Cardiovascular Profile of Ro 13–6438, a Novel Positive Inotropic Agent with Vasodilating Properties

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Abstract
The cardiovascular properties of Ro 13–6438 (R-6-chloro-l,5-dihydro-3-methylimidazo-[2,l b]quinazolin-2[3 H]-one), a novel nonglycoside, noncatechol cardiotonic agent, were investigated in vitro and in vivo by both intravenous and oral administration. Ro 13–6438 increased tension development of isolated guinea pig left atria in a concentration-dependent manner with an ECS50 of 30 μM, but had no stimulant effect on the spontaneous rate of right atria. The positive inotropic effect of Ro 13–6438 was additive to that of ouabain (0.1 μM); Ro 13–6438 suppressed the arrhythmogenic activity of high concentrations of ouabain (10 μM). In anesthetized open-chest dogs 10–300 μg/kg Ro 13–6438 i.v. produced a significant and dose-dependent increase in myocardial contractile force, with a duration of action exceeding 60 min following the highest dose. It also slightly increased heart rate, cardiac output, and coronary blood flow. Ro 13–6438 decreased systolic and diastolic blood pressure, left ventricular end-diastolic pressure, and total peripheral resistance. Thus, the direct positive inotropic effects of Ro 13–6438 were supported by a decrease in preload and afterload. In chronically instrumented, conscious dogs Ro 13–6438 increased myocardial contractility after administration of 0.03–0.3 mg/kg i.v. or 3–10 mg/kg p.o. The effects persisted for >8 h after oral administration of 10 mg/kg. The inotropic effects were accompanied by a modest increase in heart rate, which, however, had a clearly shorter duration of action than the former. The present investigations characterize Ro 13–6438 as a positive inotropic agent with additional vasodilating properties, oral activity, and only weak chronotropic effects. No tachyphylaxis or cumulation was observed.