Dynamic blood pressure load and nephropathy in the ZSF1 (fa/fa cp) model of type 2 diabetes.

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.

Characterization of dynamics in renal autoregulation using volterra models.

The dynamics of renal autoregulation are modeled using a modified Volterra representation called the fixed pole expansion technique (FPET). A data dependent procedure is proposed for selecting the pole locations in this expansion that enables a reduction in model complexity compared to standard Volterra models. Furthermore, a quantitative characterization of frequency dependent features of the renal autoregulatory response is enabled via the model's pole locations. The utility of this approach is demonstrated by applying the modeling technique to renal blood pressure and renal blood flow measurements in conscious rats. The model is used to characterize the myogenic autoregulatory response in control rats and rats whose renal autoregulation has been impaired by calcium channel blockers.

Differential effects of salt on renal hemodynamics and potential pressure transmission in stroke-prone and stroke-resistant spontaneously hypertensive rats.

Salt-supplemented stroke-prone spontaneously hypertensive rats (SHRsp) develop more severe hypertension-induced renal damage (HIRD) compared with their progenitor SHR. The present studies were performed to examine whether in addition to increasing the severity of hypertension salt also enhanced the transmission of such hypertension to the renal vascular bed in the SHRsp. "Step" and "dynamic" renal blood flow (RBF) autoregulation (AR) were examined in approximately 12-wk-old SHR and SHRsp after 3-5 days of an 8% NaCl diet. During step AR under anesthesia (n = 8-11), RBF was significantly higher in the SHRsp at all perfusion pressures (P < 0.01), but AR capacity was not different. Similarly, in separate conscious chronically instrumented rats (n = 8 each), both blood pressure (BP) and RBF were modestly but significantly higher at baseline before salt in the SHRsp (P < 0.05). However, transfer function analysis did not show significant differences in the admittance gain parameters. However, after 3-5 days of salt, although average BP was not significantly altered in either strain, RBF increased further in the SHRsp and there was a significantly greater transfer of BP into RBF power in the SHRsp. This was reflected in the significantly higher admittance gain parameters at most frequencies including the heartbeat frequency (P < 0.05 maximum). These differential hemodynamic effects of salt have the potential to enhance BP transmission to the renal vascular bed and also contribute to the more severe HIRD observed in the salt-supplemented SHRsp.

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

Renal autoregulation (AR) mechanisms provide the primary protection against transmission of systemic pressures and hypertensive renal damage. However, the relative merits of the "step" change vs. "dynamic" methods for the assessment of AR capacity remain controversial. The effects of 48-72 h of orally administered amlodipine (L-type) and mibefradil (T-type) calcium channel blockers (CCBs) on step and dynamic AR in Sprague-Dawley rats were compared. Both CCBs significantly impaired "steady-state step" AR (autoregulatory indexes = approximately 0.5 vs. approximately 0.1 in controls, P < 0.05; n = 9-10/group). By contrast, dynamic AR compensation in separate conscious rats (n = 12) was not significantly altered by either amlodipine (n = 10) or mibefradil (n = 6; fractional gain in admittance approximately 0.4-0.5 in all groups at frequencies in the range of 0.0025-0.025 Hz). However, both CCBs tended to attenuate the myogenic resonance peak along with shifting it to a significantly slower frequency (P < 0.001) during dynamic AR, but no consistent effects were observed on the tubuloglomerular feedback resonance peak. While the reasons for the insensitivity of dynamic vs. steady-state step AR capacity estimates to CCBs remain to be established, the present data indicate that dynamic AR methods may have a limited utility for assessing AR capacity but may provide potentially important insights into the operational characteristics of AR control mechanisms. A strong correlation was also observed between the average conductance and the admittance gain at the heart beat frequency (r = 0.77, P < 0.001), suggesting that such parameters may provide additional and possibly more meaningful indexes of BP transmission in conscious animals during dynamic AR.

Renal responses to hemorrhage are age dependent in conscious sheep.

Experiments were carried out in conscious, chronically instrumented lambs (n = 8) and young adult sheep (n = 11) to investigate age-dependent renal responses to hemorrhage. Various parameters of renal function were measured for 1 h before and 1 h after either 10% hemorrhage (experiment 1) or 20% hemorrhage (experiment 2). The two experiments were carried out in random order at intervals of 2-5 days. There were no effects of 10-20% hemorrhage on renal plasma flow in either age group. Blood pressure decreased after 20% but not 10% hemorrhage in both age groups. Glomerular filtration rate and filtration fraction decreased after 20% hemorrhage in both age groups, the decrease being greater in lambs than young adult sheep. In response to 20% hemorrhage, urinary flow rate and urinary Na+ excretion rate decreased by 40 min after hemorrhage in young adult sheep but not lambs and remained decreased for 60 min; urinary chloride excretion rate showed a similar response. In lambs but not young adult sheep, free water clearance increased by 20 min after 20% hemorrhage and remained above control at 60 min. Urinary osmolality decreased at 20 min after 20% hemorrhage in young adult sheep but not lambs, returning to control levels by 40 min. These data provide new information that renal responses to hypotensive hemorrhage appear to be developmentally regulated.

"Step" vs. "dynamic" autoregulation: implications for susceptibility to hypertensive injury.

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 = 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 approximately 0.4-0.5 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 +/- 0.1 vs. 0.1 +/- 0.02 and 0.2 +/- 0.04, respectively, P < 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 (<0.25 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.

Renoprotection by ACE inhibition or aldosterone blockade is blood pressure-dependent.

Renin-angiotensin-aldosterone system blockade has been shown to protect against renal damage in salt-supplemented, 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 approximately 10-week-old male SHRsp who received a standard diet and either tap water (n=10) or 1% NaCl to drink. Saline-drinking SHRsp were either left untreated (n=12), received enalapril (50 mg/L) in drinking fluid (n=9), or had subcutaneous implantation of time-release 200-mg pellets of aldactone (n=10). The average systolic BP (mean+/-SEM) during the final 3 weeks was significantly higher (P<0.05) in untreated saline-drinking (215+/-6 mm Hg) SHRsp but not aldactone-treated (198+/-4 mm Hg) or enalapril-treated treated SHRsp (173+/-1 mm Hg), as compared with tap water-drinking SHRsp (197+/-3 mm Hg). Histological renal damage scores at 8 weeks paralleled the BP in all groups, with an excellent correlation (r=0.8, P<0.001, n=41). Moreover, a renal damage score of >5 was only observed in SHRsp whose average systolic BP during the final 3 weeks exceeded 200 mm Hg, indicating a threshold relation with BP. These data show that protection by renin-angiotensin-aldosterone system blockade in this model is BP-dependent and mediated by preventing the severe increases in BP seen in untreated salt-supplemented SHRsp and further underscore the limitations of interpretations based on conventional tail-cuff BP measurements.