The long-term objective of the present proposal is to reduce mortality from ischemic acute renal failure (ARF) by shortening the duration of the disease. Previous clinical studies have shown that mortality increases from 30 to 80 % if ARF lasts more than 10 days. Both clinical and experimental investigation indicates that prolongation of ARF in large part is related to recurrent ischemic injury which is due to abnormal vascular dynamics in ARF manifested primarily by a loss of renal blood (RBF) autoregulation.
The specific aims of the planned research are to 1) investigate the effects varying magnitudes of ischemia on the response patters (hyper- or hyposensitivity) to different vasomotor stimuli, 2) determine if apparently conflicting different response patterns are due to differences in large and small vessel ischemic injury, and 3) determine the roles of the endothelium and smooth muscle in the aberrant vascular reactivity. In the first experimental protocol, complete ischemia will be induced with renal artery (RA) obstruction, incomplete ischemia with intrarenal norepinephrine (NE). RBF and renovascular resistance (RVR) changes to renal perfusion pressure (RPP) reduction and to renal nerve stimulation (RNS) will be determined before and after infusion of agents previously shown to blunt hypersensitivity responses. In separate animals, responses to vasoconstrictor and endothelium-derived relaxing factor (EDRF)-dependent and EDRF-independent vasodilators will be determined. Morphologic examination will also be performed to examine the nature and extent of endothelial and smooth muscle injury. In the second experimental protocol to be carried out in isolated perfused vessels, direct comparisons of responses will be made between large and small arterial vessels from NE- ARF and RA obstruction (RAO)-ARF kidneys to pressure changes in [Ca 2+] i. In addition, if there is a failure of [Ca 2+]i to increase to vasoconstrictor or stretch stimulation, then stimulators of release or non- release of Ca2+ from the sarcoplasmic reticulum will be examined. Finally, the role of enhanced phosphorylation mediated by protein kinase C in sensitivity to [Ca2+]i will be tested with phorbol esters.
