Our recent studies have demonstrated that vasodilatory prostaglandins play a key role in maintaining renal perfusion in patients with severe liver disease. Inhibition of prostaglandin production with anti-inflammatory drugs markedly impairs renal blood flow and glomerular filtration rate. The current project will investigate the role of the potent vasoconstrictor, thromboxane A2, as a cause of the underlying renal vasoconstriction that often progresses to severe renal failure, called the hepatorenal syndrome. Multiple methodology techniques will be used in both human and animal studies to assure the validity of prostaglandin and thromboxane measurements. The techniques include bioassay, several radioimmunoassays, radiochemical techniques, and gas chromatography-mass spectrometry. The first project will serially measure urinary prostaglandins and thromboxanes in patients with liver failure during the progression of renal impairment. Control groups include other renal, liver and thrombotic diseases. Preliminary data reveal increased thromboxane only in the hepatorenal patients. The second project will investigate the relationship of prostaglandin and thromboxane excretion to therapeutic maneuvers in liver failure patients, such as peritoneovenous shunt, to evaluate factors that may enhance or diminish renal thromboxanes production. The third project will determine the renal and extra-renal sources of urinary thromboxane production in man, using our radiochemical techniques. The fourth project continues our animal studies to determine the hemodynamic requirements that induce hypersecretion of renal thromboxanes in models of liver and kidney disease. These studies will also determine the effects of selective thromboxane inhibition. The long-term objective is to determine the physiologic and pathologic function of thromboxanes as mediators of renal circulation. These studies may lead to a new therapeutic approach with selective thromboxane inhibition in such disorders as hepatorenal syndrome.
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