The response of the calcium dependent myocardial contractility to the new cardiotonic agent sulmazole.
In vitro and in vivo animal experiments to test the positive inotropism of 2-[(2-methoxy-4-methylsulfinyl)-phenyl]-1H-imidazo[4,5-b]pyridine (sulmazole, AR-L 115 BS) have shown increases of contractility of up to 220% in the mmol/l concentration range. Comparative studies designed to attribute to sulmazole mechanisms established for other positive inotropic drugs have been negative for digitalis and beta-adrenoceptor agonists but showed slight similarities to xanthine derivatives. To explore the yet unknown mode of action of sulmazole we investigated the interaction between sulmazole and non-humoral/non-drug interventions for positive inotropism in vitro. Peak tension obtained in solutions varying in calcium content between 0.36 and 7.2 mmol/l Ca2+ were normalized with respect to the tension measured at standard 1.8 mmol/l Ca2+ for control and sulmazole treated preparations (sheep interventricularis cordis muscle and guinea pig papillary muscle). Double logarithmic plots of normalized tension versus calcium concentration were linear and superimposable for control, 10(-4), and 10(-3) mol/l sulmazole. In depleted sodium solutions (choline substitution) normalized peak tension of control and 10(-4) mol/l sulmazole containing solutions did not significantly differ. In length-tension plots sulmazole behaved as did increased extracellular calcium. We assume that the positive inotropism of sulmazole is primarily due to a displacement of calcium at non-specific ligand sites within the protein matrix of the cytosol which effectively raises the apparent intracellular calcium activity.
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D012756:Sheep; D012964:Sodium / Q000502:physiology; D013997:Time Factors
D002316:Cardiotonic Agents; D007093:Imidazoles; D012964:Sodium; C029758:sulmazole; D002118:Calcium