We propose to study the biochemical mechanisms of prostaglandin-mediated renin release. Arachidonic acid has been shown to stimulate renin secretion in vivo by its conversion to an active prostaglandin. It was subsequently shown that arachidonic acid and prostaglandin cyclic endoperoxides directly induce renin secretion from cortical slices. Recently, we have extended these findings to show that prostacyclin is a major product of both arachidonate and cyclic endoperoxide metabolism in rabbit renal cortex and that prostacyclin is the most potent metabolite in stimulating renin release from rabbit cortical slices. However, even though a prostaglandin-mediated mechanism for regulation of renin release in vivo is probable, no one has studied 1) phospholipase activation and arachidonate release, 2) prostaglandin-cyclic nucleotide interactions, 3) hydroperoxy fatty acid synthesis and function or 4) anatomical localization of these events as they relate to renin release. Using both cortical slices and isolated cells, we will study the effects of compounds known to stimulate renin release (via prostaglandins) or phospholipase activity. We plan to investigate the fate of the """"""""excess"""""""" arachidonate release upon phospholipase activation (or of exogeneous arachidonate) in terms of possible conversion to hydroperoxy fatty acids and to study the effects of hydroperoxy fatty acids on renin release. We also plan to continue and expand our preliminary experiments which suggest a prostaglandin-cyclic nucleotide interaction in regulating renin release. A major effort will also be made to isolate homogeneous viable cells from the cortex by centrifugal elutiration. Renin and cyclic nucleotides will be measured by radioimmunoassay while prostaglandins will be measured by gas chromatography-mass spectrometry.
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