Inotropic and lusitropic effects of chlorpromazine on rat left ventricular papillary muscle.
The in vitro effects of chlorpromazine on rat cardiac papillary muscle were tested at 10(-6), 10(-5) and 10(-4) M. Mechanical parameters were determined from the contraction and relaxation phases under isotonic and isometric conditions in order to assess contraction, relaxation, contraction-relaxation coupling and load sensitivity of relaxation. The peak power output Emax was determined from the force-velocity relationship. At 10(-6) M, a slight positive inotropic effect was observed, probably related to modifications in cross-bridges kinetics. Negative inotropic effects were observed with 10(-5) and 10(-4) M chlorpromazine. At 10(-5) M, shortening of the isometric relaxation and decrease in R2 = (+dF.dt-1max)/(-dF.dt-1max) suggest that chlorpromazine also diminishes myofilament Ca++ sensitivity. Emax was increased at 10(-6) M (19 +/- 5%, P less than .05), but decreased at 10(-5) M (-28 +/- 10%, P less than .05) and 10(-4) M (-82 +/- 2%, P less than .05). Modifications in the force-velocity relationship at 10(-4) M indicated that lowering myocardial performance by chlorpromazine was associated with a low muscle efficiency from a thermoenergetic point of view. At all concentrations, chlorpromazine impaired the isotonic relaxation and load sensitivity of relaxation. At 10(-4) M, muscle contracture and slowed isometric relaxation were probably due to "calcium overload." These results showed that chlorpromazine finely modulates intrinsic cardiac energetics and mechanics by acting on the sarcoplasmic reticulum, myofilament Ca++ sensitivity and cross-bridges kinetics, according to the level of load and chlorpromazine concentration used.
Clergue
M
M
INSERM U 275, Laboratoire d'Optique Appliquée, ENSTA-Ecole Polytechnique, Palaiseau, France.
Riou
B
B
Lecarpentier
Y
Y
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D000242:Cyclic AMP; D002118:Calcium; D002746:Chlorpromazine