title: 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+-Ca2+ 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 degrees C) while action potential (AP) and Ca2+ transients (Indo-1) were recorded in the absence and presence of nifedipine (10 microM). 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 Ca2+ current in neonatal myocytes. Nifedipine markedly reduced Ca2+ 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.
authors.affiliation: Department of Pediatrics, Pediatric Cardiology Molecular and Cellular Research Laboratories, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Go
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.forename: Leon
authors.initials: L
authors.lastname: Collis
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.forename: Michael
authors.initials: M
authors.lastname: Artman
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011817:Rabbits
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009543:Nifedipine