a threshold pressure (Pth), and a steep slope below Pth. Intrarenal ANP
infusion (0.9 ng.kg-1.min-1), which induced a calculated threefold
elevation of renal arterial ANP concentration (but did not change
systemic arterial ANP levels), increased the slope of the RSRC
by 81% (P less than 0.05) with no effect on Pth. A quantitatively
similar effect on the slope of the RSRC (+90%; P less than 0.05) was
observed when systemic ANP levels were raised (from 37 +/- 2 to 71 +/-
9 pg/ml; P less than
0.05) by intravenous infusions (3.6 ng.kg-1.min-1). In addition,
however, intravenously infused ANP reduced Pth from 91 to 85 mmHg (P
less than 0.05), which caused a complete suppression of the renin
response to a reduction of RPP down to 85 mmHg. These findings indicate
that ANP can inhibit renin release at physiological plasma
concentrations by shifting the RSRC to a lower pressure level; this
shift is mediated by a modulation of extrarenal renin control
mechanisms. The direct effect of ANP on renin release is one of
stimulation.
Persson-PB; Ehmke-H; Kirchheim-HR;
Janssen-B; Baumann-JE; Just-A; Nafz-B
Autoregulation and non-homeostatic behaviour of renal blood flow
in conscious dogs.
J-Physiol-Lond. 1993 Mar; 462: 261-73
1. Spontaneously occurring haemodynamic variations within 4 h affecting
renal blood flow (RBF) were compared with externally induced short
changes of renal artery pressure (RAP) in conscious resting dogs. 2. In
all animals in which RAP was servo-controlled (n = 6), perfect
autoregulation of RBF was observed. 3. In all 4 h recordings of
spontaneous renal blood flow (n = 9), certain combinations of blood
pressure and blood flow occurred remarkably frequently as indicated by
three-dimensional frequency distributions. 4. Cluster analysis
demonstrated significant differences between these areas of
accumulation (P < 0.001). The average number of 'set points' per
4 h session was 3.1 +/- 0.3. 5. The shift from one set point to another
is
probably mediated by multiple control systems impinging on renal
haemodynamics as suggested by 1/f fluctuations. 6. In seven dogs, an
additional renal venous catheter allowed measurements of the
arterial-venous (A-V) oxygen partial pressure (PO2) difference as an
indicator of the renal metabolic demand. An inverse relationship
between A-V PO2 difference and RBF (Y = X(-0.034) + 40.9, r = -0.9, P
< 0.001) was found, indicating that the metabolic demands vary
little (if at all) between the different set points. 7. The presented
data suggest a modified view of renal homeostasis. There exist distinct
combinations
between RBF and RAP, which are very stable. Autoregulation merely
buffers
the fluctuations around these set points.
Just-A; Wittmann-U; Nafz-B; Wagner-CD;
Ehmke-H; Kirchheim-HR; Persson-PB
The blood pressure buffering capacity of nitric oxide by
comparison to the baroreceptor reflex.
Am-J-Physiol. 1994 Aug; 267(2 Pt 2): H521-7
[full text PDF]
To compare the contribution of nitric oxide (NO) to the buffering of
short-term and circadian fluctuations of arterial blood pressure with
that of the baroreceptor reflex, conscious foxhounds were subjected to
continuous 24-h blood pressure recordings. A pressure transducer was
placed into the lumen of the abdominal aorta. Telemetry recordings were
done under control conditions, following blockade of NO formation by
intravenous
bolus injection of NG-nitro-L-arginine (L-NNA; 16.5 +/- 2 mg/kg body
wt)
and after total sinoaortic and cardiopulmonary denervation in five dogs
each. L-NNA produced a sustained elevation of mean arterial pressure
(MAP;
137.2 +/- 6.4 mmHg vs. control, 112.9 +/- 3.7 mmHg). After denervation,
no significant increase of MAP was found (113.5 +/- 4.1 mmHg), but the
standard deviation of the MAP histogram was significantly greater (22.5
+/- 3.1 vs. 10.6 +/- 0.9 mmHg, P < 0.05). Sequential spectral
analysis
showed that total power between 0 and 0.5 Hz was elevated more than
twofold
after L-NNA (P < 0.05). This was due primarily to increased power in
the range above 0.1 Hz. After denervation, total power increased about
three-fold (P < 0.05), almost exclusively occurring below 0.04 Hz.
Power in the range above 0.2 Hz was diminished, although not
significantly. It
is concluded that in the conscious dog, NO, as well as the baroreceptor
reflex, is an effective blood pressure buffer. NO is most effective
above
0.1 Hz, whereas the baroreceptors primarily buffer fluctuations slower
than 0.04 Hz.
Ehmke-H; Just-A; Eckardt-KU; Persson-PB;
Bauer-C; Kirchheim-HR
Modulation of erythropoietin formation by changes in blood
volume in conscious dogs.
J-Physiol-Lond. 1995 Oct 1; 488 ( Pt 1): 181-91
1. A possible influence of the filling of the circulatory system
on the plasma concentration of erythropoietin, which is the major
regulator of erythrocyte formation, was investigated in conscious dogs.
2. Over an experimental period of 5 h, the animals were subjected to
either haemorrhage (hypovolaemia), blood volume expansion
(hypervolaemia), or exchange transfusion of blood with dextran
(isovolaemic anaemia). 3. A reduction of blood volume by 20% induced by
haemorrhage increased plasma erythropoietin levels approximately
1.5-fold in the absence of significant changes in haematocrit. 4. An
expansion of blood volume by 12% induced by an intravenous infusion of
dextran did not change plasma erythropoietin levels, although the
haematocrit decreased by 0.04. 5. A reduction of the haematocrit by
0.12 in the absence of changes in blood volume induced by an
isovolaemic exchange transfusion (dextran vs. blood) increased plasma
erythropoietin levels approximately 3-fold.
6. Total renal oxygen supply did not change in any of the three
experimental protocols. 7. These data indicate that in dogs the
erythropoietin production rate is modulated by changes in blood volume,
and suggest a possible role of erythropoietin in the regulation of
blood volume.
Just-A; Wagner-CD; Ehmke-H; Kirchheim-HR;
Persson-PB
On the origin of low-frequency blood pressure variability in the
conscious dog.
J-Physiol-Lond. 1995 Nov 15; 489 ( Pt 1): 215-23
1. Baroreceptor denervation increases blood pressure variability
below 0.1 Hz. This study was undertaken to determine to what extent
these
fluctuations originate from the central nervous system or from
cardiovascular
sources. 2. Blood pressure was recorded at a rate of 10 Hz for
approximately
3.5 h in conscious, resting dogs. Power density spectra were calculated
from all 2(17) points of each recording session and integrated between
0.0002 and 0.1 Hz. 3. Blockade of the afferent limb of the baroreceptor
reflex by surgical denervation of sinoaortic and cardiopulmonary
afferents (Den; n =
6) significantly increased integrated power more than sixfold compared
with
a control group (n = 11). 4. Impairment of the efferent limb in
non-deafferented dogs by either alpha 1-adrenergic blockade with
prazosin (Praz; n = 7) or ganglionic blockade with hexamethonium (Hex;
n = 6) failed to raise variability. 5. Both prazosin (n = 6) and
hexamethonium (n = 3) reduced the increased variability
in denervated dogs. 6. In non-deafferented dogs receiving
hexamethonium, elevation of mean blood pressure to the hypertensive
level of the Den
group, by a continuous infusion of noradrenaline (n = 4), did not
change
the variability. 7. It is concluded that in the absence of changes in
posture, most of the increased blood pressure variability after
baroreceptor
denervation is derived from the central nervous system. 8. Direct
comparison
of power spectra of the Den (total variability) and Hex groups
(variability
derived from the cardiovascular system only) suggests that the central
nervous
system is also the prevalent source of low-frequency blood pressure
variability in intact animals.
Schoenberg-SO; Just-A; Bock-M; Knopp-MV;
Persson-PB; Kirchheim-HR [full text PDF]
Noninvasive analysis of renal artery blood flow dynamics with MR
cine phase-contrast flow measurements.
Am-J-Physiol. 1997 May; 272(5 Pt 2): H2477-84
It was the aim of this study to quantify the measurement of
pulsatile flow in the renal artery with the noninvasive magnetic
resonance cine phase-contrast (MRCPC) method and combine it with the
simultaneous assessment of pulsatile flow with a transit-time
ultrasound (TTUS) flowmeter. In seven
foxhounds with a chronically implanted precalibrated TTUS flow probe,
MRCPC
flow measurements were made in the renal artery with a temporal
resolution of 32 ms. Mean and pulsatile flow signal were compared by
the simultaneous ipsi- or contralateral measurement of the renal blood
flow signal by both methods (TTUS and MRCPC). In addition, comparative
MRCPC and TTUS flow measurements
were made with artificial renal artery stenosis and after the
administration
of angiotensin II. The mean flow data assessed by the noninvasive MRCPC
flow measurements showed an excellent correlation with corresponding
TTUS
recording (r = 0.99). The MRCPC flow signal displayed a waveform of the
renal artery flow profile that was very similar to the TTUS flow pulse.
The
hemodynamic changes induced by angiotensin II or due to renal artery
stenosis
were also reliably detected by MRCPC. MRCPC provides a reliable
noninvasive
method for the quantification of mean blood flow and the assessment of
the pulsatile flow signal in the renal artery and proves to be
sensitive to hemodynamic changes of pathophysiological importance.
Alternatively, the method may be used for studies in physiology that
demand a noninvasive approach.
Schoenberg-SO; Knopp-MV; Bock-M;
Kallinowski-F; Just-A; Essig-M; Hawighorst-H; Schad-L; van-Kaick-G
Renal artery stenosis: grading of hemodynamic changes with
cine phase-contrast MR blood flow measurements.
Radiology. 1997 Apr; 203(1): 45-53
PURPOSE: To analyze the blood flow dynamics in renal artery stenosis
with high-temporal-resolution cine phase-contrast magnetic resonance
(MR) flow measurements. MATERIALS AND METHODS: Cine phase-contrast MR
flow measurements were invasively validated with real-time
intraoperative
transit-time ultrasound (US). In 23 patients, 48 renal artery stenoses
were confirmed at digital subtraction angiography. Cardiac-gated cine
phase-contrast
MR flow measurements were obtained in 32-msec intervals, and flow
curves
were calculated for the whole cardiac cycle. Hemodynamic parameters
evaluated
included the decrease in mean flow and the delay and reduction in the
systolic
velocity maximum due to decrease in or absence of the early systolic
peak.
RESULTS: Overall differentiation between renal artery stenosis (n = 31)
and nonstenosed vessels (n = 17) with cine phase-contrast MR revealed a
sensitivity of 90% and specificity of 94% compared with findings at
digital
subtraction angiography. High-grade stenoses (>50%, n = 19) were
detected
with cine phase-contrast MR with sensitivity of 100% and specificity of
93%. CONCLUSION: Quantitative and qualitative analysis of cardiac-gated
cine phase-contrast MR flow velocity curves provided a highly accurate
method
to detect hemodynamic abnormalities in patients with suspected renal
artery
stenosis.
Wagner-CD; Just-A; Nafz-B; Persson-PB
[full text PDF]
Very low frequency oscillations in arterial blood pressure
after autonomic blockade in conscious dogs.
Am-J-Physiol. 1997 Jun; 272(6 Pt 2): R2034-9
The aim of this study was to investigate spontaneous variability
of arterial blood pressure in conscious foxhounds in the absence of
direct sympathetic and parasympathetic influences. Autonomic blockade
was achieved by administration of the ganglionic blocking agent
hexamethonium (n = 7). In contrast to the control group (n = 7), marked
oscillations with a cycle length of 100 s (0.01 Hz) were observed. The
relationship of the power
densities of the oscillation band (0.01 +/- 0.005 Hz) to the total
power
increased threefold (0.213 +/- 0.007 vs. 0.057 +/- 0.005; P < 0.01).
The 0.01-Hz oscillations typically commenced after some delay. To test
whether the absence of the mechanoreceptor afferents was responsible
for
these fluctuations, we investigated an additional group of foxhounds
that
were subjected to total baroreceptor and cardiopulmonary receptor
denervation (n = 7). Neither in this protocol, nor in a group subjected
to denervation and ganglionic blockade (n = 6), did we observe
sustained oscillations in this frequency range. Since the oscillations
were not seen after combined afferent (mechanoreceptor denervation) and
efferent (ganglionic) blockade, central oscillators as a source of the
oscillations can be ruled out. A simple model of a circulating
pressoric factor may explain the fluctuations, provided that there is a
time delay between the stimulus and the release or action of the
factor. The findings suggest that a circulating factor accounts for the
0.01-Hz oscillations, which is dependent on intact pathways from the
cardiac receptors or baroreceptors to the central nervous system. This
hypothesis is put forward since cardiopulmonary and baroreceptor
denervation blocked the oscillations seen after ganglionic blockade.
Schoenberg-SO; Knopp-MV; Bock-M;
Kallinowski-F; Just-A; Essig-M; Hawighorst-H; Zuna-I; Schad-L;
Allenberg-JR; van-Kaick-G
Einstufung hamodynamischer Veranderungen bei
Nierenarterienstenosen mittels MR-Cine-Phasenkontrastflussmessungen.
[Classification of hemodynamic changes in renal artery stenosis
using cine magnetic resonance phase contrast flow measurements]
Radiologe. 1997 Aug; 37(8): 651-62
PURPOSE: To evaluate the use of high-temporal resolution cine MR
phase-contrast flow measurements for assessment of flow dynamics in
renal
artery stenosis (RAS). MATERIAL AND METHODS: In a dog model, cine MR
flow measurements were validated by comparing the MR flow data to an
invasive
transit-time ultrasound reference technique for different degrees of
RAS.
Cardiac-gated MR flow curves were recorded in 56 renal arteries of 28
patients
with a temporal resolution of at least 32 ms. In all cases RAS was
confirmed
by digital subtraction angiography (DSA). Abnormalities of flow
dynamics
were assessed in the calculated flow curves using the MR parameters
mean
flow, maximum velocity, and time to systolic maximum. RESULTS: By means
of
the MR blood flow parameters high-grade stenoses (> 50%, n = 23)
were
detected with sensitivity of 100% and specificity of 94% with reference
to DSA. The overall differentiation between stenoses (n = 37) and
non-stenosed
vessels (n = 19) revealed a sensitivity of 87% and a specificity of
100%.
CONCLUSION: Analysis of cardiac-gated MR flow curves provides a
non-invasive
method to assess the hemodynamic significance of RAS and thus allows a
functional evaluation in relation to the morphologic characteristics of
the stenosis.
Just-A; Wittmann-U; Ehmke-H;
Kirchheim-HR
[full text PDF]
Autoregulation of renal blood flow in the conscious dog and the
contribution of the tubuloglomerular feedback.
J-Physiol-Lond. 1998 Jan 1; 506 ( Pt 1): 275-90
1. The aim of this study was to investigate the autoregulation of renal
blood flow under physiological conditions, when challenged by the
normal pressure fluctuations, and the contribution of the
tubuloglomerular feedback (TGF). 2. The transfer function between
0.0018 and 0.5 Hz was calculated from the spontaneous fluctuations in
renal arterial blood pressure (RABP) and renal blood flow (RBF) in
conscious resting dogs. The response of RBF to stepwise artificially
induced reductions in RABP was also studied (stepwise autoregulation).
3. Under control conditions (n = 12 dogs), the gain of
the transfer function started to decrease, indicating improving
autoregulation, below 0.06-0.15 Hz (t = 7-17 s). At 0.027 Hz a
prominent peak of high gain was found. Below 0.01 Hz (t > 100 s),
the gain reached a minimum (maximal autoregulation) of -6.3 +/- 0.6 dB.
The stepwise autoregulation (n = 4)
was much stronger (-19.5 dB). The time delay of the transfer function
was
remarkably constant from 0.03 to 0.08 Hz (high frequency (HF) range) at
1.7s and from 0.0034 to 0.01 Hz (low frequency) (LF) range) at 14.3 s,
respectively.
4. Nifedipine, infused into the renal artery, abolished the stepwise
autoregulation (-2.0 +/- 1.1 dB, n = 3). The gain of the transfer
function (n = 4) remained high down to 0.0034 Hz; in the LF range it
was higher than in the control (0.3 +/- 1.0 dB, P < 0.05). The time
delay in the HF range was reduced to 0.5 s (P < 0.05). 5. After
ganglionic blockade (n = 7) no major changes in the transfer function
were observed. 6. Under furosemide (frusemide)
(40 mg + 10 MG h-1 or 300 mg + 300 mg h-1 i.v..) the stepwise
autoregulation was impaired to -7.8 +/- 0.3 or 6.7 +/- 1.9 dB,
respectively (n = 4). In the transfer function (n = 7 or n = 4) the
peak at 0.027 Hz was abolished. The delay in the LF range was reduced
to -1.1 or -1.6 s, respectively. The transfer gain in the LF range
(-5.5 +/- 1.2 or -3.8 +/- 0.8 dB, respectively) did not differ from the
control but was smaller than that under nifedipine (P < 0.05). 7. It
is concluded that the ample capacity for regulation
of RBF is only partially employed under physiological conditions. The
abolition by nifedipine and the negligible effect of ganglionic
blockade show that above 0.0034 Hz it is almost exclusively due to
autoregulation by the kidney itself. TGF contributes to the maximum
autoregulatory capacity, but it
is not required for the level of autoregulation expended under
physiological conditions. Around 0.027 Hz, TGF even reduces the degree
of autoregulation.
Berthold-H; Just-A; Kirchheim-HR; Osswald-H;
Ehmke-H
Renal haemodynamic responses to exogenous and endogenous
adenosine in conscious dogs.
J-Physiol-Lond. 1998 Jul 1; 510 ( Pt 1): 321-30
1. Adenosine has been suggested to be the mediator of a metabolic
feedback mechanism which transfers acute changes in the tubular load
into
opposite changes in renal blood flow (RBF). The goal of the present
experiments was to assess the importance of endogenously formed
adenosine as a 'homeostatic metabolite' during short-term changes in
metabolic demand. 2. In nine
chronically instrumented conscious foxhounds, both the direct effects
of adenosine injections (10, 30 and 100 nmol) into the renal artery and
the temporal changes of RBF after short renal artery occlusions (15, 30
and 60 s duration), the most widely used experimental model to study
the
metabolic feedback mechanism in vivo, were studied. 3. Intrarenal bolus
injections
of adenosine (10, 30 and 100 nmol) induced dose-dependent decreases of
RBF
(RBF: -34 +/- 5, -59 +/- 4 and -74 +/- 4 %, respectively). This
vasoconstrictor effect of adenosine was significantly larger (RBF: -51
+/- 4, -68 +/- 4 and
-83 +/- 3 %, respectively) when the dogs received a low salt diet. 4.
The
post-occlusive responses were characterized by a transient hyperaemia
with
no detectable drop of RBF below the preocclusion level. The
post-occlusive responses were affected neither by changes in local
angiotensin II levels, nor by intrarenal infusions of hypertonic NaCl
or blockade of A1 adenosine receptors. 5. When intrarenal adenosine
levels were elevated by infusion of the adenosine uptake inhibitor
dipyridamole, a transient, although weak, post-occlusive
vasoconstriction was detected. 6. In summary, the present data
demonstrate that adenosine acts as a potent renal vasoconstrictor in
the conscious dog. The endogenous production of adenosine during
short-lasting occlusions of the renal artery, however, appears to be
too small to induce a post-occlusive vasoconstrictor response of RBF.
These results suggest that
a metabolic feedback with adenosine as 'homeostatic metabolite' is of
minor
importance in the short-term regulation of RBF in the conscious,
unstressed
animal.
Just-A; Kirchheim-HR;
Ehmke-H
[full text PDF]
Buffering of blood pressure variability by the renin-angiotensin
system in the conscious dog.
J-Physiol-Lond. 1998 Oct 15; 512 ( Pt 2): 583-93
1. The renin-angiotensin system (RAS) participates in the compensation
of major blood pressure disturbances such as haemorrhage and is
involved in the tonic long-term (> 1 day) maintenance of mean
arterial blood
pressure (MABP). Since its contribution to the short-term (< 1 h)
buffering of normal blood pressure variability is not known, this was
investigated in resting conscious dogs. 2. The regulatory efficiency
and the response time of the RAS were studied by an acute step
reduction of renal artery pressure to 70 mmHg for 1 h using a
suprarenal aortic cuff. After a delay of at least 100 s, MABP rose
exponentially by 22 +/- 5 mmHg in normal dogs (n = 4), by 6 +/- 3 mmHg
after angiotensin converting enzyme (ACE) inhibition (n = 4), and by 25
+/- 5 mmHg after ganglionic blockade (n = 4). MABP returned to control
after release of the cuff with similar time courses. The time constants
of the MABP responses were in the range of 20 min. Thus, possible
feedback oscillations of the RAS would be expected around 0.0025 Hz
(1/(4 x 100 s)); a buffering effect would be possible below this
frequency. 3. Blood pressure variability was investigated by spectral
analysis of MABP from 3.75 h recordings in the frequency ranges of
0.002-0.003 Hz (feedback oscillations) and below 0.002 Hz (buffering
effect). 4. ACE inhibition (n = 7) decreased MABP by 11 +/- 2 mmHg (P
< 0.05), but in both frequency ranges integrated spectral density
was not affected. ACE inhibition also failed to significantly change
spectral density in either of the two frequency ranges under the
following conditions: (1) during ganglionic blockade (n = 7), (2)
during a low-sodium diet (except for a very slight elevation below
0.002 Hz) (n = 7), and (3) when the fall of MABP induced by ACE
inhibition was compensated by an angiotensin II infusion (n = 7). 5. It
is concluded that in spite of its high regulatory efficiency with an
adequate response time the RAS does not directly contribute to the
short-term buffering of blood pressure variability, nor does it give
rise to feedback oscillations under normal resting conditions. Even if
the RAS is stimulated by sodium restriction its contribution to
short-term blood pressure buffering is only marginal.
Bach-A; Just-A; Berthold-H; Ehmke-H;
Kirchheim-H; Borneff-Lipp-M; Sonntag-HG
Catheter-related infections in long-term catheterized dogs.
Observations on pathogenesis, diagnostic methods, and antibiotic lock
technique.
Zentralbl-Bakteriol. 1998 Dec; 288(4): 541-52
BACKGROUND: Intravascular catheters are associated with severe
infections in patients, but only few reports on this problem in animal
research exist. OBJECTIVE: We report on catheter-related bacterial
colonization and its consequences in long-term catheterized animals.
MATERIAL AND METHOD: Foxhounds were instrumented with intravascular
catheters and flow probes to study
the regulation of renal blood flow and pressures. RESULTS: After
flushing
the catheters, alterations in renal blood flow were observed and these
could be related to bacterial colonization of intravascular catheters
with Pseudomonas species. After attention had been focused on aseptic
technique in all experimental phases and prophylactic antibiotic lock
instituted, the occurrence of Pseudomonas bacteremia ceased, and the
magnitude and incidence of catheter-related
colonization and infection by Pseudomonas species dropped considerably.
CONCLUSION: The catheter-related colonization that occurred
spontaneously
in these animals resembled findings in animal experiments in which
catheter-related
infections were deliberately induced as well as observations made with
regard to catheter-related infections in patients. This report
emphasizes
the importance of asepsis when working with animals with long-term
intravascular
catheters. We suggest that monitoring for this complication, e.g., by
means of catheter cultures at the time of removal, should routinely be
part of protocols for animal experiments using long-term intravascular
catheters.
Berthold-H; Munter-K; Just-A; Kirchheim-HR;
Ehmke-H
Contribution of endothelin to renal vascular tone and
autoregulation in the conscious dog.
Am-J-Physiol. 1999 Mar; 276(3 Pt 2): F417-24
Exogenous endothelin-1 (ET-1) is a strong vasoconstrictor in the
canine kidney and causes a decrease in renal blood flow (RBF) by
stimulating the ETA receptor subtype. The aim of the present study was
to investigate the role of endogenously generated ET-1 in renal
hemodynamics under physiological conditions. In six conscious
foxhounds, the time course of the effects of the selective ETA receptor
antagonist LU-135252 (10 mg/kg iv) on mean arterial blood pressure
(MAP), heart rate (HR), RBF, and glomerular filtration rate (GFR), as
well as its effects on renal autoregulation, were examined. LU-135252
increased RBF by 20% (from 270 +/- 21 to 323 +/- 41 ml/min, P <
0.05) and HR from 76 +/- 5 to 97 +/- 8 beats/min (P < 0. 05), but
did not alter MAP, GFR, or autoregulation of RBF and GFR. Since a
number of interactions between ET-1 and the renin-angiotensin system
have been reported
previously, experiments were repeated during angiotensin converting
enzyme
(ACE) inhibition by trandolaprilat (2 mg/kg iv). When ETA receptor
blockade
was combined with ACE inhibition, which by itself had no effects on
renal
hemodynamics, marked changes were observed: MAP decreased from 91 +/- 4
to 80 +/- 5 mmHg (P < 0.05), HR increased from 85 +/- 5 to 102 +/-
11
beats/min (P < 0.05), and RBF increased from 278 +/- 23 to 412 +/-
45
ml/min (P < 0.05). Despite a pronounced decrease in renal vascular
resistance
over the entire pressure range investigated (40-100 mmHg), the capacity
of the kidneys to autoregulate RBF was not impaired. The GFR remained
completely
unaffected at all pressure levels. These results demonstrate that
endogenously
generated ET-1 contributes significantly to renal vascular tone but
does
not interfere with the mechanisms of renal autoregulation. If ETA
receptors
are blocked, then the vasoconstrictor effects of ET-1 in the kidney are
compensated for to a large extent by an augmented influence of ANG II.
Thus
ET-1 and ANG II appear to constitute a major interrelated
vasoconstrictor
system in the control of RBF.
Just-A; Ehmke-H; Wittmann-U;
Kirchheim-HR
[full
text PDF]
Tonic and phasic influences of nitric oxide on renal blood
flow autoregulation in conscious dogs.
Am-J-Physiol. 1999 Mar; 276(3 Pt 2): F442-9
The aim of this study was to investigate the influence of the mean
level and phasic modulation of NO on the dynamic autoregulation of
renal blood flow (RBF). Transfer functions were calculated from
spontaneous
fluctuations of RBF and arterial pressure (AP) in conscious resting
dogs
for 2 h under control conditions, after NO synthase (NOS) inhibition
[NG-nitro-L-arginine methyl ester hydrochloride (L-NAME)] and after
L-NAME
followed by a continuous infusion of an NO donor
[S-nitroso-N-acetyl-DL-penicillamine
(SNAP)]. After L-NAME (n = 7) AP was elevated, heart rate (HR) and RBF
were reduced. The gain of the transfer function above 0.08 Hz was
increased,
compatible with enhanced resonance of the myogenic response. A peak of
high gain around 0.03 Hz, reflecting oscillations of the
tubuloglomerular
feedback (TGF), was not affected. The gain below 0.01 Hz, was elevated,
but
still less than 0 dB, indicating diminished but not abolished
autoregulation.
After L-NAME and SNAP (n = 5), mean AP and RBF were not changed, but HR
was
slightly elevated. The gain above 0.08 Hz and the peak of high gain at
0.03 Hz were not affected. The gain below 0.01 Hz was elevated, but
smaller
than 0 dB. It is concluded that NO may help to prevent resonance of the
myogenic response depending on the mean level of NO. The feedback
oscillations
of the TGF are not affected by NO. NO contributes to the autoregulation
below 0.01 Hz due to phasic modulation independent of its mean level.
Hardt-SE; Just-A; Bekeredjian-R; Kubler-W;
Kirchheim-HR;
Kuecherer-HF [full text PDF]
Aortic pressure-diameter relationship assessed by intravascular
ultrasound: experimental validation in dogs.
Am-J-Physiol. 1999 Mar; 276(3 Pt 2): H1078-85
Intravascular ultrasound (IVUS) has emerged as an important diagnostic
method for evaluating vessel diameter and vessel wall motion. To
evaluate the validity of IVUS in assessing changes in the
pressure-diameter relationship we compared measurements of abdominal
aortic diameters derived from IVUS with those simultaneously obtained
at the same site using implanted sonomicrometers in five chronically
instrumented conscious dogs and in seven acutely
instrumented anesthetized dogs. Five hundred eighty beats were analyzed
to obtain peak systolic and end-diastolic diameters and to calculate
aortic compliance at different blood pressure levels induced either by
an aortic pneumatic cuff or by intravenous injections of nitroglycerin
or norepinephrine. IVUS agreed closely with sonomicrometer measurements
at different blood pressure levels. However, IVUS slightly but
significantly
underestimated aortic diameters by 0.6 +/- 0.7 mm for systolic
diameters
(P < 0.001) and by 0.7 +/- 0.6 mm for diastolic diameters (P <
0.001)
compared with the sonomicrometer measurements. We conclude that IVUS is
a feasible and reliable method to measure dynamic changes in aortic
dimensions
and has the potential to provide ready access to assess aortic
compliance
in humans.
Berthold-H; Munter-K; Just-A;
Kirchheim-HR; Ehmke-H
Stimulation of the renin-angiotensin system by endothelin subtype
A receptor blockade in conscious dogs.
Hypertension. 1999 Jun; 33(6): 1420-4
Previous studies in dogs have shown additive or even synergistic
effects of combined angiotensin-converting enzyme inhibition and either
nonselective endothelin subtype A/B (ETA/B) or selective endothelin
subtype
A (ETA) receptor blockade on renal vascular resistance and mean
arterial
blood pressure. A possible mechanism underlying this interaction may be
a stimulation of the renin-angiotensin system during endothelin (ET)
receptor blockade. We therefore investigated whether plasma renin
activity
and renin release are regulated by the ETA receptor. Experiments were
made in conscious, chronically instrumented dogs receiving either
saline
or the selective ETA receptor antagonist LU 135252 (10 mg/kg IV).
Eighty
to 100 minutes after the administration of LU 135252 (n=5), heart rate
(99+/-7
versus 81+/-6 bpm; P<0.05) and renal blood flow (327+/-40 versus
278+/-36
mL/min; P<0.05) were increased significantly, whereas mean arterial
blood
pressure tended to be lower (93+/-5 versus 105+/-7 mm Hg). These
changes
were associated with a 2-fold increase in plasma renin activity
(0.74+/-0.12
versus 0.37+/-0.10 ng angiotensin I per milliliter per hour;
P<0.05).
Measurements of renin release at various renal perfusion pressures
(n=5)
with the use of a vascular occluder implanted around the left renal
artery
revealed that ETA receptor blockade did not alter renin release at
resting
renal perfusion pressure (78+/-25 versus 71+/-39 U/min) but strongly
enhanced
the sensitivity of pressure-dependent renin release <80 mm Hg
approximately
2.2-fold. In conclusion, selective ETA receptor blockade is associated
with
a stimulation of the circulating renin-angiotensin system, which
results
from both a sensitization of pressure-dependent renin release and a
larger
proportion of blood pressure values falling into the low pressure
range,
where renin release is stimulated. These find-ings strengthen the view
that
ET and the renin-angiotensin system closely interact to regulate
vascular
resistance and provide a physiological basis for synergistic
hypotensive effects of a combined blockade of both pressor systems.
Bekeredjian R., Hardt S.E., Just A.,
Hansen A., Kuecherer H.
Influence of catheter position and equipment-related factors on
the accuracy of intravascular ultrasound measurements
J Invas Cardiol 11: 207-212, 1999
Background. Intravascular ultrasound (IVUS) is frequently used as an
adjunct to coronary angiography to guide revascularization procedures
and, more recently, to estimate atherosclerotic plaque volumes.
Although accuracy of IVUS imaging and analysis is crucial for these
measurements, available data are scare. The purpose of this in vitro
study is to determine the extent to which transducer position and
equipment-related factors
influence measurements accuracy.
Methods. Cross-sectional views of tubular vessel phantoms (diameter
2-14 mm) were acquired 3,2 French catheters in coaxially centered,
eccentric and oblique positions. Catheters were sequentially connected
totwo different ultrasound systems (A and B) to estimate
equipment-related variability. In system B, two software versions were
used to analyze ultrasound images. Longitudinal views of phantom
segments were reconstructed to document transducer misplacement.
Results. Oblique transducer positioning resulted in a non-linear
overestimation of phantom areas that was independent of lumen size and
also resulted in dramatic distortions of theree-dimensionally
reconstructed
phantom geometry. Eccentric positioning did not significantly influence
measurement accuracy. In coaxial positioning, differences between
measured
and true areas increased non-linearly from 0,36 to 4,5 mm 2
in system B and in a linear fashion from -0.01 to 2.68 mm2 in system A
with increasing phantom diameters. Relative differences decreased form
11.4% to 2.9% with increasing reference areas in system B (positive
off-set
error). When using updated software in system B, the off-set error was
negative and relative error dimininshed from-1.34% to 0.44% with
increasing
phantom size.
Conclusion. Transducer position and equipment-related factors influence
the accuracy of intravascular ultrasound, which may lead to
misinterpratation of vessel size and geometry even in straight vessel
segments. Transducer position may be controlled by the reconstruction
of longitudinal images. Ultrasound equipment should be calibrated
before using it for quantative measurements.
Berthold H., Just A., Kirchheim H.R., Ehmke H.
[full
text PDF]
Interaction between nitric oxide and endogenous vasoconstrictors
in the control of renal blood flow
Hypertension, 34: 1254-1258, 1999
The level of renal blood flow (RBF) is controlled by opposing
vasoconstrictor and vasodilator influences. In a recent investigation
in normotensive dogs, we found that combined blockade of endothelin
type A (ETA) receptors and angiotensin II formation induces marked
increases in RBF that were much
larger than the effects of blocking either system alone. The aim of the
present study was to determine the contribution of nitric oxide (NO) to
this
vasodilator response. Experiments were made in 6 conscious, chronically
instrumented
dogs subjected to 5 different experimental treatments on separate days.
Blockade of ETA receptors alone by the selective antagonist LU 135252
had only minor effects on RBF compared with time-control experiments.
Additional blockade of angiotensin II formation by
angiotensin-converting enzyme inhibition with trandolaprilat caused a
substantial increase of RBF by 50%. This vasodilation was entirely
suppressed when NO formation was prevented by inhibition of NO synthase
with NG-nitro-L-arginine methyl ester HCl. However, when during NO
synthase inhibition renal vascular NO
concentrations were clamped at control levels by infusing the NO
donor S-nitroso-N-acetyl-D,L-penicillamine, the vasodilator response
to combined blockade of ETA receptors and angiotensin II formation was
completely restored (RBF 60%). These results indicate that the
vasodilation
after combined ETA receptor blockade and angiotensin-converting enzyme
inhibition is not mediated by an increase in NO release but results
from
the unmasking of the tonic influence that is normally exerted by
constitutively released NO. Accordingly, the tonic activity of
endothelial NO synthase
appears to be of major importance in the physiological regulation of
renal
vascular resistance by determining the vasomotor responses to
endothelin
and angiotensin II.
Schoenberg S.O., Bock M., Kallinowski F.,
Just
A. [full text PDF]
Correlation of hemodynamic impact and morphologic degree of renal
artery stenosis in a canine model
J Am Soc Nephrol 11: 2190-2198, 2000
In a non-invasive comprehensive magnetic resonance (MR) exam, the
morphologic degree of renal artery stenosis was correlated to
corresponding changes in renal artery flow dynamics. Different degrees
of stenosis were created using a chronically implanted inflatable
arterial cuff in 7 dogs. For each degree of stenosis an ultra fast 3D
gadolinium MR angiography with
high spatial resolution was performed, followed by cardiac-gated MR
flow
measurements with high temporal resolution for determination of
pulsatile flow profiles and mean flow. Flow was also measured by a
chronically-implanted flow probe. In 3 of the dogs also transstenotic
pressure gradients (?P) were measured via implanted catheters. Five
different degrees of stenosis could be differentiated in the MR
angiograms (0%, 30%, 50%, 80%, ?90%). The MR flow data agreed with the
flowprobe within ± 20%. Stenoses between 30% and 80% gradually
reduced the early systolic peak (Max1) of
the flow profile, but only minimally affected the midsystolic peak
(Max2)
or mean flow. Stenoses ?90% significantly depressed mean flow by
>50%.
The ratio between Max1 and Max2 (Rmax1/2) gradually fell with the
degree
of stenosis. The onset of significant mean flow reduction and ?P were
indicated by a drop of Rmax1/2 below 1–1.2. Thus, the analysis of
high-resolution flow profiles allows detection of early hemodynamic
changes
even at degrees of stenoses not associated with a reduction of mean
flow.
Rmax1/2 allows differentiation of the grade of hemodynamic compromise
for
a given morphologic stenosis independent of mean flow in a single
comprehensive MR exam.
Just A., Schneider C., Ehmke H., Kirchheim
H.R.
[full text
PDF]
Large vasodilatations in skeletal muscle in resting conscious
dogs and their contribution to blood pressure variability
J Physiol, J Physiol (London) 527: 611-622, 2000
1. Large ( up to +400 % ) transient ( ~ 20 s ) increases of blood flow
were observed in the external iliac arteries of resting conscious dogs
( n=10 ) in the absence of major alerting or muscular activity. At the
same time arterial pressure ( AP ) slightly fell while heart rate ( HR
) rose. 2. The vasodilatations were resistant to atropine, ganglionic,
ß-adrenergic, and NO-synthase inhibition, but were suppressed by
spinal or general anaesthesia. 3. Vasodilatations of similar appearance
were elicited by an alerting sound; these were abolished by atropine.
4. The spontaneous vasodilatations occurred simultaneously and their
magnitudes were well correlated between both legs, but were not
correlated to the amount of concomitant activation of the
surface electromyogram. The duration of this activation almost never
outlasted
10 s. 5. The reactive hyperaemia observed after a total occlusion of
the
artery even for 16 s was not large enough to explain the size of the
spontaneous vasodilatations. Occlusion during peak flow of the
vasodilatations did
not affect the size of the reactive hyperaemia. 6. Spectral analysis
made
separately for data segments with vasodilatation and those without
revealed,
that the vasodilatations substantially enhanced the variability of AP
and
HR at frequencies below ~ 0.1 Hz. 7. In conclusion, large coordinated
skeletal
muscle vasodilatations were identified in resting conscious dogs, which
are initiated neurally, but not by sympathetic-cholinergic or
nitroxidergic
fibres and which do not show any clear correlation to muscular
contraction.
The vasodilatations substantially affect the regulation of skeletal
muscle
blood flow and explain a significant portion of AP and HR variability.
Just A., Faulhaber J., Ehmke
H.
[full text PDF]
Autonomic cardiovascular control in conscious mice
Am J Physiol Regulatory Integrative Comp Physiol 279: R2214-R2221,
2000
Autonomic cardiovascular control was characterized in conscious,
chronically catheterized mice by spectral analysis of arterial pressure
(AP) and heart rate (HR) during autonomic blockade or baroreflex
modulation
of autonomic tone. Both spectra were similar to those obtained in
humans, but at ~10x higher frequencies. The 1/f-relation of the
AP spectrum changed to a more shallow slope below 0.1 - 0.2 Hz.
Coherence between AP and HR reached 0.5 or higher below 0.3 - 0.4 Hz
and also above 2.5 Hz. Muscarinic blockade (atropine) or
beta-adrenergic blockade (atenolol) did not significantly affect the AP
spectrum. Atropine reduced HR variability at all frequencies, but this
effect waned above 1 Hz. Beta-adrenergic blockade (atenolol) slightly
enhanced the HR variability only above 1 Hz. Alpha-adrenergic blockade
(prazosin) reduced AP variability between 0.05 and 3 Hz, most
prominently at 0.15 - 0.7 Hz. A shift of the autonomic nervous tone by
a hypertensive stimulus (phenylephrine) enhanced, while a hypotensive
stimulus (nitroprusside) depressed AP variability at 1 - 3 Hz; other
frequency ranges of the AP spectrum were not affected except for a
reduction below 0.4 Hz after nitroprusside. Variability of HR was
enhanced after phenylephrine at all frequencies and reduced after
nitroprusside. As with atropine, the reduction with nitroprusside waned
above 1 Hz. In conclusion, in mice HR variability is dominated by
parasympathetic tone at all frequencies, during both blockade and
physiological
modulation of autonomic tone. There is a limitation for further
reduction
but not for augmentation of HR variability from the resting state above
1 Hz. The impact of HR on AP variability in mice is confined to
frequencies
higher than 1 Hz. Limits between frequency ranges are proposed as 0.15
Hz
between VLF and LF and 1.5 Hz between LF and HF.
Schoenberg S.O., Bock M., Just A.
Experimentelle Fluss- und Perfusionsmessungen im Tiermodell mit
der Magnetresonanztomographie
[Experimental flow and perfusion measurements in the animal model
with magnetic resonance tomography]
Radiologe 41: 146-153, 2001
AIM: Validation of non-invasive methods for morphologic and functional
imaging of the kidney under physiologic and pathophysiologic
conditions. MATERIAL AND METHODS: In chronically instrumented animals
(foxhounds)
comparative measurements of renal flow and perfusion were performed.
Magnetic
resonance imaging techniques were compared to data obtained from
implanted
flow probes and total kidney weight post mortem. In the MR system,
different
degrees of renal artery stenosis could be induced by means of an
implanted
inflatable cuff. The degree of stenosis was verified with
high-resolution
3D contrast-enhanced MR angiography (3D-CE-MRA) using an intravascular
contrast agent. RESULTS: The MR-data agreed well with the invasively
obtained
results. Artifacts resulting from the implanted flow probes and other
devices
could be kept to a minimum due to appropriate selection of the probe
materials
and measurement strategies. Stenoses could be reproduced reliably and
quantified
from the induced morphologic and functional changes. CONCLUSION:
Morphologic
and functional MR techniques are well suited for non-invasive in vivo
assessment of renal blood flow physiology
Just A., Toktomambetova L., Ehmke H., Kirchheim
H.R.
[full text PDF]
Dynamic characteristics and underlying mechanisms of renal
blood flow autoregulation in the conscious dog
Am J Physiol Renal Physiol 280: F1062-F2071, 2001
The time course of the autoregulatory response of renal blood flow
(RBF) to a step increase of renal artery pressure (RAP) was studied in
conscious dogs. After reducing RAP to 50 mmHg for 60s renal vascular
resistance (RVR) decreased to 50%. When RAP was suddenly increased
again
RVR returned to baseline with a characteristic time course (control;
n=15):
Within the first 10s it rose rapidly to 70% of baseline (first
response),
thus comprising 40% already of the total RVR-response. Thereafter, it
increased at a much slower rate until it started to rise rapidly again
at 2030s after the pressure step (second response). After passing an
overshoot
of 117% at 43s, RVR returned to baseline values. Similar responses were
observed after RAP reduction for 5min or following complete occlusions
for 60s. When the tubuloglomerular feedback (TGF) was inhibited by
furosemide
(40mgi.v., n=12), the first response was enhanced, now providing 60% of
the total response, while the second response was completely abolished.
Instead, RVR slowly rose to reach the baseline at 60s (third response).
The same pattern was observed, when furosemide was given at a much
higher dose (>600mg i.v.; n=6) or in combination with clamping of
the plasma
levels of nitric oxide (n=6). In contrast to RVR, vascular resistance
in
the external iliac artery after a 60s complete occlusion started to
rise
with a delay of 4s and returned to baseline within 30s. It is
concluded,
that in addition to the myogenic response and the TGF, a third
regulatory
mechanism significantly contributes to RBF autoregulation. This
mechanism
is independent of nitric oxide. The three mechanisms contribute about
equally to resting RVR. The myogenic response is faster in the kidney
than in the hindlimb.
Kristen A.V., Just A., Haass M., Seller
H.
[full
text PDF]
Central hypercapnic chemoreflex modulation of renal sympathetic
nerve activity in experimental heart failure
Bas Res Cardiol, 97: 177-186, 2002
Activation of the sympathetic nervous system plays an important role in
the pathophysiology and progression of congestive heart failure (CHF).
The precise mechanisms responsible for sympathetic activation in CHF
are not yet clearly established. An altered central hypercapnic
chemoreflex
modulation of sympathetic nerve activity (SNA) might be an explanation.
Therefore, the response of postganglionic renal SNA to elevation of CO2
concentration in the inspiratory air to 2, 4, and 6% was determined in
anesthetized,
artificially ventilated rats after denervation of peripheral baro- and
chemoreceptors 2 weeks (group A; n=8) or 6 weeks (group B; n=11) after
induction
of an aorto-caval shunt, or 4 weeks after aortic banding (group C;
n=7).
In all CHF models, left ventricular enddiastolic pressure was increased
(A 8 +/- 1, B 8 +/- 1, C 10 +/- 2 mmHg) as compared to sham operated
controls
(A 3 +/- 1, B 4 +/- 1, C 5 +/- 1 mmHg). Indicative of left ventricular
hypertrophy and pulmonary congestion, wet weight of heart (A + 60%, B +
93%, C + 49%) and lungs (A + 15%, B + 36%, C + 12%) were also enhanced
as compared to controls. Elevation of inspiratory CO2 concentration to
2,4, and 6% increased renal SNA by approximately 10, 20, and 30% from
resting activity in all groups. The maximum SNA responses at 6% CO2 in
the groups with CHF (A + 390 +/- 95, B + 425 +/- 133, C + 368 +/- 158
microVs) did not differ from those in the respective controls (A + 510
+/- 130, B + 570 +/- 180, C + 275
+/- 25 microVs). It is concluded that under these experimental
conditions the central hypercapnic chemoreflex sensitivity is not
altered in either of
the employed models of CHF and therefore may not play a major role for
the
well-known elevation of SNA in CHF.
Just A., Ehmke H., Wittmann U., Kirchheim
H.R.
[full text PDF]
Role of angiotensin II in dynamic renal blood flow autoregulation
of the conscious dog
J Physiol 538: 167-177, 2002
The influence of angiotensin II (ANGII) on the dynamic characteristics
of renal blood flow (RBF) was studied in conscious dogs by testing the
response to a step increase in renal artery pressure (RAP) after a 60
s period of pressure reduction (to 50 mmHg) and by calculating the
transfer function between physiological fluctuations in RAP and RBF.
During the RAP reduction, renal vascular resistance (RVR) decreased and
upon rapid restoration of RAP, RVR returned to baseline with a
characteristic time course: within the first 10 s, RVR rose rapidly by
40 % of the initial change (first response, myogenic response). A
second rise began after 20-30 s and reached baseline after an overshoot
at 40 s (second response, tubuloglomerular feedback
(TGF)). Between both responses, RVR rose very slowly (plateau). The
transfer
function had a low gain below 0.01 Hz (high autoregulatory efficiency)
and two corner frequencies at 0.026 Hz (TGF) and at 0.12 Hz (myogenic
response).
Inhibition of angiotensin converting enzyme (ACE) lowered baseline RVR,
but not the minimum RVR at the end of the RAP reduction
(autoregulation-independent
RVR). Both the first and second response were reduced, but the
normalised
level of the plateau (balance between myogenic response, TGF and
possible
slower mechanisms) and the transfer gain below 0.01 Hz were not
affected.
Infusion of ANGII after ramipril raised baseline RVR above the control
condition.
The first and second response and the transfer gain at both corner
frequencies were slightly augmented, but the normalised level of the
plateau was not
affected. It is concluded that alterations of plasma ANGII within a
physiological
range do not modulate the relative contribution of the myogenic
response
to the overall short-term autoregulation of RBF. Consequently, it
appears
that ANGII augments not only TGF, but also the myogenic response.
Aumann S., Schoenberg S.O., Just A.,
Briley-Saebo K., Bjornerud A., Bock M., Brix G.
Quantification of renal perfusion using an intravascular contrast
agent (part 1): Results in a canine model
Magn Reson Med 49:276-87, 2003
In this work absolute values of regional renal blood volume (rRBV) and
flow (rRBF) are assessed by means of contrast-enhanced (CE) MRI using
an intravascular superparamagnetic contrast agent. In an animal study,
eight foxhounds underwent dynamic susceptibility- weighted MRI upon
injection of contrast agent. Using principles of indicator dilution
theory and deconvolution analysis, parametric images of rRBV, rRBF, and
mean transit time (MTT) were computed. For comparison, whole-organ
blood flow was determined invasively by means of an implanted flow
probe, and the weight of the kidneys was evaluated postmortem. A mean
rBV value of 28 ml/100 g was found in the
renal cortex, with a corresponding mean rBF value of 524 ml/100 g/min
and
an average MTT of about 3.4 s. Although there was a systematic
difference
between the absolute blood flow values determined by MRI and the
ultrasonic
probe, a significant correlation (r(s) = 0.72, P < 0.05) was
established.
The influence of the arterial input function (AIF), T(1) relaxation
effects,
and repeated measurements on the precision of the perfusion
quantitation
is discussed.
Schoenberg S.O., Aumann S., Just A., Bock
M., Knopp M.V., Johansson L.O., Ahlstrom H.
Quantification of renal perfusion abnormalities using an
intravascular contrast agent (part 2): Results in animals and humans
with renal artery stenosis
Magn Reson Med 49:288-98, 2003
The
interrelation between the morphologic degree of renal artery stenosis
and changes in parenchymal perfusion is assessed using
an intravascular contrast agent. In seven adult foxhounds, different
degrees of renal artery stenosis were created with an inflatable clamp
implanted around the renal artery. Dynamic susceptibility-weighted
gradient-echo imaging was used to measure signal-time curves in the
renal artery and the renal parenchyma during
administration of 1.5 mg/kg BW of an intravascular ultrasmall particle
iron oxide (USPIO) contrast agent. From the dynamic series, regional
renal
blood volume (rRBV), regional renal blood flow (rRBF), and mean transit
time (MTT) were calculated. The morphologic degree of stenosis was
measured
in the steady state using a high-resolution 3D contrast-enhanced (CE)
MR angiography (MRA) sequence (voxel size = 0.7 x 0.7 x 1 mm(3)). Five
patients with renoparenchymal damage due to long-standing renal artery
stenosis were evaluated. In the animal stenosis model, cortical
perfusion
remained unchanged for degrees of renal artery stenosis up to 80%. With
degrees of stenoses > 80%, cortical perfusion dropped to 151 +/- 54
ml/100 g of tissue per minute as compared to a baseline of 513 +/- 76
ml/100
g/min. In the patients, a substantial difference in the cortical
perfusion
of more than 200 +/- 40 ml/100 g/min between the normal and the
ischemic
kidneys was found. The results show that quantitative renal perfusion
measurements
in combination with 3D-CE-MRA allow the functional significance of a
renal
artery stenosis to be determined in a single MR exam. Differentiation between
renovascular and renoparenchymal disease thus becomes feasible.
Just A., Arendshorst W.J.
[full
text
PDF]
Dynamics and contribution of mechanisms mediating renal blood
flow autoregulation
Am J Physiol Regul. Integr. Comp.
Physiol, 285: 619-631,
2003
We investigated dynamic characteristics of renal blood flow (RBF)
autoregulation and the relative contribution of the underlying
mechanisms
within the autoregulatory pressure range in Sprague-Dawley rats. Renal
arterial
pressure (RAP) was reduced by suprarenal aortic constriction for 60 s,
and
then rapidly released. Changes in renal vascular resistance (RVR)
were assessed following the rapid step reduction and rise in RAP. In
response
to the rise, RVR initially fell 5-10% and subsequently increased ~20%,
reflecting
autoregulatory efficiency (AE) of 93%. Within the initial 7-9 s,
RVR
rose to 55% of the total response providing AE of 37%, reaching maximum
speed at 2.2 s. A secondary RVR increase began at 7-9 s and
reached
maximum speed at 10-15 s. The response times suggest that the initial
RVR
reflects the myogenic response and the secondary tubuloglomerular
feedback
(TGF). During inhibition of TGF by furosemide, AE was 64%. The
initial
rise in RVR was accelerated (0.29 vs 0.20 mmHg/(ml/min/g)/s, p<0.05)
and
enhanced, providing AE of 49% (p=0.005 vs 37%), but it represented only
88% of the total response. The remaining 12% indicates participation of
a third regulatory component. The latter contributed up to 50% when the
step increase in RAP began below the autoregulatory range.
Augmentation
of TGF by acetazolamide affected neither AE nor the relative myogenic
contribution.
Infusion of the Ca2+-channel blocker diltiazem markedly inhibited AE
and
the primary and secondary increases of RVR but left a slow component.
In
response to reduction of RAP the initial vasodilation constituted 73%
of
the total response, but was not affected by furosemide. Contribution of
the third component was 9%. In conclusion, RBF autoregulation is
primarily
due to myogenic response and TGF, contributing 55% and 33-45% in
response
to a rise and 73 % and 18-27 % to reduction of RAP. The data imply
interaction
between TGF and myogenic response affecting strength and speed of the
myogenic
response during rises of RAP. The data suggest a third regulatory
system
contributing <12% normally, but up to 50% at low RAP; its nature
awaits
further investigation.
Just A., Olson
A.J.M., Arendshorst
W.J.
[full
text PDF]
Dual constrictor and dilator actions of
ETB receptors in the rat renal microcirculation: interactions with ETA
receptors.
Am J Physiol Renal Physiol 286: F660-F668, 2004
The vascular actions of
endothelin-1 (ET-1) reflect the combination of vasoconstrictor ETA
and ETB receptors on smooth muscle cells and vasodilator ETB
receptors on endothelial cells. The present study investigated the
contribution
of ET receptor subtypes using a comprehensive battery of agonists and
antagonists infused directly into the renal artery of anesthetized rats
to evaluate the actions of each
receptor class alone
and their interactions.
Boffa J.J., Just A., Coffman T.M., Arendshorst W.J.
[full text PDF]
Thromboxane
receptor mediates renal vasoconstriction and contributes to acute renal
failure in endotoxemic mice.
J Am Soc Nephrol, 15: 2358-2365, 2004
Sepsis
is a major cause of acute renal failure (ARF) and death. Thromboxane A2
(TxA(2)) may mediate decreases of renal blood flow (RBF) and/or GFR
associated with LPS-induced sepsis. This study tested whether TxA(2)
receptor blockade, with the use of TxA(2) receptor knockout (TP-KO)
mice or a selective TP receptor antagonist (SQ29,548), would alleviate
LPS-induced renal vasoconstriction and ARF. Under basal conditions,
anesthetized TP-KO mice displayed a lower mean arterial pressure than
wild-type (WT) mice (102 versus 94 mmHg; P < 0.05). RBF, renal
vascular resistance (RVR), GFR, and urine flow did not differ among
groups under basal conditions, suggesting little tonic influence of
TxA(2) on renal TP receptors in health. In endotoxemic WT mice, 14 h
after LPS (Escherichia coli LPS 8.5 mg/kg intraperitoneally), mean
arterial pressure was reduced to 85 mmHg (P < 0.001), as were RBF
(5.0 versus 9.3 ml/min per g kidney wt; P < 0.001) and GFR (0.38
versus 1.03 ml/min per g kidney wt; P < 0.001). Heart rate and RVR
(71 versus 47 mmHg/ml per min; P < 0.05) increased. The decreases in
RBF and GFR after LPS were attenuated in TP-KO mice versus WT mice
(both P < 0.05). In both TP-KO and TP antagonist-treated mice, RVR
remained stable in response to LPS versus WT mice that did not receive
LPS. Delayed TP-antagonist treatment (12 h after LPS injection)
ameliorated RBF and RVR but did not restore GFR. In other WT animals,
TP-antagonist treatment for 2 h before intravenous LPS abolished the
early renal vasoconstriction and alleviated the decrease in GFR. These
results demonstrate that renal vasoconstriction during endotoxemic
shock induced by LPS is mediated by TP receptors as indicated by
pharmacologic blockade and genetic disruption of TP receptors.
Just A., Olson A.J.M.,
Falck J.R., Arendshorst W.J.
[full
text PDF]
Nitric oxide and
NO-independent mechanisms mediate ETB receptor buffering of
ET-1-induced renal vasoconstriction in the rat.
Am J Physiol Regul Integr Comp
Physiol 288: R1168-R1177, 2005
Vascular ETB receptors exert both dilator and constrictor
actions in a complex interaction with ETA receptors. The aim of this
study was to clarify the presence and relative importance of nitric
oxide and other possible mechanisms underlying the dilator effects of
ETB receptors in the rat kidney. Complete inhibition of NO production
(L-NAME, 25 mg/kg, iv) enhanced the renal vasoconstriction elicited by
entothelin-1 (ET-1) injected into the renal artery from -15 to -30%.
Counteraction of the L-NAME-induced vasoconstriction by infusion of the
NO-donor nitroprusside (NP) into the renal artery did not reverse this
effect (+NP=-29%), but nevertheless effectively buffered Ang
II-mediated renal vasoconstriction. Similarly, renal vasoconstrictor
responses to ET-1 were enhanced after a smaller dose of L-NAME
administered into the renal artery (-22 vs. -15%) and unaffected by
subsequent infusion of a vasodilator dose of NP (-21%). These results
indicate that the responsiveness to ET-1 is buffered by endothelial ETB
receptor stimulated phasic release of NO rather than the static mean
ambient NO level. In other experiments, intrarenal infusion of
ETB-receptor antagonist BQ788 further enhanced the constrictor response
to ET-1 seen during NP + L-NAME (-92 vs. -49%), revealing a
NO-independent dilator component. In controls, the vasoconstriction to
ET-1 was unaffected by vehicle (-27 vs. -20%) and markedly enhanced
during ETB receptor antagonism (-70%). The same pattern of ET-1
responses was observed when indomethacin was given to inhibit
cyclooxygenase (control=-20%, indo=-22%, +ETB-antagonist=-56%) or
MS-PPOH or Miconazole+indomethacin to inhibit epoxygenase alone
(control=-10%, MSPPOH=-11%, +ETB-antag.=-35%) or in combination
(control=-14%, indo+mico=-20%, +ETB-antag.=-43%). We conclude that
phasic release of endogenous NO, but not the static ambient level,
mediates part of the dilator effect of ETB receptors. In addition,
playing a major buffering role is a NO-independent mechanism, perhaps
reflecting clearance of ET by ETB receptors, that is distinct from
prostanoids and epoxyeicosatrienoic acids.
Just A.,
Arendshorst W.J.
[full text
PDF] [Perspectives article by W.A. Cupples]
Nitric oxide
blunts myogenic autoregulation in rat renal but not skeletal muscle
circulation via tubuloglomerular feedback.
J Physiol (London) 569: 959-974, 2005
This rat renal blood flow (RBF) study quantified the impact of
nitric oxide synthase (NOS) inhibition on the myogenic response and the
balance of autoregulatory mechanisms in the time domain following a 20
mmHg-step increase or decrease in renal arterial pressure (RAP). When
RAP was increased, the myogenic component of renal vascular resistance
(RVR) rapidly rose within the initial 7-10 s, exhibiting a ~ 5 s time
constant and providing ~ 36% of perfect autoregulation. A secondary
rise between 10 - 40 s brought RVR to 95% total autoregulatory
efficiency; reflecting TGF and possibly one or two additional
mechanisms. The kinetics were similar after the RAP decrease.
Inhibition of NOS (L-NAME) increased RAP, enhanced the strength (79%
autoregulation) and doubled the speed of the myogenic response, and
promoted the emergence of RVR oscillations (~ 0.2 Hz); the strength
(52%) was lower at control RAP. An equi-pressor dose of angiotensin II
had no effect on myogenic or total autoregulation. Inhibition of
tubuloglomerular feedback (TGF) (furosemide) abolished the L-NAME
effect on the myogenic response. RVR responses during furosemide,
assuming complete inhibition of TGF, suggest a third mechanism that
contributes 10-20% and is independent of TGF, slower than myogenic, and
abolished by NOS inhibition. The hindlimb circulation displayed a
solitary myogenic response similar to the kidney (35% autoregulation)
that was not enhanced by L-NAME. We conclude that NO normally restrains
the strength and speed of the myogenic response in RBF but not hindlimb
autoregulation, an action dependent on TGF, thereby allowing more and
slow RAP fluctuations to reach glomerular capillaries.
Just A.,
Olson A.J., Whitten C.L., Arendshorst W.J.
[full text PDF]
Superoxide
mediates acute renal vasoconstriction produced by angiotensin II and
catecholamines by a mechanism independent of nitric oxide.
Am J
Physiol Heart Circ Physiol. 292: H83-H92, 2007
NAD(P)H oxidases (NOX) and reactive oxygen species (ROS) are involved
in vasoconstriction and vascular remodeling during hypertension
produced by chronic angiotensin II (Ang II) infusion. These
effects are thought to be mediated largely through superoxide anion (O2-)
scavenging of nitric oxide (NO). Little is known about the role
of ROS in acute vasoconstrictor responses to agonists. We
investigated renal blood flow (RBF) reactivity to Ang II (4 ng),
norepinephrine (NE, 20 ng), and α1-adrenergic agonist phenylephrine
(PE, 200 ng) injected into the renal artery (ira) of anesthetized
Sprague-Dawley rats. The NOX inhibitor apocynin (1-4 mg/kg/min
ira, 2 min) or the superoxide dismutase mimetic tempol (1.5-5 mg/kg/min
ira, 2 min) rapidly increased resting RBF by 8±1% (p<0.001)
or 3±1% (p<0.05), respectively. During NO-synthase
(NOS)-inhibition (L-NAME, 25 mg/kg iv), the vasodilation tended to
increase (apocynin 13±4%, tempol 10±1%). During
control conditions, both Ang II and NE reduced RBF by
24±4%. Apocynin dose-dependently reduced the constriction
by up to 44% (p<0.05). Similarly, tempol blocked the acute
actions of Ang II- and NE by up to 48-49% (p<0.05). In other
animals, apocynin (4 mg/kg/min ira) attenuated vasoconstriction to Ang
II, NE, and PE by 46-62% (p<0.01). During NOS-inhibition,
apocynin reduced the reactivity to Ang II and NE by 60-72% (p<0.01),
and tempol reduced it by 58-66% (p<0.001). We conclude that
NOX-derived ROS substantially contribute to basal RBF as well as to
signaling of acute renal vasoconstrictor responses to Ang II, NE, and
PE in normal rats. These effects are due to (O2-)
rather than H2O2, occur rapidly, and are independent of scavenging of
NO.
Just A., Arendshorst
W.J.
[full
text PDF] [online supplement]
A novel mechanism
in renal blood flow autoregulation and the autoregulatory role of A1
adenosine receptors in mice.
Am J Physiol Renal Physiol 293:
F1489-F1500, 2007
Autoregulation of renal blood flow (RBF) is mediated by a fast
myogenic response (MR; approximately 5 s), a slower tubuloglomerular
feedback (TGF; approximately 25 s), and potentially additional
mechanisms. A1 adenosine receptors (A1AR) mediate TGF in superficial
nephrons and contribute to overall autoregulation, but the impact on
the other autoregulatory mechanisms is unknown. We studied dynamic
autoregulatory responses of RBF to rapid step increases of renal artery
pressure in mice. MR was estimated from autoregulation within the first
5 s, TGF from that at 5-25 s, and a third mechanism from 25-100 s.
Genetic deficiency of A1AR (A1AR-/-) reduced autoregulation at 5-25 s
by 50%, indicating a residual fourth mechanism resembling TGF kinetics
but independent of A1AR. MR and third mechanism were unaltered in
A1AR-/-. Autoregulation in A1AR-/- was faster at 5-25 than at 25-100 s
suggesting two separate mechanisms. Furosemide in wild-type mice (WT)
eliminated the third mechanism and enhanced MR, indicating TGF-MR
interaction. In A1AR-/-, furosemide did not further impair
autoregulation at 5-25 s, but eliminated the third mechanism and
enhanced MR. The resulting time course was the same as during
furosemide in WT, indicating that A1AR do not affect autoregulation
during furosemide inhibition of TGF. We conclude that at least one
novel mechanism complements MR and TGF in RBF autoregulation, that is
slower than MR and TGF and sensitive to furosemide, but not mediated by
A1AR. A fourth mechanism with kinetics similar to TGF but independent
of A1AR and furosemide might also contribute. A1AR mediate classical
TGF but not TGF-MR interaction.
Just A., Whitten C.L., Arendshorst
W.J.
[preprint PDF]
[full
text PDF at Am J Physiol]
Reactive oxygen
species participate in acute renal vasoconstrictor responses induced by
ETA and ETB receptors.
Am J Physiol Renal Physiol 294:
F719-28, 2008
Reactive oxygen species (ROS) play important roles in renal
vasoconstrictor responses to acute and chronic stimulation by
angiotension II and norepinephrine, as well as in long-term effects of
endothelin-1 (ET-1). Little is known about participation of ROS in
acute vasoconstriction produced by ET-1. We tested the influence of
NAD(P)H oxidase inhibition by apocynin (4 mg/kg/min, infused into the
renal artery (ira)) on ETA and ETB receptor signaling in the renal
microcirculation. Both receptors were stimulated by ET-1, ETA receptors
by ET-1 during ETB antagonist BQ-788, and ETB by ETB agonist
sarafotoxin 6C. ET-1 (1.5 pmol injected ira) reduced renal blood flow
(RBF) 17+/-4%. Apocynin raised baseline RBF (+10+/-1%, p<0.001) and
attenuated the ET-1 response to 10+/-2%, i.e., 35+/-9% inhibition
(p<0.05). Apocynin reduced ETA-induced vasoconstriction by 42+/-12%
(p<0.05) and that of ETB-stimulation by 50+/-8% (p<0.001). During
nitric oxide (NO) synthase inhibition (LNAME), apocynin blunted
ETA-mediated vasoconstriction by 60+/-8% (p<0.01), whereas its
effect on the ETB-response (by 87+/-8%, p<0.001) was even larger
without than with NO present (p<0.05). The cell-permeable superoxide
dismutase mimetic tempol (5 mg/kg/min ira), which reduces O2(-) and may
elevate H2O2, attenuated ET-1 responses similar to apocynin (by
38+/-6%, p<0.01). We conclude that ROS, O2(-) rather than H2O2,
contribute substantially to acute renal vasoconstriction elicited by
both ETA and ETB receptors and to basal renal vasomotor tone in vivo.
This physiological constrictor action of ROS does not depend on
scavenging of NO. In contrast, scavenging of O2(-) by NO seems to be
more important during ETB stimulation. Key words: renal hemodynamics,
vascular smooth muscle, afferent arteriole, reactive oxygen species,
nitric oxide.
Just-A
Nitric oxide and renal autoregulation.
[full text PDF]
Kidney-Blood-Press-Res. 1997; 20(3): 201-4
Blockade of NO synthesis reduces mean RBF by about 30%. The GFR is
slightly reduced or not changed at all. The autoregulatory capacity for
both RBF and GFR in response to static or dynamic pressure changes is
not affected. This suggests that under normal conditions, the renal
vasculature is subject to a strong continuous influence by endogenous
NO, which determines the mean RBF. However, although the
tubuloglomerular feedback and myogenic response may be modulated by NO,
the accuracy of the renal haemodynamic autoregulation as well as the
mean GFR seem to be kept independent of
the influence on mean RBF.
Kirchheim-HR; Just-A; Ehmke-H
[full
text PDF]
Physiology and pathophysiology of baroreceptor function and
neuro-hormonal abnormalities in heart failure.
Basic-Res-Cardiol. 1998; 93 Suppl 1: 1-22
This review deals with the neuro-hormonal changes in congestive heart
failure, a syndrome that is usually initiated by a reduction of cardiac
output. Inorder to do this, we should like to 1) summarise previous and
more recent evidence for a number of these neuro-humoral derangement's,
2)
review the experimental evidence for an abnormality in the function of
the
arterial- and cardiopulmonary baroreceptor reflexes and 3) discuss,
whether
this abnormality or an interaction with renal mechanisms might cause
the
neuro-hormonal derangements in congestive heart failure.
Schoenberg-SO; Knopp-MV; Bock-M;
Floemer-F; Kallinowski-F; Essig-M; Hawighorst-H; Just-A; Laub-G;
Prince-MR; van-Kaick-G
MR-Bildgebung der Nieren. Neue Ansatze in der Diagnostik.
[MRI of the kidneys. New diagnostic strategies]
Radiologe. 1999 May; 39(5): 373-85
AIM: New diagnostic strategies for evaluation of the kidney by fast MR
imaging techniques. MATERIAL AND METHODS: A comprehensive morphologic
and functional evaluation of the kidney is proposed using fast MR
imaging of renal morphology, multiphase 3D gadolinium MR angiography,
MR urography and MR flow measurements. A single MR examination is
designed to grade
renovascular disease and assess the hemodynamic and functional
significance,
detect and characterize renal lesions and evaluate the urinary tract.
RESULTS: The combined analysis of morphologic and functional data
allows reliable assessment of renal artery stenosis, benign and
malignant renal masses
and diseases of the renal collecting system and ureters, as well as
congenital abnormalities in good agreement to the results of
conventional imaging
modalities. The improved tissue contrast and additional functional
information
compensates for the disadvantage of a lower spatial resolution.
CONCLUSION:
Combined morphologic and functional MR examination represents a
reliable,
non-invasive and cost-effective alternative imaging modality for
comprehensive
diagnostic evaluation of renal disease.
Kuecherer H.F., Just A., Kirchheim
H.R.
[full text PDF]
Evaluation of aortic compliance in humans (Editorial)
Am J Physiol, 278: H1411-H1413, 2000
Schoenberg S.O., Bock M., Aumann S.,
Just A.,
Essig M., Floemer F., Knopp M.V., van Kaick G.
Quantitative Erfassung der renalen Funktion mit der
Magnetresonanztomographie
[Quantitative recording of renal function with magnetic resonance
tomography]
Radiologe 40: 925-937, 2000
AIM: To show the potential of various methods in magnetic resonance
imaging for the evaluation of renal function. MATERIAL AND METHODS: A
combined assessment of renal morphology, renal hemodynamics and
function is proposed. Various techniques are explained, including
multiphasic 3D gadolinium
MR angiography, MR phase-contrast flow measurements, quantitative
perfusion measurements with intravascular contrast agents, and MR
renography and
MR urography. The use of these techniques is demonstrated for
renovascular diseases. RESULTS: The combined use of these techniques
allows renal artery stenosis to be accurately detected and evaluation
of renal blood flow,
perfusion, glomerular filtration rate, and renal excretion. Based on
true
quantitative parameters, the
hemodynamic and functional significance of the stenosis can be
assessed. Renovascular diseases can be differentiated from
renoparenchymal disease. CONCLUSION: For the assessment of renal
function, functional magnetic resonance imaging techniques are an
important alternative to nuclear medicine. The
predictive value regarding the effect of revascularization is currently
under investigation.
Ehmke H., Just A.
[full text PDF]
The Orexins: Linking Circulatory Control with Behavior
(Editorial)
Am J Physiol Regul Integr Comp
Physiol 285: 519-521, 2003
Just
A.
[full text PDF]
The Mechanisms of
Renal Blood Flow Autoregulation. Dynamics and
Contributions. (Invited review)
Am J Physiol Regul Integr Comp
Physiol 292: R1-R17, 2007
Autoregulation of renal blood flow (RBF) is caused
by the myogenic response (MR), tubuloglomerular feedback (TGF), and a
third regulatory mechanism that is independent of TGF but slower than
MR. The underlying cause of the third regulatory mechanism remains
unclear; possibilities include ATP, Ang II or a slow component of MR.
Other mechanisms, which, however, exert their action through modulation
of MR and TGF are pressure-dependent change of proximal tubular
reabsorption, resetting of RBF and TGF, as well as modulating
influences of Angiotensin II (Ang II) and nitric oxide (NO). MR
requires <10 s for completion in the kidney and normally follows
first-order kinetics without rate-sensitive components. TGF takes 30-60
s and shows spontaneous oscillations at 0.025-0.033 Hz. The third
regulatory component requires 30-60 s; changes in proximal tubular
reabsorption develop over 5 min and more slowly for up to 30 min, while
RBF and TGF resetting stretch out over 20-60 min. Due to these kinetic
differences, the relative contribution of the autoregulatory mechanisms
determines the amount and spectrum of pressure fluctuations reaching
glomerular and postglomerular capillaries and thereby potentially
impinge on filtration, reabsorption, medullary perfusion, and
hypertensive renal damage. Under resting conditions, MR contributes
~50% to overall RBF autoregulation, TGF 35-50%, and the third mechanism
less than 15%. NO attenuates the strength, speed and contribution of
MR, whereas Ang II does not modify the balance of the autoregulatory
mechanisms.
Kirchheim H.R., Just A.
Renal autoregulation.
In: W.P. Anderson (ed). Advances in Organ Biology: The Renal
Circulation.
JAI Press Inc., Greenwich, USA, in
press 2000; ISBN 0-7623-0613-0
Just A., Ehmke H.
[full
text PDF]
Praktikum der Kreislaufphysiologie am Menschen (Practical course
for cardiovascular physiology in humans)
Physiologie Heft 12, 1999
(Bericht über Unterrichtsmethoden, Report on teaching
methods)
Author's translation:
We would like to present here a practical course, based on which
we have been teaching the physiology of circulatory regulation in
Heidelberg since two years. All experiments included herein are made on
human subjects. By the use of non-invasive measurements of arterial
pressure (Finapres), heart rate, and stroke volume (cardioimpedance),
the arterial pressure pulse curve, hydrostatic pressure differences, as
well as peripheral resistance are demonstrated. The student is led to
the understanding of integrative regulatory functions by observation of
the influences of respiration
on the circulation as well as by investigation of the function and the
time course of the baroreceptor reflex response (neck chamber), the
hemodynamic responses to a reduction of the central blood volume (lower
body negative pressure), as well as the consequences of the
Valsalva-manoever. With
the same or slightly expanded equipment, also many more interesting
experiments are feasable.
Musch
T.I., Carroll R.G., Just A., Lane P.H., Talman W.T. [full text PDF]
A
broader view of animal research.(comment)
BMJ. 334(7588):274, 2007
Perel et al examined only immediate preclinical testing of new drug
therapies,1 but animal research aids medical science in many more ways
Animal studies play a part in the initial development of candidate
drugs, and the development and testing of medical devices and surgical
procedures. Even more crucial, animal research informs clinical
research by building the foundation of biological knowledge. Basic
research that expands our understanding of how life systems function
indicates to clinicians not only what direction to pursue but what
directions are possible.
Although animal research informs clinical research, its circumstances
and experimental goals differ from those of clinical research. Thus
their protocols and experimental designs necessarily differ. Animal
studies generally seek a mechanism of action for treatment, rather than
treatment efficacy. They are usually conducted on defined, genetically
homogenous subjects with near perfect compliance, as opposed to the
large scale diversity of genetics and behaviour of a clinical
population. Some clinically necessary procedures, such as double
blinding, serve little purpose in an animal study, since rats are not
susceptible to the placebo effect. Furthermore, accepted standards for
animal welfare as well as many national and institutional protocols
insist that sample sizes of animal studies be small. Despite these
differences, the protocol used by Perel et al to determine that the
animal studies were of "poor" quality was based, for the most part, on
standards meant for large clinical trials.
Recent abstracts, not yet published as original publication
Just A., Arendshorst W.
Calcium signaling at different sites along the interlobular
arteriole and in cremaster muscle arterioles
FASEB J 16 (4): A473, abstract 397.2, 2002
Responses of intracellular calcium ([Ca2+]i) were investigated in
response to increased external KCl (50 mM) and norepinephrine (NE
1µM) in microdissected interlobular ILA, n=6) and cremaster
muscle arterioles (CMA, n=5) from rats using FURA-2. In response to NE
[Ca2+]i reached a transient peak after 5-15 sec and then declined to a
constant elevated plateau level. High KCl evoked a more square-shaped
response. The responses did not differ between proximal, middle and
distal segments of the ILA. In CMA the peak after high KCl was larger
than in ILA (+53±5 vs +32±3 nM,
p=0.004), while the plateau level and the response to NE were similar.
In
dose response curves for KCl (10 - 100 mM) and NE (10 nM - 3o µM)
CMA
showed a higher maximum peak response to KCl (117±36 vs
44±8
nM), while sensitivity (ED50 47±3 vs 53±5 mM) and plateau
response
were not different from ILA. The peak response to KCl was unaffected by
?-adrenergic
blockade indicating it was not due to perivascular nerves. Responses to
NE
were the same in both vessels. The time to peak after NE was not
significantly
different between CMA and ILA (13±2 vs 9±2 s for NE and
10±2
vs 11±1 s for KCl). In conclusion, there are only subtle
variations
in the pattern of the [Ca2+]i response along the ILA. The response to
NE
was surprisingly similar between both vessel types, while in response
to
high KCl CMA showed an exaggerated peak increase of [Ca2+]i.
Just A., Groome R.L., Arendshorst W.J.
Role of prostaglandins in the modulation of renal vascular
responsiveness to angiotensin II with chronic changes in sodium intake.
FASEB J 17 (5-I): A95, abstract 90.11, 2003
The responsiveness of vascular beds to the constrictor effects of
angiotensin II (AngII) decreases during chronic sodium restriction.
AngII is known to downregulate vascular AT1 receptors and to stimulate
local production of vasodilator prostaglandins (PGE2, PGI2). During
sodium restriction the expression of cyclooxygenase-2 (COX-2) is
upregulated in the renal cortex. Thus, we investigated the role of COX
metabolites on the modulation of
the renal blood flow (RBF) responses to AngII (4 ng) injected into the
renal artery in rats kept on low or high salt diet for 10 days. Resting
RBF and urine output were significantly lower in the low salt animals.
The
AngII-induced constriction was smaller after sodium restriction
(13±1%
vs 25±3% reduction of basal RBF, p<0.001). COX-inhibition by
indomethacin enhanced the AngII response in both groups by a similar
amount
(D=+6±2% vs +7±2%), but the
response
to a larger dose of AngII (8 ng) in low salt rats was more enhanced by
indomethacin (D=+20±5%, p<0.05).
Exogenous PGE2 blunted the AngII response more in the low salt group
(57±13% vs
13±9%, p<0.05), whereas the effect of PGI2 (iloprost) did not
differ between groups (36±8% vs 33±6%). We conclude that
the
buffering efficiency of PGE2 but not PGI2 is enhanced during sodium
restriction,
possibly due to upregulation of EP4 receptors. This effect contributes
in
part to the attenuated constrictor response to AngII during salt
deprivation.
Supported by NIH grant RO1-HL02334.
Pressure-dependent
variation of the contribution of
myogenic response and tubuloglomerular feedback to renal blood flow
autoregulation.
FASEB J
18 (4): A286, abstract 205.4, 2004
Renal blood flow (RBF)
autoregulation is mediated by an intrinsic myogenic response (MR),
tubuloglomerular feedback (TGF) and possibly a third regulatory
mechanism.
Micropuncture studies suggest a reduction of TGF at lower renal artery
pressure
(RAP). We investigated the relative participation of the regulating
mechanisms
at varying RAP in anesthetized euvolemic rats. The contribution of MR
was
derived from the autoregulatory changes in renal vascular resistance
occurring
within the first 7-9 s after a 20 mmHg step perturbation of
RAP
within the autoregulatory pressure range. Elevation of baseline RAP by
iv
infusion of angiotensin II enhanced the contribution of MR
(51±3 vs
42±2 %, p<0.05, n=8). A similar change was seen during
increased RAP
with phenylephrine (62±5 vs 39±5 %, p<0.01,
n=6) or baroreflex
stimulation by carotid occlusion (63±4 vs 48±4 %,
p<0.05, n=9). The
pressure-dependency was reversed by mechanical restoration of RAP to
basal
levels. Reduction of RAP below resting levels to 90 mmHg
diminished
autoregulation, but the fraction of MR did not change (51±3 vs
51±2 %,
n=10). Marked inhibition of TGF by furosemide enhanced the contribution
of MR
more at resting (78±3 vs 48±3 %, p<0.001, n=6)
than at reduced RAP
(61±4 % vs 54±5 %, p>0.5) indicating
contribution of TGF is
reduced and that of a third mechanism enhanced at lower RAP. We
conclude that elevation of RAP (or vasoconstriction) enhances
the participation of MR in autoregulation of RBF. Reduction of RAP
reduces TGF
and augments a third mechanism. The mechanisms mediating changes in the
efficiency of MR as a function of RAP or initial vascular tone requires
further
investigation as does the nature of the third mechanism.
Supported by NIH, R01-HL02334