Our understanding of the role of the action potential and the underlying membrane currents to initiate and regulate the excitation-contraction coupling process in normal myocardium while still not clarified has been greatly advanced by voltage clamp techniques. In contrast, there is virtually no information available concerning the electrophysiological aspects of excitation-contraction coupling in hypertrophied myocardium. We have recently demonstrated that action potential duration is significantly lengthened and plateau voltage reduced in papillary and trabecular muscle cells from cats with chronic ventricular systolic hypertension and concomitant ventricular hypertrophy. We now propose to (1) characterize the changes in membrane current responsible for the changes in the action potential; (2) define the changes in the several conductances and their kinetics underlying the changes in membrane current; (3) correlate the changes in membrane current with the reduction in contractility associated myocardial hypertrophy; (4) and, by controlling the time course of the action potential in normal and hypertrophic myocardium, determine if the change in the action potential observed in hypertrophic myocardium has a significant effect on contractility. Papillary muscles and ventricular trabeculae of cats in which pressure overload stress has induced right ventricular hypertrophy will be studied with conventional electrophysiological techniques in conjunction with the single sucrose gap voltage clamp technique. Rigorous procedures will be used to evaluate the quality of the sucrose gap and of the spatial and temporal control of membrane voltage. The proposed studies will indicate whether alterations in myocardial contractility associated with hypertrophy result from changes in the electrophysiological properties of the myocardial sarcolemma. If electrophysiological changes can account for at least part of the loss in contractility of hypertrophic heart muscle, it would explain why the biochemical approach has not been able to account fully for the contractility loss associated with ventricular hypertrophy and failure.
NIH ExPorter
NIH ExPorter