THROMBOXANE IN SEVERE HYPERTENSION

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Thromboxane is a metabolite of arachidonic acid having platelet aggregatory and vasoconstrictor properties and is generated in large amounts when platelets are stimulated to aggregate. Our preliminary findings in young animals with genetic hypertension have suggested to us that there is an underlying role of thromboxane in hypertension. This has led us to hypothesize that thromboxane may play an important hypertensinogen role when vascular damage is present such as in severe hypertension. Enhanced thromboxane formation subsequent to the vascular platelet deposition and fibrinoid necrosis which occurs may lead to further blood pressure elevation and vascular damage and associated complications such as stroke and kidney dysfunction. To test our hypothesis that thromboxane is involved in the marked elevation of blood pressure in severe hypertension, and its sequelae, studies will be performed in both SHRSP (a genetic model) and rats with complete ligation of the aorta between the renal arteries (a surgically-induced model of severe hypertension) treated with thromboxane synthase inhibitors, thromboxane receptor antagonists or chemically stable prostacyclin mimetics. Water and electrolyte balance, systolic arterial pressure, and urinary iTxB2 will be measured in both treated and non-treated conscious animals. Similar studies will be carried out in animals which are sham operated for aortic ligation and WKY. Platelet and renal functional studies will be performed as well as measurements of blood levels of thromboxane and vascular arachidonic acid metabolism in both treated and non-treated animals. These studies will evaluate the role of enhanced thromboxane production in the development of severe hypertension and its sequelae and may provide insights into newer modes of antihypertensive therapy in man.