S-12-5: IMPAIRMENT OF RENAL BLOOD FLOW AUTOREGULATION AND PRESSURE-NATRIURESIS: ROLE IN THE DEVELOPMENT OF HEART FAILURE IN REN-2 TRANSGENIC HYPERTENSIVE RATS

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Objective: The prognosis of patients with heart failure (HF), particularly those who were hypertensive before the onset of HF, remains poor and new therapeutic strategies are needed, based on understanding the pathophysiology of the progression of HF. We hypothesized that the kidney is here not simply a victim but also a culprit of the progression. Specifically, we hypothesized that the impairment of renal blood flow (RBF) autoregulation and pressure-natriuresis relationship is present in the very early HF phase, and precedes HF decompensation. Design and method: In Ren-2 transgenic rats (TGR), a model of hypertension with increased endogenous activity of the renin-angiotensin system (RAS), HF was induced by volume overload achieved by creation of the aorto-caval fistula (ACF). One week after ACF creation or sham-operation animals were prepared for studies evaluating in vivo RBF autoregulatory capacity and pressure-natriuresis relationship after stepwise changes in renal arterial pressure (RAP) that were induced by aortic clamps. Sham-operated TGR were evaluated at physiological level of RAP, then at RAP reduced to 125, 100, 90 and 80 mmHg. In ACF TGR RAP was reduced to 100, 90 and 80 mmHg, followed by period of RAP increased to 125 mmHg. Results: In sham-operated TGR as compared with ACF TGR the basal mean arterial pressure (156 ± 3 vs. 98 ± 3 mmHg), RBF (11.45 ± 0.6 vs. 8.13 ± 0.3 ml.min-1.g-1), urine flow (UF) (38.3 ± 3.1 vs. 8.7 ± 1.0 μl.min-1.g-1) and absolute sodium excretion (UNaV) (4.77 ± 0.54 vs. 0.46 ± 0.11 μmol.min-1.g-1) were all significantly lower. In sham-operated TGR reductions in RAP resulted in significant decreases in RBF whereas in ACF TGR it did not change in response to RAP alterations. Stepwise reductions in RAP resulted in marked decreases in UF and UNaV in sham-operated as well as in ACF TGR, however, these decreases were significantly greater in the former. Conclusions: Our data show that at the physiological RAP level ACF TGR displayed marked reduction in RBF, UF and UNaV as compared with sham-operated TGR. However, in contrast to sham-operated TGR, ACF TGR displayed well-maintained RBF autoregulatory capacity and better slope of pressure-natriuresis relationship. Thus, even in the very early HF stage the renal dysfunction is demonstrable but such dysfunction and the subsequent onset of HF decompensation cannot be simply ascribed to impaired RBF autoregulation and pressure-natriuresis relationship, at least not in the high-output HF model of originally RAS-dependent hypertensive rat.