Modulation of Na+-Ca2+ exchange in cardiac sarcolemmal vesicles by Ca2+ antagonists

Abstract

The purpose of this study was to examine the effect of three classes of Ca2+ antagonists, diltiazem, verapamil and nifedipine on Na+-Ca2+ exchange mechanism in the sarcolemmal vesicles isolated from canine heart. Na+-Ca2+ exchange and Ca2+ pump (ATP-dependent Ca2+ uptake) activities were assessed using the Millipore filtration technique. Sarcolemmal vesicles used in this study are estimated to consist of several subpopulations wherein 23% are inside-out and 55% are right side-out sealed vesicles in orientation. The affect of each Ca2+ antagonist on the Na+ dependent Ca2+ uptake was studied in the total population of sarcolemmal vesicles, in which none of the agents depressed the initial rate of Ca2+ uptake until concentrations of 10 microM were incubated in the incubation medium. However, when sarcolemmal vesicles were preloaded with Ca2+ via ATP-dependent Ca2+ uptake, cellular Ca2+ influx was depressed only by verapamil (28%) at 1 microM in the efflux medium with 8 mM Na+. Furthermore, inhibition of Ca2+ efflux by verapamil was more pronounced in the presence of 16 mM Na+ in the efflux medium. The order of inhibition was verapamil greater than diltiazem greater than nifedipine. These results indicate that same forms of Ca2+-antagonist drugs may affect the Na+-Ca2+ exchange mechanism in the cardiac sarcolemmal vesicles and therefore we suggest this site of action may contribute to their effects on the myocardium.

Nonequilibrium Reactivation of Na + Current Drives Early Afterdepolarizations in Mouse Ventricle

“…That is, by potentiating SR Ca 2+ release through increased SR Ca 2+ load and fractional release. It is for this reason, and the well known promiscuity of available Ca 2+ channel antagonists 42, 43 that we have avoided experiments involving I CaL antagonists in this study. As such, we strongly recommend against interpreting the ability of I Ca L inhibitors to reduce EAD incidence in the mouse as inferring a role for I Ca L reactivation in driving murine EADs.…”

Intracellular calcium levels and calcium fluxes in the CA1 region of the rat hippocampal slice during in vitro ischemia: relationship to electrophysiological cell damage

“…Although nifedipine has other, nonchannel, effects at these concentrations, they should not account for the reduced accumulation. The bestestablished of these effects are inhibition of the Ca-ATPase (Hata et al, 1988) and inhibition of mitochondrial Na/Ca exchange (Vaghy et al, 1982) both of which would increase Ca accumulation. It has been suggested that nifedipine partially blocks plasmalemma Na/Ca exchange (Carvalho et al, 1986) which could account for the inhibition of influx, but in well-controlled studies on heart sarcolemma the drug does not affect this process (Hata et al, 1988).…”

L-Type Calcium Channel Antagonists and Suppression of Expression of Plasminogen Receptors

“…4 -6 As in macrophage, 11 the L-type Ca 2ϩ antagonists also block the Na ϩ /Ca 2ϩ exchanger. 4,6,8 This exchanger is also present at the nuclear membranes 1 and could be also a target of some Ca 2ϩ blockers. Thus, in a cell type where a biophysical study of the L-type Ca 2ϩ channel was never demonstrated, the use of molecular biology techniques and/or L-type Ca 2ϩ channel blockers, as pharmacological specific tools for studying such a channel, should be carefully interpreted.…”