NEW INSIGHTS INTO CARDIAC EXCITATION-CONTRACTION COUPLING IN NORMAL AND HYPERTENSION FAILURE ANIMAL-MODELS/

Application of the confocal microscope to enzymatically isolated cardi ac myocytes has revealed that excitation-contraction coupling is a 'lo cal control phenomenon'. The whole cell calcium transient is made up o f the temporal and spatial summation of a large number of microscopic calcium release events called 'calcium sparks', The opening of a singl e calcium channel in the surface membrane can activate a calcium spark and there is a non-linear relationship between the amplitude of the s ingle calcium channel flux and the probability of activating a calcium spark (P-s). Mathematical modelling shows that the relationship betwe en surface membrane calcium channel gating and the activation of calci um release channels in internal stores is very sensitive to the geomet ric relationship between these channels. Under normal conditions, the gating behaviour of the surface membrane calcium channels may be near optimal (or well 'tuned') for activating calcium sparks which will min imise the requirement for calcium influx into the cell. In the spontan eous hypertensive rat (SHR) model of hypertension, the relationship be tween calcium channel activity and calcium release from internal store s is altered in a way that results in a reduced contraction strength. The relationship between the calcium channel current and P-s is restor ed by beta-adrenergic stimulation in the hypertrophy model but not in hearts which are failing. These results suggest that a novel approach to treating certain types of heart failure could be to modify the gati ng behaviour of the sarcolemmal calcium channel to 'retune' ability of the sarcolemmal calcium channels to activate calcium release from int ernal stores, and thereby improve contractility without increasing cal cium influx into the cell.