CA2-FAILURE( CURRENTS IN COMPENSATED HYPERTROPHY AND HEART)

Transmembrane voltage-gated Ca2+ channels play a central role in the d evelopment and control of heart contractility which is modulated by th e concentration of free cytosolic calcium ions (Ca2+). Ca2+ channels a re closed at the normal membrane resting potential of cardiac cells. D uring the fast upstroke of the action potential (AP), they are gated i nto an open state by membrane depolarisation and thereby transduce the electrical signal into a chemical signal. In addition to its contribu tion to the AP plateau, Ca2+ influx through L-type Ca2+ channels induc es a release of Ca2+ ions from the sarcoplasmic reticulum (SR) which i nitiates contraction. Because of their central role in excitation-cont raction (E-C) coupling, L-type Ca2+ channels are a key target to regul ate inotropy [1]. The role of T-type Ca2+ channels is more obscure. In addition to a putative part in the rhythmic activity of the heart, th ey may be implicated at early stages of development and during patholo gy of contractile tissues [2]. Despite therapeutic advances improving exercise tolerance and survival, congestive heart failure (HF) remains a major problem in cardiovascular medicine. It is a highly lethal dis ease; half of the mortality being related to ventricular failure where as sudden death of the other patients is unexpected [3]. Although HF h as diverse aetiologies, common abnormalities include hypertrophy, cont ractile dysfunction and alteration of electrophysiological propel ties contributing to low cardiac output and sudden death. A significant pr olongation of the AP duration with delayed repolarisation has been obs erved both during compensated hypertrophy (CH) and in end-stage HF cau sed by dilated cardiomyopathy(Fig. 1A) [4-8], This lengthening can res ult from either an increase in inward currents or a decrease in outwar d currents or both. A reduction of K+ currents has been demonstrated [ 6,9]. Prolonged Na+/Ca2+ exchange current may also be involved [9]. In contrast, there is a large variability in the results concerning Ca2 currents (I-Ca). The purpose of this paper is to review results obtai ned in various animal models of CH and HF with special emphasis on rec ent studies in human cells. We focus on: (i) the pathophysiological ro le of T-type Ca2+ channels, present in some animal models of hypertrop hy; (ii) the density and properties of L-type Ca2+ channels and altera tion of major physiological regulations of these channels by heart rat e and beta-adrenergic receptor stimulation: and (iii) recent advances in the molecular biology of the L-type Ca2+ channel and future directi ons. (C) 1998 Published by Elsevier Science B.V.