PROSTAGLANDINS AND LOCAL CONTROL OF THE CIRCULATION

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The objective is to define the role of endogenously synthesized prostaglandins and other autocoids in control of the circulation and modulation of organ function. The grant will focus on the kidney, the peripheral vasculature and the stomach. The renal studies include: 1) Studies on the mechanism of renal vasoconstriction during the infusion of hypertonic saline into the kidney. This in vivo model of tubuloglomerular feedback will be used to determine a) the role of adenosine in mediating the response; b) the role of atrial natriuertic factor in blocking or "resetting" the response during salt loading and c) the role that A1-adenosine and A2-adenosine receptors have in mediating the response under varying conditions of salt balance. 2) Studies on the renal secretion of platelet activating factor (PAF) to test the hypothesis that renal synthesis of PAF and prostaglandins are linked. The vascular studies include 1) clinical studies to test the hypothesis that the antihypertensive drugs propranolol, hydralazine and thiazides enhance vascular prostacyclin synthesis, which accounts for the ability of cyclooxygenase inhibitors to reduce the antihypertensive efficacy and 2) clinical studies on furosemide induced venodilation and its relation to the prostaglandin and renin-angiotensin systems. The gastric studies will examine the factors controlling histamine release from the gastric mucosa since both the prostaglandins and H2-histamine blockers specifically act by inhibiting histamine-induced acid secretion by the parietal cell. Methods for the renal studies include in vivo canine models that will allow intrarenal infusions of hypertonic saline and drugs, and sampling of the renal vein for secretion of PAF; the isolated perfused rat kidney will also be used to complement the in vivo studies. For gastric studies, a canine model with isolation of the circulation of the gastric fundus and corpus will be used so that substances inducing or blocking histamine release can be studied without production of systemic effects. The clinical studies will be performed in normal and hypertensive volunteers. Analytical methodology includes negative ion chemical ionization gas chromatography-mass spectrometry (NICI GC-MS) for analysis of the major oxidative metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1Alpha, in the urine and PAF in the blood and urine. Radioimmunoassay will be used for urinary PGE2. A radioenzymtic assay is used for the histamine analysis. These studies should increase our understanding of the physiologic role of prostaglandins and related substances in the control of the renal and peripheral vasculature and gastric function and will provide data relevant to common human diseases including hypertension and peptic ulcer disease.