Substantial clinical and experimental evidence supports the predominant role of hypertensive mechanisms in the progression of both diabetic and non-diabetic renal diseases. In both situations, preglomerular vasodilation results in enhanced BP transmission, increased glomerular pressures (Pgc) and eventual glomerulosclerosis (GS). However, conventional assessment of such transmission (BP and/or Pgc) fails to explain the vast differences in the time course of GS in models of mass reduction (RMR) and diabetes (Table 1, page 27) or the differences in glomeruloprotection provided by different therapeutic agents. Because BP in conscious animals exhibits rapid spontaneous fluctuations at multiple frequencies, they postulate that BP transmission is a dynamic process that can be assessed only by determining in conscious animals: a) the amplitude and frequencies of BP fluctuations; and b) the time constants and magnitude of the autoregulatory changes in preglomerular resistance in response to BP fluctuations. The combined application of BP radiotelemetry and chronic renal arterial blood flow probes has made it possible to define these parameters of dynamic BP transmission by using Fast Fourier Transformation and frequency domain analysis of renal vascular admittance.
Specific Aim #1 a and b will test the hypothesis that differences in: a) autoregulatory kinetics and/or; b) patterns of BP fluctuations account for the striking differences in the time course of the development of GS (4-12 months), in four rat models of RMR and diabetes characterized by an elevated Pgc in the absence of overt hypertension: uninephrectomy, (UNX); RK-NX 5/6 (by surgical excision not infarction); and partially treated streptozotocin (STZ) diabetes, with and without UNX. GS in individual animals and in groups will be correlated with BP patterns and autoregulatory dynamics. If the hypothesis is valid then the degree of alterations in the determinants of dynamic pressure transmission--prolongation of time constants and decrease in magnitude of the autoregulatory responses; increase in amplitude and/or frequencies of BP fluctuations-- will collectively show the following pattern: NX 5/6 > DM + UNX, > UNX ? Dm > sham. The hypertensive infarction model (RK-1 5/6), followed for 7 weeks, will be employed for Specific Aims #2 and #3. Large and presently unexplained differences are observed within and between different classes of Ca+ channel blockers (CCB), in their effects on GS in the RK-1 model.
Specific Aim #2, will test the hypothesis that such differences are due to differences between CCBs in their separate dose-response relationships for BP reduction and for CCB caused impairment of renal autoregulatory kinetics.
Specific Aim #3 (a) will test the hypothesis that the protection provided by endothelin receptor antagonists and heparin in the RK-1 model is primarily mediated through favorable effects on the determinants of dynamic pressure transmission.
Specific Aim #3 (b) will test the hypothesis that chronic administration of growth factors IGF-I and EGF will attenuate the impairment of renal autoregulatory responses observed in RK-1 rats and therefore, will have a favorable impact on GS. The BP and autoregulatory parameters of dynamic pressure transmission will be defined in individual animals and groups and will be correlated with GS. Collectively, these studies will provide unique data that will: 1) characterize the fundamental nature and mechanics of BP transmission after RMR and in diabetes; 2) yield important insights into the pathophysiology of renal autoregulatory response; 3) will define """"""""normotension"""""""" in the setting of enhanced pressure transmission; 4) delineate the pathogenesis of the continued progression of renal disease in normotensive and """"""""adequately"""""""" treated hypertensive patients; 5) define the mechanisms responsible for the variable effects of different CCBs on GS; and 6) identify the BP parameters that need to be controlled for optimal protection of the renal microvasculature and possibly other target organs.
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