New insights into cardiac excitation-contraction coupling in normal and hypertension/failure animal models.
Application of the confocal microscope to enzymatically isolated cardiac myocytes has revealed that excitation-contraction coupling is a ¿local control phenomenon'. The whole cell calcium transient is made up of the temporal and spatial summation of a large number of microscopic calcium release events called ¿calcium sparks'. The opening of a single calcium channel in the surface membrane can activate a calcium spark and there is a non-linear relationship between the amplitude of the single calcium channel flux and the probability of activating a calcium spark (Ps). Mathematical modelling shows that the relationship between surface membrane calcium channel gating and the activation of calcium release channels in internal stores is very sensitive to the geometric 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 minimise the requirement for calcium influx into the cell. In the spontaneous hypertensive rat (SHR) model of hypertension, the relationship between the calcium channel activity and calcium release from internal stores is altered in a way that results in a reduced contraction strength. The relationship between the calcium channel current and Ps is restored 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 gating behaviour of the sarcolemmal calcium channel to ¿retune' ability of the sarcolemmal calcium channels to activate calcium release from internal stores, and thereby improve contractility without increasing calcium influx into the cell.
Cannell
M B
MB
Department of Pharmacology & Clinical Pharmacology, St. George's Hospital Medical School, London, UK.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000503:physiopathology*; D018613:Microscopy, Confocal; D009200:Myocardial Contraction; D051381:Rats
D002118:Calcium