Dual effects of nicardipine: evidence from intracellular Ca2+ transients and twitch contractions observed in single myocytes obtained from rat heart.
Mechanisms responsible for dual actions of nicardipine were examined using myocytes isolated from ventricular muscle of rat heart. About 60% of isolated rat myocytes showed positive force-frequency relationships. These cells had lower intracellular Ca2+ concentrations at rest. In the remaining cells that had higher resting Ca(2+)-concentrations, an increase in frequency of stimulation from 1 Hz to 2 Hz produced either no change or reduction in the amplitude of Ca2+ transients and twitch contractions. In 13 of 34 myocytes that showed positive force-frequency relationships, nicardipine enhanced the Ca2+ transient and produced sustained positive inotropic effects. In 11 of 20 cells that showed negative force-frequency relationships, nicardipine produced negative inotropic effects. Inhibition was partly reversed by an increase in extracellular CaCl2 concentration from 1.2 to 3.6 mM. In the remaining cells, nicardipine failed to either increase or decrease the amplitude of Ca2+ transient or twitch contraction. Bay K-8644 produced positive inotropic effects in most cells. These results indicate that nicardipine either enhances or inhibits Ca2+ transients and twitch contractions depending on the Ca2+ loading state of myocytes. The present results are consistent with the hypothesis that nicardipine stabilizes the state of Ca2+ channels, either in the inactivated state in cells that are well loaded with Ca2+, or in the activated state when the degree of Ca2+ loading is relatively low.
Jiang
J
J
Department of Pediatric Pharmacology, National Children's Hospital Medical Research Center, Tokyo, Japan.
Temma
K
K
Akera
T
T
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects; D002478:Cells, Cultured; D004558:Electric Stimulation; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology*; D051381:Rats
D015220:Calcium Channels; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009529:Nicardipine; D002118:Calcium