Opposite cardiac actions of the enantiomers of Bay K 8644 at different membrane potentials in guinea-pig papillary muscles.
The influence of membrane potential on the effects of the enantiomers and the racemate of Bay K 8644 [1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluor-methylphenyl)-p yri dine-5-carboxylate] on force of contraction and on action potentials were studied in guinea-pig papillary muscles in order to detect possible changes in the direction of drug action or in potency. Membrane potential was varied by changing the potassium concentration ([K+]o) in the bathing solution. At normal resting potential, (-)-Bay K 8644 enhanced force of contraction and prolonged the action potential duration measured at 50% of repolarization (APD) to the same extent as the racemate and with similar pD2 values. After membrane depolarization by raising [K+]o from 5.4 to 17.4 mmol/l, the (-)-enantiomer and the racemate prolonged the APD to a similar degree but enhanced force to a lesser extent. The maximum rate of depolarization of slow action potentials, Vmax, was increased at the highest concentrations (10(-5) mol/l). The effects of (+)-Bay K 8644 were more complicated. At high concentrations (10(-5) mol/l) it decreased force of contraction and APD, the pD2 values were one order of magnitude lower than for the (-)-enantiomer and the racemate. A high concentration (+)-Bay K 8644 (10(-5) mol/l) virtually abolished contractile activity at all membrane potentials, the extent of shortening in APD increased with membrane depolarization in elevated [K+]o. Vmax of slow action potentials was decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
Ravens
U
U
Institut für Pharmakologie, Universität-Gesamthochschule Essen, Federal Republic of Germany.
Schöpper
H P
HP
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D013237:Stereoisomerism
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester