The renin-angiotensin system and the third mechanism of renal blood flow autoregulation

Abstract

Seeliger E, Wronski T, Ladwig M, Dobrowolski L, Vogel T, Godes M, Persson PB, Flemming B. The renin-angiotensin system and the third mechanism of renal blood flow autoregulation. Am J Physiol Renal Physiol 296: F1334 -F1345, 2009. First published April 1, 2009 doi:10.1152/ajprenal.90476.2008.-Autoregulation of renal blood flow comprises three mechanisms: the myogenic response (MR), the tubuloglomerular feedback (TGF), and a third mechanism (3M). The nature of 3M is unknown; it may be related to hypotensive resetting of autoregulation that probably relies on pressure-dependent stimulation of the renin-angiotensin system (RAS). Thus we used a normotensive angiotensin II clamp in anesthetized rats and studied autoregulation 1) by slow ramp-shaped reductions in renal perfusion pressure (RPP) followed by ramp-shaped RPP restorations and 2) by means of the step response technique: after 30 s of either total or partial suprarenal aortic occlusion, a step increase in RPP was made and the response of renal vascular conductance analyzed to assess the mechanisms' strength and initial direction (vasodilation or constriction). The angiotensin clamp abolished the resetting of autoregulation during ramp-shaped RPP changes. Under control conditions, the initial TGF response was dilatory after total occlusions but constrictive after partial occlusions. The initial 3M response presented a mirror image to the TGF: it was constrictive after total but dilatory after partial occlusions. The angiotensin clamp suppressed the TGF and turned the initial 3M response following total occlusions into dilation. We conclude that 1) pressure-dependent RAS stimulation is a major cause behind hypotensive resetting of autoregulation, 2) TGF sensitivity strongly depends on pressure-dependent changes in RAS activity, 3) the 3M is modulated, but not mediated, by the RAS, and 4) the 3M acts as a counterbalance to the TGF and might possibly be related to the recently described connecting tubule glomerular feedback. renal hemodynamics; time domain; oscillations; hindquarter CHANGES IN PERFUSION PRESSURE alter local blood flow by a variety of mechanisms. On one hand, changes in pressure result in passive circular stretching or destretching of vessels and thus in parallel changes in blood flow. On the other hand, via various pathways, pressure changes evoke active responses of vascular smooth muscles, i.e., vasoconstriction or vasodilation. First, pressure-induced flow changes result in metabolic changes in the tissue that, in turn, impinge on vascular muscles, as exemplified by the phenomenon of reactive hyperemia (5, 6). Second, flow changes alter shear stress, which impacts on vascular muscles, e.g., via altered release of nitric oxide (8). Third, in many vascular beds the phenomenon of blood flow autoregulation is observed, i.e., the ability to dampen or even to abolish the effects that changes in perfusion pressure would otherwise inevitably have on flow (16,35).Compared with blood flow control of other vascular beds, control of renal blood flow (RB...

Connecting tubule glomerular feedback antagonizes tubuloglomerular feedback in vivo

“…Recent studies have pointed to the existence of another mechanism of renal blood flow autoregulation simply dubbed the third mechanism, which has been identified in vivo in mice (13), rats (11,12,25,26,29), and dogs (14,15) by analyzing the renal vascular resistance curve immediately after changing renal perfusion pressure. Apparently this third mechanism is slower than the myogenic response and TGF, and is present even when TGF is abolished, for example, in A 1 adenosine receptor knockout mice (10).…”

“…Apparently this third mechanism is slower than the myogenic response and TGF, and is present even when TGF is abolished, for example, in A 1 adenosine receptor knockout mice (10). Seeliger et al (25) studied renal blood flow autoregulation and determined that this mechanism counterbalances TGF and may be related to CTGF. Our data showed that, in the presence of HCTZ, blocking CTGF with benzamil potentiated the decrease in P SF at 20, 40, and 80 nl/min, suggesting that, at these rates, 1) CTGF was activated and 2) CTGF antagonized TGF, since when CTGF was absent TGF was potentiated.…”

Renal Autoregulation in Health and Disease

“…Several rat studies have characterized dynamic adjustments of the renal vasculature following a brief period of complete occlusion of the aorta (1342,1397,1398,1626), but this evoked metabolic and vasoactive factors, in addition to basic pressure-dependent autoregulatory mechanisms. Studies in the rat of complete renal ischemia for 30 s followed by a rapid single step increase in RPP reported time-dependent oscillations in the RBF responses at ϳ10, 35, and 115 s, reflecting the operation of three distinct autoregulatory mechanisms (1626), likely the myogenic, MD-TGF, and third mechanisms.…”

Oxidative Stress in Hypertension: Role of the Kidney

“…At least three mechanisms participate in autoregulation of RBF: a fast myogenic response, a slower TGF response, and a third, very slow component of uncertain causality (131,256). Just and Arendhorst (130) demonstrated that the myogenic response in the mouse kidney contributed 60%, TGF 40%, and the third mechanism 5% to RBF autoregulation.…”