. "Step" vs. "dynamic" autoregulation: implications for susceptibility to hypertensive injury. Am J Physiol Renal Physiol 285: F113-F120, 2003. First published March 11, 2003 10.1152/ajprenal.00012.2003.-Renal autoregulatory (AR) mechanisms provide the primary protection against transmission of systemic pressures, and their impairment is believed to be responsible for the enhanced susceptibility to hypertensive renal damage in renal mass reduction (RMR) models. Assessment of AR capacity by the "step" change methodology under anesthesia was compared with that by "dynamic" methods in separate conscious control Sprague-Dawley rats and after uninephrectomy (UNX) and 3 ⁄4 RMR (RK-NX) (n ϭ 7-10/group). Substantially less AR capacity was seen by the dynamic vs. the step methodology in control rats. Moreover, dynamic AR capacity did not differ among controls, UNX, and RK-NX rats (fractional gain in admittance ϳ0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). By contrast, significant impairment of step AR was seen in RK-NX vs. control or UNX rats (AR indexes 0.7 Ϯ 0.1 vs. 0.1 Ϯ 0.02 and 0.2 Ϯ 0.04, respectively, P Ͻ 0.01). We propose that the step and dynamic methods evaluate the renal AR responses to different components of blood pressure (BP) power with the step AR assessing the ability to buffer large changes in average BP (DC power), whereas the present "dynamic" methods assess the AR ability to buffer slow BP fluctuations (Ͻ0.25 Hz) superimposed on the average BP (AC power), a substantially smaller component of total BP power. We further suggest that step but not dynamic AR methods as presently performed provide a valid index of the underlying susceptibility to hypertensive glomerular damage after RMR. renal hemodynamics; hypertension; nephrosclerosis; myogenic response; tubuloglomerular feedback CHRONIC RENAL DISEASE regardless of etiology tends to follow a progressively downhill course (8, 36). Experimental animal models of renal mass reduction (RMR) exhibit a similar course of progressive glomerulosclerosis (GS) and nephron loss. On the basis of investigations in such models, it has been proposed that the loss of a critical degree of functional renal mass results in the initiation and perpetuation of pathogenetic mechanisms that are intrinsic to the reduced functional renal mass state (8,19,35,36,39,40). Several lines of evidence have indicated that an exaggerated transmission of systemic blood pressure (BP) to the glomerular capillaries is one such major pathogenetic mechanism (3-7, 23-26, 39-41). The pathophysiological basis for this enhanced glomerular BP transmission after RMR has been postulated to be due to an impairment of the renal autoregulatory (AR) mechanisms that normally provide the primary protection against BP increases, episodic or sustained, from being transmitted to the renal microvasculature (3,5,7,(23)(24)(25)(26)(27)(37)(38)(39)(40)(41).To date, such renal AR impairment in RMR models has only been demonstrated using the conventional "step" AR methodology in which grade...

Abstract-Renin-angiotensin-aldosterone system blockade has been shown to protect against renal damage in saltsupplemented, stroke-prone spontaneously hypertensive rats (SHRsp). Based on intermittent tail-cuff blood pressure (BP) measurements, it has been claimed that such protection is BP-independent and mediated by a blockade of the direct tissue-damaging effects of angiotensin and/or aldosterone. BP radiotelemetry was performed for 8 weeks in Ϸ10-week-old male SHRsp who received a standard diet and either tap water (nϭ10) or 1% NaCl to drink. Saline-drinking SHRsp were either left untreated (nϭ12), received enalapril (50 mg/L) in drinking fluid (nϭ9), or had subcutaneous implantation of time-release 200-mg pellets of aldactone (nϭ10 Key Words: hypertension, renal Ⅲ rats, stroke-prone SHR Ⅲ nephrosclerosis Ⅲ autoregulation T he stroke-prone spontaneously hypertensive rat (SHRsp) is a widely used model to investigate hypertensive target organ damage because of an enhanced susceptibility to develop stroke and renal damage as compared with its progenitor SHR strain. 1-9 Both hypertension and target organ damage are markedly accelerated by salt supplementation. [2][3][4][5]8 Nevertheless, the pathogenesis of such target organ damage is widely believed to be at least in part blood pressure (BP)-independent and mediated by the direct tissue damagepromoting effects of the renin-angiotensin-aldosterone system (RAAS). 5,10 -17 This is based on the fact that ACE inhibitors or angiotensin receptor blockers and more recently aldosterone receptor antagonists have been shown to markedly reduce the severity of renal damage and/or the incidence of stroke without significantly reducing BP. However, BP in such studies has only been measured intermittently with the tail-cuff methodology. Given the spontaneous, rapid, and often large BP fluctuations that are characteristically observed in conscious hypertensive rats, such methodology is inherently inadequate for an accurate assessment of the BP load, the quantification of the antihypertensive effects of pharmacological interventions, or the precise contribution of hypertension to renal damage, as has been clearly demonstrated in this and/or other models of renal damage. 6 -8,18 -25 The present studies were therefore undertaken to examine the effects of RAAS blockade on continuous radiotelemetrically measured BP and the contribution of such BP effects to the observed renoprotection in salt-supplemented SHRsp rats. Methods Animals and Animal CareThe SHRsp were obtained from a colony transferred to Hines, Ill, from the colony maintained at the University of Michigan in Ann Arbor since 1981. Only male rats were used, and all were cared for in accordance with the Principles of the Guide for the Care and Use of Laboratory Animals (Department of Health, Education, and Welfare). They were housed in a constant-temperature room with a 12-hour light and 12-hour dark cycle as described below, and they had free access to a standard (1.05% NaCl) rodent chow (Purina) and drinking fluid (tap w...

Effects of calcium channel blockers on "dynamic" and "steady-state step" renal autoregulation.

Previous studies have shown that renal autoregulation dynamically stabilizes renal blood flow (RBF). The role of renal nerves, particularly of a baroreflex component, in dynamic regulation of RBF remains unclear. The relative roles of autoregulation and mesenteric nerves in dynamic regulation of blood flow in the superior mesenteric artery (MBF) are similarly unclear. In this study, transfer function analysis was used to identify autoregulatory and baroreflex components in the dynamic regulation of RBF and MBF in Wistar rats and young spontaneously hypertensive rats (SHR) anesthetized with isoflurane or halothane. Wistar rats showed effective dynamic autoregulation of both MBF and RBF, as did SHR. Autoregulation was faster in the kidney (0.22 ± 0.01 Hz) than in the gut (0.13 ± 0.01 Hz). In the mesenteric, but not the renal bed, the admittance phase was significantly negative between 0.25 and 0.7 Hz, and the negative phase was abrogated by mesenteric denervation, indicating the presence of an arterial baroreflex. The baroreflex was faster than autoregulation in either bed. The presence of sympathetic effects unrelated to blood pressure was inferred in both vascular beds and appeared to be stronger in the SHR than in the Wistar rats. It is concluded that a physiologically significant baroreflex operates on the mesenteric, but not the renal circulation and that blood flow in both beds is effectively stabilized by autoregulation.

Diabetes and increased blood pressure (BP) are believed to interact synergistically in the pathogenesis and progression of diabetic nephropathy. The present studies were performed to examine if there were differences in BP load and/or protective renal autoregulatory capacity between the obese diabetic Zucker fatty /spontaneously hypertensive heart failure F1 hybrid (ZSF1) (fa/fa cp) rats and their lean controls. By approximately 26 wk of age, ZSF1 (n = 13) but not their lean controls (n = 16) had developed substantial proteinuria (180 +/- 19 vs. 16 +/- 1.4 mg/24 h) and glomerulosclerosis (19 +/- 2.4 vs. 0.6 +/- 0.2%; P < 0.001). However, average ambient systolic BP by radiotelemetry (12-26 wk of age) was modestly lower in ZSF1 than in lean controls (130 +/- 1.4 vs. 137 +/- 1.7 mmHg, P < 0.002), although the 24-h BP power spectra showed a mild increase at frequencies <0.1 Hz in the ZSF1. Autoregulatory capacity under anesthesia in response to step changes in perfusion pressure between 100 and 140 mmHg was similarly well preserved in both ZSF1 and lean controls at 16-18 wk of age [autoregulatory indexes (AI) <0.1]. Similarly, differences were not observed for dynamic autoregulation in conscious rats [transfer functions between BP (input) and renal blood flow (output) using chronic Transonic flow probes]. Collectively, these data indicate that the pathogenesis of nephropathy in the ZSF1 model of type 2 diabetic nephropathy is largely independent of differences in systemic BP and/or its potential renal transmission. However, these data do not exclude the possibility that the diabetic milieu may alter the glomerular capillaries in the ZSF1, such that there is an enhanced local susceptibility to injury with even normal glomerular pressures.