The cellular mechanisms underlying training-induced changes in myocardial contractility are not well understood. However, it appears that the best biochemical correlates of improved contractile function include alterations in sarcolemmal (SL) and sarcoplasmic reticular (SR) processes that are involved in the regulation of transarcolemmal and sarcoreticular Ca2+ movement. In order to gain a better understanding of the functional significance of these biochemical changes, the impact of treadmill training (TR) on the primary avenues of cellular CA2+ influx (""""""""L"""""""" type Ca2+ channel) and efflux (NaCa exchange) will be examined using whole cell patch clamp techniques on single, left ventricular (LV) cardiac myocytes. (The female rat model, sedentary (SED) and TR, will be used). (i) The effect of TR on the magnitude of """"""""L"""""""" type current (ICa) and ICa inactivation kinetics will be determined. Similarly, the voltage- and intracellular [Ca2+]-dependence of NaCa exchange current (INa/Ca) will be examined. These studies are important because (1) ICa is centrally involved in regulating Ca2+ release from the SR and (2) the beat-to-beat dynamic equilibrium achieved by ICa and INa/Ca largely defines cellular and SR Ca2+ content; SR Ca2+ release is proportional to SR Ca2+ content. (ii) The effect of TR on SR Ca2+ content will be examined using rapid cooling contractures (RCC); the relative (SED v TR) effects of experimental manipulations designed to differentially perturb influx and efflux mechanisms on RCC amplitude will be examined. RCC experiments will be performed on single LV myocytes and trebecular muscle preparations. (iii) The effect of TR on Ca2+ handling in a global preparation exhibiting a high degree of native cellular organization will be determined using a perfused, isovolumic rat heart preparation. Significant information regarding the dynamic regulation of releasable SR Ca2+ can be derived by examining the contractile response of the heart to systematically varied extrasystolic and post-extrasystolic intervals. These whole organ data will be critical in our understanding of the significance of the cellular changes that are produced by TR. (iv) The effect of TR on the responsiveness of the contractile element to activation by Ca2+ will be examined using a permeabilized LV trebecular muscle preparation exhibiting sarcomeric organization. Exercise training is a singularly unique nonpathophysiological stressor that is capable of eliciting biochemical and positive functional changes in the myocardium. Training can also be of significant value in disease prevention and rehabilitation. Information resulting from this project will contribute to our understanding of the functional plasticity of the myocardium and may be important in understanding the cellular lesions underlying certain pathological states, and the mechanisms involved in ameliorating those lesions.
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