Cellular Ca2+ regulation is altered in hearts having undergone left ventricular (LV) hypertrophy secondary to renovascular hypertension (RvHtn). In single paced LV myocytes, RvHtn elicits reductions in the amplitude of the cytosolic [Ca2+] ([Ca2+]c) transient and the rate at which [Ca2+]c returns to basal levels. These alterations in [Ca2+]c dynamics occur concomitantly with a reduced myocyte contractile response and slowed myocyte relaxation. At the whole organ level, Ca2+-dependent LV contractile autoregulation is compromised by RvHtn. These intrinsic functional changes in global and single cell function appear to occur concomitantly with alterations in the expression and/or function of several sarcolemmal (SL) and sarcoplasmic reticular (SR) Ca2+ regulatory proteins. Exercise training has been shown to prevent and/or reverse decrements in LV contractile function that result from RvHtn and to elicit adaptive responses at several Ca2+ regulatory loci. PRIMARY OBJECTIVES of this proposal are to determine if endurance training (i) can restore normal [Ca2+]c dynamics and contractile function to single LV myocytes isolated from RvHtn rats. (ii) Steps will be taken to localize the cellular processes that are responsible for altered myocyte [Ca2+]c dynamics in RvHtn myocytes and (iii) to identify the influence of training on those processes. to accomplish these objectives, RvHtn and LV hypertrophy will be produced in male Fisher 344 rats using a Goldblatt, 2 kidney-1 clip procedure. LV myocardium and single LV myocytes isolated from sedentary normotensive (NSd), trained normotensive (NTr), sedentary hypertensive (HSd), and trained hypertensive (HTr) rats will be studied. Morphology, contractile function, and [Ca2+]c dynamics in NSd, NTr, HSd, and HTr myocytes will be assessed using fluorescence and video microscopy. In the LV myocyte studies, pacing and perfusion conditions will be altered to differentially perturb cellular Ca2+ influx and efflux mechanisms; rapid cooling contractures will be used to bioassay the amount of releasable Ca2+ that is in the SR. Caffeine contracture studies will be used to assess the relative roles of SR Ca2+ uptake and Na+-Ca2+ exchange in relaxation in intact myocytes. For the sake of interpretive relevance, studies of global LV contractile function will be conducted in parallel to the single myocyte experiments. Biochemical, pharmacological, and immunochemical techniques will be used to assess the singular and combined effects of training and RvHtn on the expression and/or function of key SL and SR Ca2+ and Na+ regulatory proteins; myocyte Ca2+ and Na+ regulation are intimately linked. A better understanding of the Ca2+ regulatory changes that occur in response to training and RvHtn, and the impact of these changes on single myocyte and global LV function may prove useful in the development of clinical strategies to prevent myocardial dysfunction associated with hypertensive heart disease.

R01HL044146

1990-05-01

1999-04-30