Hearts having undergone left ventricular (LV) hypertrophy secondary to renovascular hypertension (RVH) display a reduced responsiveness to the positive inotropic effects of extracellular Ca2+ (Ca2+o) during both heterometric and homeometric autoregulation. These intrinsic functional changes appear to occur concomitantly with changes in several sarcolemmal (SL) Ca2+ regulatory processes which include a reduction in slow Ca2+ channel dihydropyridine binding sites and a depression in SL ATP-dependent Ca2+ pump activity PRIMARY OBJECTIVES of this proposal are to determine if endurance training (i) can restore normal Ca2+o-dependent autoregulatory function to hypertrophied hearts and (ii) can reverse the changes in SL Ca2+ regulatory processes which are produced by RVH. Towards these objectives, RVH and LV hypertrophy (HYP) will be produced in male Fisher 344 rats using a Goldblatt, 2 kidney-1 clip procedure. Hearts isolated from sedentary sham-operated controls (S-SH), endurance trained sham- operated controls (T-SH), sedentary rats with LV HYP (S-HYP), and trained rats with LV HYP (T-HYP) will be studied. Ca2+o-dependent heterometric and homeometric autoregulatory function of S-SH, T-SH, S-HYP, and T-HYP hearts will be assessed using an isolated, perfused working heart preparation. The specific binding of [3H]PN200-110 to intact, rod-shaped LV myocytes and to enriched SL membrane fractions will provide an estimate of slow Ca2+ channel number in S-SH, T-SH, S-HYP, and t-HYP hearts. The effects of training and RVH on sarcolemmal ATP-dependent Ca2+ pump activity in LV myocardium will be determined via an assessment of vesicular 45Ca2+ uptake in a highly enriched, inside-out SL membrane preparation. The relationship between the SL markers of Ca2+ regulatory function and Ca2+o- dependent, functional autoregulation in isolated working hearts will be examined. Finally, the possible impact of these in vitro changes on several indices of cardiovascular function in vivo will be ascertained by measuring maximal cardiac output, stroke volume, and heart rate in S-SH, T-SH, S-HYP, and T- HYP animals. Several endurance exercise training modalities have been shown to prevent and/or reverse decrements in cardiac function that result from LV HYP secondary to RVH. A better understanding of the cellular changes underlying these alterations in cardiac function produced by training and RVH, and the impact of these changes on the intact animal may ultimately prove useful in the development of clinical strategies to prevent myocardial dysfunction associated with hypertensive heart disease.
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