Most biological actions of prostaglandins and thromboxane A2 are thought to be mediated by alterations of tissue cyclic nucleotide concentrations. We have evidence suggesting that in cultured renal tubular MDCK cells retaining differentiated properties, endogenous prostaglandins regulate cyclic nucleotide concentrations. Moreover, cyclic AMP and its analogues inhibit the release of arachidonate and the conversion of arachidonate to PGs suggesting the possibility of self-regulation of prostaglandin synthesis by feedback inhibition. I propose to identify the specific endogenous prostaglandins which may regulate cyclic AMP concentrations in primary renal papillary collecting tubule cells, aortic endothelial and aortic smooth muscle cells. Emphasis in aortic cultures will be placed on prostacyclin (Prostaglandin I2), a potent vasodilator and anti-platelet aggregator. I will examine the hypothesis that Alpha- and Beta-adrenergic agents, and platelet-derived thromboxane A2 and 12-hydroperoxy eicosatetraenoic regulate PG biosynthesis in the aformentioned cultured cells by influencing cyclic AMP and cyclic GMP concentrations. I also propose to investigate the possibility that vasopressin and cAMP mediate increased phosphorylation of phosphatidylinositol to polyphosphonositides. This mechanism may explain, in part, cAMP-induced inhibition of arachidonate release and vasopressin-enhanced water permeability across the distal renal tubule. Among the many biochemical methods which will be used are radioimmunoassay of prostaglandins and cyclic nucleotides, as well as radiometric thin-layer chromatography of prostaglandins and phospholipids. Increased understanding of prostaglandin-cyclic nucleotide interactions in cultured renal and vascular cells will be of potential benefit to our understanding of renal water metabolism as well as of regulation of vascular tone and thrombosis.
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