PROSTAGLANDINS AND LOCAL CONTROL OF THE CIRCULATION

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In spite of the recent discovery of new arachidonic acid products, the cyclooxygenase products are likely to be the major substances of importance in the control of the circulation and function of several organs. The long term objective of this proposal is to define the role of endogenously synthesized prostaglandins (PGs) in controlling the circulation and modulating organ function. The studies will focus on the kidney, the peripheral vasculature, and the stomach as sites where PGs play an important role. The renal studies include 1) clinical studies to define the role of the renal PGs system in the initiation and maintenance of a water diuresis; 2) studies in the isolated perfused rat kidney to determine whether PGE2 or PGI2 is more important in renin release; and 3) studies in the whole dog to determine the role of PGs in mediating tubulo-glomerular feedback. The vascular studies include clinical studies to 1) determine the role of prostacyclin (PGI2) in mediating the antihypertensive effects of propranolo, hydrochlorothiazide, or hydralazine; 2) determine the mechanism of furosemide-induced venodilation including the role of the renin-angiotensin system and the PG system; and 3) determine whether organic nitrates enhance PGI2 synthesis in man, and if so, whether PGI2 is necessary for the clinical effects. The gastric studies will further define the control of PG synthesis in the parietal cell in vitro and determine whether gastric secretagogues, calcium, and/or acid secretion per se is the important trigger. In vivo the interactions between the PG system, histamine release, the gastric seretagogues, and the polypeptide inhibitors of acid secretion will be investigated. Methods include the use in the clinical studies of gas chromatographic-mass spectrometric assays for PGE2 and the major urinary metabolite of PGI2, dinor-6-keto-PGF1Alpha. Only when validated will the radioimmunoassay for PGE2 be used. Additional assays include RIA for thromboxane B2 and plasma renin activity, radioenzymatic assay for histamine, radiochromatographic studies to assess arachidonic acid conversion into its products in the kidney and parietal cells, and cellular 14C-aminopyrine uptake to assess acid production by parietal cells. Cyclooxygenase inhibitors will be used along with these assays to determine the functional significance of the cyclooxygenase products in the systems studied. The emphasis of these studies is on clinically relevant observations. The therapeutic use of cyclooxygenase inhibitors is commonplace and unwanted side effects are not rare. These studies should not only increase our understanding of physiologic processes but should help us anticipate the adverse or beneficial effects of non-steroidal antiinflammatory agents as well as their interactions with other therapeutic agents and natural substances.