Negative inotropic effect of nifedipine in the immature rabbit heart is due to shortening of the action potential

Abstract

Contractions in neonatal rabbit ventricular myocytes seem to depend predominantly on Ca2+ influx through the Na+-Ca 2+ exchanger (NCX). Unexpectedly, neonates are sensitive to the negative inotropic effect of L-type Ca2+ channel blockers. L-type Ca2+ channel blockers depress contractile function indirectly in neonatal myocytes by shortening the action potential duration (APD), thereby decreasing the influx of activator Ca2+ through the NCX. Freshly isolated ventricular myocytes from adult and neonatal (1-5 d) rabbits were electrically stimulated (0.5 Hz; 35°C) while action potential (AP) and Ca2+ transients (Indo-1) were recorded in the absence and presence of nifedipine (10 μM). In separate experiments, cells were voltage-clamped with a constant AP waveform (APD90 = 170 ms) to determine the effect of nifedipine on Ca2+ transients independent from effects on the AP. Voltage-clamp experiments confirmed that nifedipine blocks L-type Ca 2+ current in neonatal myocytes. Nifedipine markedly reduced Ca 2+ transient amplitude and APD in both adults (transient = 20 ± 7%; APD90 = 31 ± 4% of control) and neonates (transient = 38 ± 10%; APD90 = 57 ± 6% of control). When the AP was held constant by voltage clamping, nifedipine significantly reduced the amplitude of Ca2+ transients in adults (27 ± 9% of control) but had no effect on Ca2+ transient amplitude in neonatal myocytes. These results are consistent with the concept that immature ventricular myocytes are less reliant on L-type calcium channels and are more dependent on NCX for contraction. The negative inotropic effect of L-type Ca2+ channel blockers in neonates is attributable to shortening of the AP. Copyright © 2005 International Pediatric Research Foundation, Inc.