T-TYPE AND L-TYPE CA2-CHANNEL ANTAGONISTS REDUCE CONTRACTILITY IN GUINEA-PIG CARDIAC MYOCYTES()

The aim of this study was to investigate the influence of L- and T-typ e Ca2+-channel blockade on myocardial contractility in guinea pig card iomyocytes. Left ventricular myocardium from guinea pig contains both L- and T-type Ca2+ channels. The T-type Ca2+ influx was inhibited with mibefradil (1-100 mu M), a novel compound with a threefold higher aff inity for T- compared with L-type Ca2+ channels. In comparison, L-type Ca2+ influx was reduced by the benzodiazepine diltiazem (1-100 mu M). The effect of mibefradil and diltiazem on electrically driven (0.5 Hz ) isolated cardiomyocytes (n = 12) was studied in a concentration-depe ndent manner. The change of the contraction amplitude (percentage of c ell shortening) was continuously recorded with an one-dimensional high -speed camera. Both mibefradil and diltiazem concentration-dependently reduced (p < 0.05 vs. control) the contraction amplitude in isolated myocytes from guinea pig. The concentration at which the contraction a mplitude of guinea pig cardiomyocytes was reduced by 50% (EC50) was 31 .6 mu M for diltiazem and 6.3 mu M for mibefradil, indicating that the T-type Ca2+-channel blocker mibefradil is more potent in reducing con tractility in guinea pig cardiac myocytes in comparison with the L-typ e Ca2+-channel antagonist diltiazem. Mean values for cell shortening i n percentage +/- SEM for mibefradil (0, 1, 10, 100 mu M) were 100%, 78 +/- 9.2%, 36 +/- 5.4%, and 24 +/- 3.6%. The corresponding values for diltiazem were 100%, 92 +/- 12.5%, 79 +/- 8.9%, and 35 +/- 2.6%. In co ntrast, the increase of the extracellular Ca2+ concentration (2-7.5 mM ) resulted in a significant increase of the contraction amplitude (+21 3 +/- 14%). Therefore, blockade of the Ca2+ influx through voltage-dep endent T- or L-type Ca2+ channels decreases contraction in isolated ca rdiac myocytes from guinea pigs containing L- and T-type Ca2+ channels .