The long-term objective is to understand why patients with chronic hypertension (HTN) have a marked increase in morbidity and mortality when they develop left ventricular hypertrophy (LVH), and to determine whether reversal of HTN and regression of LVH will reduce the associated morbidity and mortality. Patients with chronic HTN also have a high incidence of coronary artery and ischemic heart disease. We hypothesize that LVH makes the heart less tolerant to ischemia. Accordingly, our specific aims are to use hypertensive rats and rabbits to define basic interactions between ischemic and hypertensive heart disease. HTN will be induced in rats by uninephrectomy + deoxycortisone (DOC) + high salt and in rabbits by unilateral renal artery clip and contralateral nephrectomy. Studies will be done 1) Prior to induction of HTN, 2) After HTN but before LVH, 3) After LVH has developed, 4) After reversal of HTN but before regression of LVH, and 5) After regression of LVH. Reversal of HTN will be done by several methods to evaluate potential differences between classes of pharmacologic agents. We hypothesize that, relative to normal hearts, hypertrophied hearts, will have: 1) a decreased tolerance to transient global or regional ischemia. We will measure: a) Contractile and diastolic function before and after transient ischemia; function will be compared in intact animals, isolated perfused hearts, and skinned cardiac fiber preparations. Changes in function will be correlated with the capillary/myocyte ratio, myocardial glycogen, and collagen content. b) Myocardial infarction (MI) size after transient coronary occlusion and reperfusion. c) The effect of lowering BP during the acute MI phase. 2) Impaired post-MI healing and repair. We will measure a) The incidence of post-MI LV rupture and aneurysm formation, b) Mechanical properties of post-MI scar tissue, c) The effect of BP lowering during post-MI healing and repair. 3) Impaired coronary vasomotor function. We will measure: a) Myocardial blood flow, endo/epicardial distribution and the maximum vasodilator response, and b) the critical degree of coronary perfusion pressure decrease required to produce cellular hypoxia, c) The mechanical interrelationship between the coronary circulation and the myocardium. 4) Reversal of HTN and regression of LVH may reverse these LVH associated abnormalities. We postulate that anti-HTN agents which increase or preserve myocardial glycogen content may be particularly beneficial in increasing myocardial tolerance to transient ischemia.
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