Inotropic and lusitropic effects of MCI-154 (6-[4-(4- pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone) on human myocardium

Abstract

We studied the inotropic and lusitropic responses to MCI-154 in 12 right or left ventricular trabeculae carneae isolated from 7 organ donors (non-cardiac) without known cardiovascular disease who met accepted criteria for brain death. Isometric tension was recorded from muscles superfused with a physiologic salt solution at 30 degrees C, and stimulated to contract at three-second intervals. Concentration-response curves were developed over a range of MCI-154 organs bath concentrations (10(-7) M to 3 x 10(-4) M; n = 9). Six experiments were conducted using 10(-6) M carbachol, a muscarinic agonist, in the presence of a maximally effective concentration of MCI-154 to test for dependence of tension development on cyclic adenosine monophosphate. Three experiments were conducted with MCI-154, 3 x 10(-5) M, in muscles loaded with the bioluminescent calcium indicator aequorin. MCI-154 produced a concentration-dependent rise in peak tension in the human muscle (positive inotropic effect), equivalent to 70% of the maximal response to calcium (P less than 0.001). Relaxation was enhanced (positive lusitropic effect), as evidenced by a fall in the time to 80% relaxation from 311 +/- 13 ms (baseline) to 248 +/- 15 ms at 10(-5) M (P less than 0.01). Aequorin studies showed the increase in tension to be accompanied by large increases in cystolic calcium, the principal mechanism of action. Carbachol caused MCI-154--induced maximum peak tension to decrease by 5 +/- 1%. While not excluding a cyclic adenosine monophosphate--mediated MCI action, this modest carbachol inhibition suggests the existence of additional mechanism(s) of action. MCI-154 had a negative lusitropic effect at high concentrations (greater than 10(-4)M) which may have been due to intracellular calcium overload, evidenced by the large amplitude aequorin signals. This does not exclude sensitization of the myofilaments to calcium as a possibility. Extrapolated to the in vivo setting, these experiments suggest that MCI-154 may be an effective positive inotropic agent in man.