Modulation of L-type Ca2+ channels in neonatal rat heart by a novel Ca2+ channel agonist

Abstract

L-type Ca2+ channels are essential in triggering the intracellular Ca2+ release and contraction in heart cells. In this study, we used patch clamp technique to compare the effect of two pure enantiomers of L-type Ca2+ channel agonists: (+)-CGP 48506 and the dihydropyridine (+)-SDZ-202 791 in cardiomyocytes from rats 2–5 days old. The predominant Ca2+ current activated by standard step pulses in these myocytes was L-type Ca2+ current. The di hy dro py ri dine antagonist (+)-PN200-110 (5 μM) blocked over 90% of Ca2+ currents in most cells tested. CGP 48506 lead to a maximum of 200% increase in currents. The threshold concentration for the CGP effect was at 1 μM and the maximum was reached at 20 μM. SDZ-202 791 had effects in nanomolar concentrations and a maximum effect at about 2 μM. The maximal effect of (+)-SDZ-202 791 was a 400% increase in the amplitude of Ca2+ currents and was accompanied by a 10–15 mV leftward shift in the voltage dependence of activation. CGP 48506 increased the currents equally at all voltages tested. Both compounds slowed the deactivation of tail currents and lead to the appearance of slowly activating and slowly deactivating current components. However, SDZ-202 791 had larger effects on deactivation and CGP 48506 had larger effect on the rate of Ca2+ current activation. The effect of SDZ-202 791 was fully additive to that of CGP 48506 even after maximum concentrations of CGP. This observation suggests that the two Ca2+ channel agonists may act at two different sites on the L-type Ca2+ channel. We suggest that CGP 48506 would be a potential cardiotonic agent without the deleterious proarrhythmic effects attributable to the dihydropyridine agonists.Key words: heart failure, calcium channels, dihydropyridine, CGP 48506 (5-methyl-6-phenyl-1, 3,5,6-tetra hydro-3,6-methano-1,5-benzodiazocine-2,4-dione).