An exaggerated transmission of BP due to an impairment of the normally protective renal autoregulatory (AR) mechanisms, plays a predominant role in the progression of diabetic and non-diabetic chronic renal disease. Given the basic lability ofBP, such transmission to the renal microvasculature must be dynamic. But, current assessments of the dynamic BP transmission do not correlate with the observed susceptibility to hypertensive renal damage in experimental models. Both theoretical considerations and our recent data indicate that such methods and interpretations are seriously flawed because they do not consider the relevant quantitative aspects oftotal BP load (power), its individual components, and their transmission to the renal microvasculature. In terms ofphysical energy, BP power consists of two components (a) DC power (average BP) and (b) AC power (BP fluctuations from average BP). The AC power in turn is due to (i) BP fluctuations at the heart beat (RB) frequency and (ii) slower BP fluctuations. Quantitatively, DC power > AC power at RB frequency> AC power from slower BP fluctuations. Renal AR capacity provides the primaiy protection against the transmission of the BP powerto the renal microvasculature, but existent methods to assess such capacity, """"""""step"""""""" vs """"""""dynamic"""""""" AR yield markedly discrepant estimates. The present application proposes to comprehensively test an integrated working hypothesis. We postulate that there are two aspects of renal AR (a) basal AR response to the average ambient BP in response to oscillating BP signals at the heart beat frequency (not examined by current methods) and (b) additional """"""""dynamic"""""""" AR in response to superimposed BP variability occurring at slower frequencies (<0.25 Hz). The capacity to set an appropriate basal ambient autoregulatory resistance (BAAR) provides the primary protection against hypertensive damage by determining the fraction of the total average B? power and the power at the heart beat frequency that is transmitted to the glomerular capillaries, while the capacity for superimposed """"""""dynamic"""""""" AR provides protection against the more limited BP (AC) power from slower BP fluctuations.
Specific Aim 1 (a) will test the hypothesis that graded RMR (renal mass reduction) and partially treated diabetes will result in graded impairments in BAAR and its associated ARparameters but not in """"""""dynamic"""""""" AR; (b) will compare and contrast the dose response effects of """"""""L"""""""" and """"""""T"""""""" type calcium channel blockers with those of graded RMR and diabetes (c) use micropuncture methods to directly assess AR of Poc in these models; (d) will test the hypothesis that systolic BP is the trigger B? signal for BAAR.
Specific Aim 2 - Complementary studies will be performed in the in-vitro perfused hydronephrotic kidney preparation to test these same concepts and to directly assess glomerular pressure transmission.
Specific Aim 3 a&b will test the predictions of the proposed hypothesis that the heart rate, systolic BP and pulse pressure have independent effects on the total BP exposure of the renal microvasculature and thereby on hypertensive renal damage. Collectively, these investigations will provide much needed insights into the dynamics of BP transmission in real-time and help address such basic questions as, what degree of BP control and of which B? parameter (systolic, average (mean), diastolic, pulse pressure, BP lability) is required for optimal renal protection?
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