Positive inotropic effects of RP 62719, a new pure class III antiarrhythmic agent, on guinea pig myocardium.
The mechanical effects of RP 62719 [(-)1-[-2-(3,4-dihydro-2H-1- benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)-piperidine] were tested in vitro on guinea pig left ventricular papillary muscle. RP 62719 is a novel pure class III antiarrhythmic agent known to prolong the cardiac action potential duration by selectively blocking the inward rectifying K+ current. Mechanical parameters were determined from contraction and relaxation phases under isotonic and isometric conditions. At a concentration of 0.02 microM, RP 62719 did not produce significant effects on inotropy or lusitropy. At 0.2 and 2 microM, the drug improved contraction under both heavy and low loading conditions, as evidenced by a 30% increase in maximum unloaded shortening velocity (Vmax, P < .001), peak amplitude of shortening (delta L, P < .001), peak isometric active force normalized per cross-sectional area (AF/s, P < .001) and positive peak of the force derivative per mm2 (+dF/s, P < .001). At the same concentrations, positive lusitropic effects were evidenced by an increase in maximum lengthening velocity (maxVr) and negative peak of force derivative per mm2 (-dF/s, P < .001). At a higher concentration (20 microM), effects of RP 62719 on inotropy and lusitropy were less marked, thus accounting for the bell-shaped form of the dose-response curve. An increase in the extracellular Ca++ concentration from 2.5 to 3.75 mM improved inotropy to a similar extent (+30-50%) as did 2 microM RP 62719. However, lusitropy and mechanical coupling between contraction and relaxation were not modified in the same proportion under RP 62719 and under 3.75 mM Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)
Beregi
J P
JP
Institut National de la Santé et de la Recherche Médicale, Unité 275, LOA-ENSTA-Ecole Polytechnique, Palaiseau.
Escande
D
D
Coudray
N
N
Mery
P
P
Mestre
M
M
Chemla
D
D
Lecarpentier
Y
Y
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D002839:Chromans; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010880:Piperidines; D015221:Potassium Channels / Q000187:drug effects; D013268:Stimulation, Chemical
D000889:Anti-Arrhythmia Agents; D002839:Chromans; D010880:Piperidines; D015221:Potassium Channels; C063899:terikalant; D002118:Calcium