Polichnowski AJ, Griffin KA, Long J, Williamson GA, Bidani AK. Blood pressure-renal blood flow relationships in conscious angiotensin II-and phenylephrine-infused rats. Am J Physiol Renal Physiol 305: F1074 -F1084, 2013. First published July 3, 2013 doi:10.1152/ajprenal.00111.2013.-Chronic ANG II infusion in rodents is widely used as an experimental model of hypertension, yet very limited data are available describing the resulting blood pressurerenal blood flow (BP-RBF) relationships in conscious rats. Accordingly, male Sprague-Dawley rats (n ϭ 19) were instrumented for chronic measurements of BP (radiotelemetry) and RBF (Transonic Systems, Ithaca, NY). One week later, two or three separate 2-h recordings of BP and RBF were obtained in conscious rats at 24-h intervals, in addition to separate 24-h BP recordings. Rats were then administered either ANG II (n ϭ 11, 125 ng·kg Ϫ1 ·min Ϫ1 ) or phenylephrine (PE; n ϭ 8, 50 mg·kg Ϫ1 ·day Ϫ1 ) as a control, ANG IIindependent, pressor agent. Three days later the BP-RBF and 24-h BP recordings were repeated over several days. Despite similar increases in BP, PE led to significantly greater BP lability at the heart beat and very low frequency bandwidths. Conversely, ANG II, but not PE, caused significant renal vasoconstriction (a 62% increase in renal vascular resistance and a 21% decrease in RBF) and increased variability in BP-RBF relationships. Transfer function analysis of BP (input) and RBF (output) were consistent with a significant potentiation of the renal myogenic mechanism during ANG II administration, likely contributing, in part, to the exaggerated reductions in RBF during periods of BP elevations. We conclude that relatively equipressor doses of ANG II and PE lead to greatly different ambient BP profiles and effects on the renal vasculature when assessed in conscious rats. These data may have important implications regarding the pathogenesis of hypertension-induced injury in these models of hypertension.hypertension; hemodynamics; blood pressure variability INCREASED ACTIVITY OF THE renin-angiotensin-aldosterone system (RAAS) (40,56,73) is postulated to be a major contributor to chronic kidney disease progression through both blood pressure (BP)-dependent and -independent mechanisms (7,28,39,73). Accordingly, chronic ANG II infusion is extensively used to investigate mechanisms that mediate renal damage in hypertensive states characterized by enhanced RAAS activation (3,20,42,65,71). Renal parenchymal injury with significant tubulointerstitial fibrosis and a propensity to develop salt-sensitive hypertension has been observed after ANG II infusions (44, 57). Both barotrauma and renal vasoconstrictionmediated tissue ischemia have been postulated to initiate the pathogenic cascades that lead to renal injury after chronic ANG II infusions. However, despite its wide use, there is a paucity of experimental data describing the BP-renal blood flow (RBF) relationships in conscious ANG II-infused animals, and the relative contribution of these two initiating mechanisms ...

ANG II is thought to increase the susceptibility to hypertension-induced renal disease (HIRD) via blood pressure (BP)-dependent and BP-independent pathways; however, the quantitative relationships between BP and HIRD have not been examined in ANG II-infused hypertensive rats. We compared the relationship between radiotelemetrically measured BP and HIRD in Sprague-Dawley rats (Harlan) chronically administered ANG II (300-500 ng·kg(-1)·min(-1), n = 19) for 4 wk versus another commonly employed pharmacological model of hypertension induced by the chronic administration of N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg·kg(-1)·day(-1), n = 23). [DOSAGE ERROR CORRECTED]. Despite the significantly higher average systolic BP associated with ANG II (191.1 ± 3.2 mmHg) versus l-NAME (179.9 ± 2.5 mmHg) administration, the level of HIRD was very modest in the ANG II versus l-NAME model as evidenced by significantly less glomerular injury (6.6 ± 1.3% vs. 11.3 ± 1.5%, respectively), tubulointerstitial injury (0.3 ± 0.1 vs. 0.7 ± 0.1 injury score, respectively), proteinuria (66.3 ± 10.0 vs. 117.5 ± 10.1 mg/day, respectively), and serum creatinine levels (0.5 ± 0.04 vs. 0.9 ± 0.07 mg/dl, respectively). Given that HIRD severity is expected to be a function of renal microvascular BP transmission, BP-renal blood flow (RBF) relationships were examined in additional conscious rats administered ANG II (n = 7) or l-NAME (n = 8). Greater renal vasoconstriction was observed during ANG II versus l-NAME administration (41% vs. 23% decrease in RBF from baseline). Moreover, administration of ANG II, but not l-NAME, led to a unique BP-RBF pattern in which the most substantial decreases in RBF were observed during spontaneous increases in BP. We conclude that the hemodynamic effects of ANG II may mediate the strikingly low susceptibility to HIRD in the ANG II-infused model of hypertension in rats.

The N(ω)-nitro-l-arginine methyl ester (l-NAME) model is widely employed to investigate the role of nitric oxide (NO) in renal injury. The present studies show that Sprague-Dawley rats from Harlan (H) and Charles River (CR) exhibit strikingly large differences in susceptibility to l-NAME nephropathy. After 4 wk of l-NAME (∼50 mg·kg(-1)·day(-1) in drinking water), H rats (n = 13) exhibited the expected hypertension [average radiotelemetric systolic blood pressure (BP), 180 ± 3 mmHg], proteinuria (136 ± 17 mg/24 h), and glomerular injury (GI) (12 ± 2%). By contrast, CR rats developed less hypertension (142 ± 4), but surprisingly no proteinuria or GI, indicating a lack of glomerular hypertension. Additional studies showed that conscious H, but not CR, rats exhibit dose-dependent renal vasoconstriction after l-NAME. To further investigate these susceptibility differences, l-NAME was given 2 wk after 3/4 normotensive nephrectomy (NX) and comparably impaired renal autoregulation in CR-NX and H-NX rats. CR-NX rats, nevertheless, still failed to develop proteinuria and GI despite moderate hypertension (144 ± 2 mmHg, n = 29). By contrast, despite an 80-90% l-NAME dose reduction and lesser BP increases (169 ± 4 mmHg), H-NX rats (n = 20) developed greater GI (26 ± 3%) compared with intact H rats. Linear regression analysis showed significant (P < 0.01) differences in the slope of the relationship between BP and GI between H-NX (slope 0.56 ± 0.14; r = 0.69; P < 0.008) and CR-NX (slope 0.09 ± 0.06; r = 0.29; P = 0.12) rats. These data indicate that blunted BP responses to l-NAME in the CR rats are associated with BP-independent resistance to nephropathy, possibly mediated by a resistance to the renal (efferent arteriolar) vasoconstrictive effects of NO inhibition.

The relative contribution of self-perpetuating- vs. hemodynamic-induced fibrosis to the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) is unclear. In the present study, male Sprague-Dawley rats underwent right uninephrectomy and were instrumented with a blood pressure radiotelemeter. Two weeks later separate groups of rats were subjected to 40 minutes renal ischemia-reperfusion or sham surgery and followed for 4 or 16 weeks to determine the extent to which glomerulosclerosis and tubulointerstitial fibrosis as a result of the AKI – CKD transition (i.e., at 4 weeks post AKI) change over time during the progression of CKD (i.e., at 16 weeks post AKI). On average, tubulointerstitial fibrosis was ~3-fold lower (P<0.05) whereas glomerulosclerosis was ~6-fold higher (P<0.05) at 16 vs. 4 weeks post AKI. At 16 weeks post AKI, marked tubulointerstitial fibrosis was only observed in rats exhibiting marked glomerulosclerosis, proteinuria, and kidney weight consistent with a hemodynamic pathogenesis of renal injury. Moreover, quantitative analysis between blood pressure and renal injury revealed a clear and modest blood pressure threshold (average 16 week systolic blood pressure of ~127 mmHg) for the development of glomerulosclerosis. In summary, very modest levels of blood pressure may be playing a substantial role in the progression of renal disease following AKI in settings of preexisting CKD associated with 50% loss of renal mass. In contrast, these data do not support a major role of self-perpetuating tubulointerstitial fibrosis in the progression CKD following AKI in such settings.

The diet-induced obesity (DIO) model is frequently used to examine the pathogenesis of obesity-related pathologies; however, only minimal glomerulosclerosis (GS) has been reported after 3 mo. We investigated if GS develops over longer periods of DIO and examined the potential role of hemodynamic mechanisms in its pathogenesis. Eight-week-old male obesity-prone (OP) and obesity-resistant (OR) rats (Charles River) were administered a moderately high-fat diet for 5 mo. Radiotelemetrically measured blood pressure, proteinuria, and GS were assessed. OP (n=10) rats developed modest hypertension (142±3 vs. 128±2 mmHg, P<0.05) and substantial levels of proteinuria (63±12 vs. 12±1 mg/day, P<0.05) and GS (7.7±1.4% vs. 0.4±0.2%) compared with OR rats (n=8). Potential hemodynamic mechanisms of renal injury were assessed in additional groups of OP and OR rats fed a moderately high-fat diet for 3 mo. Kidney weight (4.3±0.2 vs. 4.3±0.1 g), glomerular filtration rate (3.3±0.3 vs. 3.1±0.1 ml/min), and glomerular volume (1.9±0.1 vs. 2.0±0.1 μm3×10(-6)) were similar between OP (n=6) and OR (n=9) rats. Renal blood flow autoregulation was preserved in both OP (n=7) and OR (n=7) rats. In contrast, Nω-nitro-L-arginine methyl ester (L-NAME) administration in conscious, chronically instrumented OP (n=11) rats resulted in 15% and 39% increases in blood pressure and renal vascular resistance, respectively, and a 16% decrease in renal blood flow. Minimal effects of L-NAME were seen in OR (n=9) rats. In summary, DIO-associated GS is preceded by an increased hemodynamic sensitivity to L-NAME but not renal hypertrophy or hyperfiltration.

Adaptive IIR filter analysis is more complicated than for the FIR case because (a) some algorithm signals are generated by the adaptive filter itself, and (b) the prediction error relates to the adapted parameters via a filtering operation. Averaging analyses of stability address the first issue by linearization about the convergence point, and the second by using passivity of the error operator. However, published results do not fully account for signal dynamics in the linearization, nor have initial conditions in the passivity analysis been considered. This paper addresses these gaps. Our motivation to revisit these broadly applicable issues is for analyzing recently developed adaptive algorithms that have application to biological systems.

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BackgroundRenal autoregulation maintains stable renal function despite BP fluctuations and protects glomerular capillaries from hypertensive injury. However, real-time dynamics of renal autoregulation in conscious animals have not been characterized.MethodsTo develop novel analytic methods for assessing renal autoregulation, we recorded concurrent BP and renal blood flow in conscious rats, comparing animals with renal autoregulation that was intact versus impaired (from 3/4 nephrectomy), before and after additional impairment (from the calcium channel blocker amlodipine). We calculated autoregulatory indices for adjacent short segments of increasing length (0.5, 1, 2.5, 5, 10, and 20 seconds) that exhibited a mean BP difference of at least 5 mm Hg.ResultsAutoregulatory restoration of renal blood flow to baseline after BP changes in conscious rats occurs rapidly, in 5–10 seconds. The response is significantly slower in states of impaired renal autoregulation, enhancing glomerular pressure exposure. However, in rats with severe renal autoregulation impairment (3/4 nephrectomy plus amlodipine), renal blood flow in conscious animals (but not anesthetized animals) was still restored to baseline, but took longer (15–20 seconds). Consequently, the ability to maintain overall renal blood flow stability is not compromised in conscious rats with impaired renal autoregulation.ConclusionsThese novel findings show the feasibility of renal autoregulation assessment in conscious animals with spontaneous BP fluctuations and indicate that transient increases in glomerular pressure may play a greater role in the pathogenesis of hypertensive glomerulosclerosis than previously thought. These data also show that unidentified mechanosensitive mechanisms independent of known renal autoregulation mechanisms and voltage-gated calcium channels can maintain overall renal blood flow and GFR stability despite severely impaired renal autoregulation.