A. Just - Home

THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Department of Cell & Molecular Physiology

Armin Just, MD PhD
Dept. Cell & Molecular Physiology
University of North Carolina at Chapel Hill
6341 Medical Biomolecular Research Building
103 Mason Farm Road, CB#7545
Chapel Hill, NC 27510
USA
Tel.: +1 (919) 966-9933
Fax.: +1 (919) 966-6927
E-mail: just@med.unc.edu

-> Summary of Research Interests
-> Biographical Sketch
-> List of Publications
-> List of Publications with abstracts
-> Homepage Laboratory of Dr. William J. Arendshorst at UNC
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Last updated: April 2008

Summary of Research Interests

   The interest of my research concentrates on the dynamics of cardiovascular regulation in health and disease. This pertains to the response times and frequency ranges of both the control of systemic arterial pressure as well as the regulation of regional organ blood flow.

Blood pressure variability
   My early studies have shown that the majority of resting bloood pressure variability in the lower frequency range (< 0.01 Hz) derives from within the central nervous sytem and is transmitted to the circulation by sympathetic vasomotor nerves (80%), rather than originating directly within the circulation (20%) [2]. In addition to these sympathetically mediated fluctuations, we identified an additional source of central nervously derived blood pressure and heart rate variability [8]: In resting conscious dogs large skeletal muscle vasodilatations occur, which are initiated neurally, but not by sympathetic cholinergic or nitroxidergic nerves. These vasodilatations also seem to be independent of metabolic factors and uncorrelated to major muscular contraction in the quietly resting dogs. This dilator pathway might also be pivotal in the well known but unclarified initial vasodilatation at the onset of muscular exercise.
   Other studies investigated the regulatory mechanisms striving to keep these blood pressure fluctuations small. In the frequency range below 0.04 Hz such buffering is predominantly provided by the baroreceptor reflex [1], while endogenous nitric oxide [1] and renin-angiotensin system [5] only marginally contribute in this frequency range. In conscious mice, spectra of cardiovascular variability were found to be very similar to those in dogs and humans, albeit shifted to 8-10-times higher frequencies [9]. Furthermore, in contrast to larger mammals, the capacity for reduction of heart rate variability from the resting level seems to be limited in the HF-range in mice [9]. This means that the LF/HF-ratio, which is used in humans as indicator of the sympathovagal balance, is not a useful parameter in mice.
   A recent work compared the kinetics of vasomotor responses in the renal and skeletal muscle circulation using both in in vivo blood flow studies in response to sympathetic nerve stimulation and in in vitro experiments measuring calcium transients in isolated microvessels during stimulation with norepinephrine. In contrast to the monophasic blood flow response in skeletal muscle, the time course in the kidney seems to be biphasic with the faster component resembling the response in skeletal muscle [24]. However, dynamics and magnitude of calcium transients appear to be similar in isolated vessels from both vascular beds [22].

Renal blood flow autoregulation
   Dynamic analysis of blood flow autoregulation of the kidney by transfer function analysis confirmed that the two known underlying mechanisms, the myogenic response ( MR ) and the tubuloglomerular feedback ( TGF ) are both active under physiological conditions in the conscious resting animal [4]. To more directly and more quantitatively assess the contribution of the two regulating mechanisms, MR and TGF, a method was developed for investigation of the time course of the response of RBF autoregulation to a rapid step change in renal artery pressure. Because the two mechanisms have different response times, their actions can be dissociated in time by this approach. These investigations indicated that in addition to MR and TGF a novel third mechanism is involved in RBF autoregulation with a time course even slower than TGF [11]. A similar mechanism, although with somewhat faster time course than the third mechanism was seen when TGF was inhibited indicating that an autoregulatory mechanism exists that is distinct from TGF but slower than MR [11]. Depending on whether the latter is the same as the third mechanism but with variable speed or yet another one, these findings indicate that at least a third regulatory mechanism exists in RBF autoregulation, possibly even a fourth. Quantitative analysis indicated that in the conscious resting dog and for large pressure perturbations MR and TGF contribute ~30% to the total response, each, while the remaining 30% seem to be brought about by the novel third and/or fourth mechanism(s) [11].
   In subsequent work, the method was further refined to allow for assessment of the response to small perturbations of arterial pressure within the physiological pressure range. These studies revealed contributions of 50% for MR, 35-50% for TGF, and up to 15% for the third/fourth mechanism [14] [17]. We also demonstrated significant interactions between TGF and MR [14].
   Further investigations assessed whether this balance among the regulating mechanisms is constant or can be modulated and what the modulating factors are. Despite the well known augmenting effects of angiotensin II on baseline resistance, as well as on both MR and TGF, the relative contribution of the regulating mechanisms is not modified by varying levels of plasma angiotensin II in either dogs [12] or rats [17]. In contrast, the balance of contributions is strongly modulated by nitric oxide which mitigates the speed, strength, and contribution of MR to autoregulation [17]. All three of these effects induce a slow-down of the speed of the overall autoregulation [17]. This influence of nitric oxide depends on the integrity of TGF and accordingly does not afect the strength of MR in the skeletal muscle circulation [17]. Transfer function analysis demonstrated a buffering role of nitric oxide on feedback oscillations of the MR in the renal circulation and also revealed a novel modulating influence of nitric oxide in a confined frequency range below 0.01 Hz [6 ]. In contrast to nitric oxide and similar to angiotensin II, sympathoadrenergic stimulation by phenylephrine or by baroreflex activation only slightly enhanced MR [23]. Reduction of arterial pressure to hypotensive levels close to the lower limit of autoregulation (70-90 mmHg) reduced MR, abolished TGF and enhanced the contribution of the third/fourth autoregulatory mechanism [23].
    To further characterize the third and fourth mechanisms, mice were studied that are genetically deficient in TGF due to targeted deletion of A1 adenosine receptors (A1AR), the major signaling pathway of TGF [19]. In these animals, the TGF-component of autoregulation was eliminated as expected associated with impaired overall autoregulation. However, myogenic response and the third/fourth mechanism(s) were not different than in wild-type mice. When TGF was pharmacologically inhibited by furosemide in these mice, the third mechanism was eliminated and another mechanism became apparent with a time course faster than the third mechanism, slower than MR, and similar to TGF [19]. These results indicate that the third mechanism is independent of A1AR and substantially slower than classical TGF. The findings also suggest that a fourth regulatory mechanism exists that is independent of A1AR and furosemide. Since in the presence of furosemide and absence of A1AR, TGF is unlikely to be functional, the fourth meachanism appears to be distinct from classical TGF.
    Ongoing studies on this topic investigate the roles of A1AR and P2X1-ATP-receptors (P2X1R) in TGF and autoregulation on the level of the whole kidney. This is important, because a major controversy exists in the field on this question. Given our findings of a third and fourth autoregulatory mechanism with unknown underlying causes, we will test the tempting hypothesis that the contribution of P2X1R to autoregulation is not due to TGF but to mediating the third and/or fourth mechanism. Further investigations will look for other possible causes of the third and fourth mechanism.
    Further studies aim to detect the signaling pathways underlying the modulating influence of nitric oxide to define the roles of NO derived from nNOS located in the macula densa and from eNOS in the endothelial cells.

Other renal hemodynamic studies
    An initial work of NIH-funded studies under the direction of Dr. William J. Arendshorst investigated the involvement of prostanoids in the known reduction during sodium restriction of the responsiveness of the renal circulation to angiotensin II [21]. We found that the efficiency of PGE₂ but not PGI₂ is augmented during sodium restriction, contributing to the blunted angiotensin II responsiveness in this condition.
    Subsequent projects investigated the interactions between the receptor subtypes for endothelin. Initially, we identified and quantified the dual vasodilator and constrictor influences exerted by the ETB-receptor subtype and their dependence on whether ETA receptors are co-stimulated or not [15]. In a follup work we found that the buffering effect of ETB receptors is due to release of nitric oxide, but also to another, nitric oxide-independent, mechanism. The latter was also found to be separate from cyclooxygenase and epoxygenase metabolites and may thus reflect clearance of ET by ETB receptors [16].
   Recent studies investigated the role of reactive oxygen species (ROS) in acute renal vasoconstrictor responses to various constrictor agents. The results indicate that ROS, most likely superoxide, contribute about half of the acute constrictor effect induced by angiotensin II and norepinephrine in the kidney [18]. A subsequent study found the same degree of ROS involvement in acute renal vasoconstrictor responses to endothelin or to selective activation of ETA or ETB receptors [20]. The similarity across various agonists suggests that the vasoconstrictor signaling of ROS may be a general feature G-protein coupled receptors in the kidney that may also extend to other vascular beds. Furthermore, the constrictor contribution of ROS to either of these agonists was found to be independent of nitric oxide and therefore cannot be explained by scavenging of the dilator effect of nitric oxide by superoxide [18], [20]. In fact, in the case of ETB-receptor stimulation, the contribution of ROS was even larger in the absence than in the presence of nitric oxide [20], indicating that scavenging in the opposite direction, i.e. blunting of superoxide by nitric oxide, may occur under certain physiological conditions.
   Current investigations study the role of ROS in RBF autoregulation and in the autoregulatory mechanisms. Results indicate that ROS contribute slightly to RBF autoregulation in the presence of nitric oxide, mildly strenghtening MR with little influence on TGF or third mechanism [25]. However, in the absence of nitric oxide, ROS seem to lead to profound augmention of MR. This not only confirms our previous findings of nitric oxide-independent effects of ROS, but may represent the mechanism underlying the strong enhancement of MR in the kidney observed during inhibition of nitric oxide production described above [17].

Collaborations with clinical partners
   Analysis of the flow pulse curve was used to further develop a noninvasive diagnostic tool for the comprehensive assessment of renal artery stenosis by nuclear magnetic resonance in cooperation with collegues at the German Cancer Research Center (DKFZ, Drs. Stefan O. Schoenberg and Michael Bock) and the University Department of Surgery in Heidelberg (Prof. Ulrich Kallinowsky) [3]. A later study brought the changes of the flow pulse in direct correlation with the angiographic degree of stenosis [10].
    In a collaboration with cardiologists from the Department of Internal Medicine in Heidelberg (Dr. Arnt Kristen and Prof. Markus Haass) the hypercapnic reflex modulation of sympathetic nerve activity was investigated in anesthetized rats [13]. It was found that the central component of this reflex is not modulated in different models of congestive heart failure in these rats.
    Another collaboration with the Department of Internal Medicine (Drs. Stefan Hardt, Raffi Bekeredjian, and Prof. Helmut Kuecherer) assessed the applicability of intravascular ultrasound measurements for the evaluation of arterial compliance [7].
    A collaboration with the Mouse Cardiovascular Pathophysiology Core Facility in the Carolina Cardiovascular Biology Center at the UNC Chapel Hill (Drs. Susan S. Smyth, Mauricio Rojas, and David Clemmons) aims to develop pertinent methods and investigate vascular compliance and pulse wave velocity in anesthetized and conscious mice.

Selected references

1. Just A., Wittmann U., Nafz B., Wagner C.D., Ehmke H., Kirchheim H.R., Persson P.B. The blood pressure buffering capacity of endogenous nitric oxide by comparison to the baroreceptor reflex. Am J Physiol 267: H521-H527, 1994 [abstract][full text PDF]
2. Just A., Wagner C.D., Ehmke H., Kirchheim H.R., Persson P.B. On the origin of low frequency blood pressure variability in the conscious dog. J Physiol (London) 489: 215-223, 1995 [abstract]
3. Schoenberg S.O., Just A., Bock M., Knopp M.V., Persson P.B., Kirchheim H.R. Noninvasive analysis of renal blood flow dynamics with MR CINE phase-contrast flow measurements Am J Physiol 272: H2477-H2484, 1997 [abstract][full text PDF]
4. Just A., Wittmann U., Ehmke H., Kirchheim H.R. Autoregulation of renal blood flow in the conscious dog and the contribution of the tubuloglomerular feedback. J Physiol (London) 506: 275-290, 1998 [abstract] [full text PDF]
5. Just A., Kirchheim H.R., Ehmke H. Buffering of blood pressure variability by the renin-angiotensin system in the conscious dog. J Physiol (London) 512: 583-593, 1998 [abstract] [full text PDF]
6. Just A., Ehmke H., Wittmann U., Kirchheim H.R. Tonic and phasic influences of nitric oxide on renal blood flow autoregulation in the conscious dog. Am J Physiol 276: F442-F449, 1999 [abstract] [full text PDF]
7. Hardt S.E., Just A., Bekeredjian R., Kübler W., Kirchheim H.R., Kuecherer H. Aortic pressure-diameter relationship assessed by intravascular ultrasound: experimental validation in dogs Am J Physiol 276: H1078-H1085, 1999 [abstract][full text PDF]
8. Just A., Schneider C., Ehmke H., Kirchheim H.R. Large vasodilatations in skeletal muscle in resting conscious dogs and their contribution to blood pressure variability J Physiol (London) 527: 611-622, 2000 [abstract] [full text PDF]
9. Just A., Faulhaber J., Ehmke H. Autonomic cardiovascular control in conscious mice Am J Physiol 279: R2214-R2221, 2000 [abstract] [full text PDF]
10. Schoenberg S.O., Bock M., Kallinowski F., Just A. Correlation of hemodynamic impact and morphologic degree of renal artery stenosis in a canine model. J Am Soc Nephrol 11: 2190-2198, 2000 [abstract] [full text PDF]
11. Just A., Toktomambetova L., Ehmke H., Kirchheim H.R. Dynamic characteristics and underlying mechanisms of renal blood flow autoregulation in the conscious dog Am J Physiol 280: F1062-F2071, 2001[abstract] [full text PDF]
12. Just A., Ehmke H., Wittmann U., Kirchheim H.R. Role of angiotensin II in dynamic renal blood flow autoregulation of the conscious dog J Physiol 538: 167-177, 2002 [abstract] [full text PDF]
13. Kristen A.V., Just A., Haass M., Seller H. Central hypercapnic chemoreflex modulation of renal sympathetic nerve activity in experimental heart failure Bas Res Cardiol, 97: 177-186, 2002 [abstract] [full text PDF]
14. Just A., Arendshorst W.J. Dynamics and contribution of mechanisms mediating renal blood flow autoregulation. Am J Physiol Regul. Integr. Comp. Physiol 285: 619-631, 2003 [abstract] [full text PDF]
15. Just A., Olson A.J.M., Arendshorst W.J. 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   [abstract] [full text PDF]
16. Just A., Olson A.J.M., Falck J.R., Arendshorst W.J. 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. [abstract] [full text PDF]
17. Just A., Arendshorst W.J. Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback.. J Physiol (London) 569: 959-974, 2005 [abstract] [full text PDF]
18. Just A., Olson A.J., Whitten C.L., Arendshorst W.J. 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 [abstract] [full text PDF]
19. Just A., Arendshorst W.J. 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 [abstract] [preprint PDF]   [online supplement]
20. Just A., Whitten C.L., Arendshorst W.J. Reactive oxygen species participate in acute renal vasoconstrictor responses induced by ETA and ETB receptors. Am J Physiol Renal Physiol, 294: F719-28, 2008 [abstract] [preprint PDF]

Abstracts:
21. 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 (abstract). FASEB J 17 (5-I): A95, abstract 90.11, 2003   [abstract]
22. Just A., Arendshorst W. Calcium signaling at different sites along the interlobular arteriole and in cremaster muscle arterioles (abstract). FASEB J 17 (5-I): A95, abstract 90.11, 2003 [abstract]
23. Just A., Arendshorst W. Pressure-dependent variation of the contribution of myogenic response and tubuloglomerular feedback to renal blood flow autoregulation (abstract). FASEB J 18 (4): A286, abstract 205.4, 2004 [abstract]
24. Just A., Arendshorst W.J. Frequency response characteristics of sympathetic and autoregulatory vasomotor responses in the kidney and hindlimb (abstract). FASEB J 20 (4): A759, abstract 472.4, 2006 [abstract]
25. Just A., Arendshorst W.J. The role of reactive oxygen species in renal blood flow autoregulation (abstract). FASEB J 22: 761.19, 2008 [abstract]
( click here for the complete list of publications )

Biographical Sketch

Education

                           Institution                                                    Degree                Years                      Field of Study
    Albert-Ludwigs-Universität, Freiburg i.Br., Germany                                    10/85 - 09/88                 Medicine
    Ruprecht-Karls-Universität, Heidelberg, Germany                MD                  09/88 - 05/92                 Medicine
    Ruprecht-Karls-Universität, Heidelberg, Germany                Dr.med.         10/88 - 12/92                 Physiology
    Ruprecht-Karls-Universität, Heidelberg, Germany                habil.    03/94 - 07/00                 Physiology

Positions

    8/1992 - 1/1993    Internship
                                      Institut für Physiologie und Pathophysiologie
                                      Abt. Biophysik des Kreislaufs
                                      Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
    2/1993 - 1/1994    Internship
                                      Klinikum der Universität, Abt. Innere Medizin III (Cardiology, Angiology, Pulmonology)
                                      Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
    2/1994 - 3/1994    Residency
                                      Klinikum der Universität, Abt. Innere Medizin III (Cardiology, Angiology, Pulmonology)
                                      Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
    3/1994 - 9/1995    Postdoctoral Research Associate (Stipendiate of the German Research Foundation)
                                       Institut für Physiologie und Pathophysiologie
                                       Abt. Biophysik des Kreislaufs,   Prof. H.R. Kirchheim
                                       Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
   10/1995 - 8/2000   Postdoctoral Scientist
                                       Institut für Physiologie und Pathophysiologie,
                                       Abt. Biophysik des Kreislaufs and Abt. Autonomes Nervensystem,   Prof. H.R. Kirchheim and Prof. H.Seller
                                       Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany
    8/2000 - 7/2002    Visiting Research Instructor
                                       Dept. of Cell & Molecular Physiology,   Prof. W.J. Arendshorst
                                       University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
    8/2002 - present    Research Instructor
                                       Dept. of Cell & Molecular Physiology,   Prof. W.J. Arendshorst
                                       University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Honors
    1994 – 1995          Postdoctoral Stipend, German Research Foundation, Graduiertenkolleg für Experimentelle Nieren- und
Kreislaufforschung.
    2004         Arthur C. Guyton Award for Excellence in Integrative Physiology of the American Physiological Society
    2006         New Investigator Award of the Water and Electrolyte Homeostasis Section of the American Physiological Society

Other Experience

    1996 - 2000         Chief instructor for the subcourse Cardiovascular Regulation within the 12-subcourse practical course for physiology
                                      for medical students at the University of Heidelberg.
    9-10/1996            Invited lecturer for physiology
                                      Dept. of Physiology, Kyrgyz Medical Academy, Bishkek, Kyrgyzstan, Central Asia
                                      supported by the German Academic Exchange Service (DAAD)
    8/2001-present     Editorial Board member
                                      American Journal of Physiology, Regulatory, Integrative and Comparative Physiology
    2006 - 2008         Committee member of the Animal Care and Experimentation Committee
                                    of The American Physiological Society