THROMBOXANE IN SEVERE HYPERTENSION

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Spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) develop severe hypertension, renal dysfunction, cerebrovascular lesions and stroke. We have found that chronic therapy with the angiotensin-converting enzyme (ACE) inhibitors enalapril and captopril maintained kidney function and markedly improved survival of saline-drinking SHRSP even though blood pressure was not substantially lowered. Histological examination of brains and kidneys from SHRSP treated with ACE inhibitors revealed no evidence of the severe cerebrovascular and renal lesions observed in untreated SHRSP. The aim of this project is to determine whether the effect of ACE inhibitors to prevent stroke and kidney dysfunction in SHRSP is the expression of alterations in the renin-angiotensin system (RAS). Time- related changes in components of the RAS will be determined during the development of severe hypertension, renal dysfunction and stroke. Agents that interfere with the formation or block the actions of angiotensin II (ANG II) will be used to establish whether these agents alter the occurrence of stroke, renal dysfunction and severe hypertension. The actions of AGE inhibitors will also be examined under conditions in which severe hypertension is associated with elevated levels of ANG II (ANG II- induced hypertension) or reduced levels of ANG II (DOCA-salt hypertension). Whether the effect of ACE inhibitors to prevents stroke and kidney dysfunction is an expression of inhibition of tissue ACE will also be examined. The dose dependence for inhibition of tissue ACE and the time dependence for reversal of tissue ACE inhibition after ACE inhibitor treatment is withdrawn will correlated with pathophysiologic changes in salt-loaded SHRSP. Whether the beneficial effects of ACE inhibitor treatment relates to alterations in blood pressure elevation of salt-loaded SHRSP will be examined in studies in which ACE inhibitor therapy is commenced early or late in development of severe hypertension. Other antihypertensive agents will be administered as positive concurrent controls to determine if renal function is spared and stroke diminished as a result of alterations in blood pressure. Stroke is currently the nation's third largest killer (over 150,000 Americans/year). Our studies will provide important information in an area relevant to the therapy of hypertension, kidney dysfunction and stroke.