Cardiovascular profile of Ro 13-6438, a novel positive inotropic agent with vasodilating properties.

The cardiovascular properties of Ro 13-6438 (R-6-chloro-1,5-dihydro-3- methylimidazo -[2,1-b] quinazolin -2[ 3H]-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 EC50 of 30 microM, 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 microM); Ro 13-6438 suppressed the arrhythmogenic activity of high concentrations of ouabain (10 microM). IN anesthetized open-chest dogs 10-300 micrograms/kg Ro 13-6438 i.v. produced a significant and dose-dependent increase in myocardial force, with a duration of action exceeding 60 min following the highest dose. It also slightly increased heart rate, cardiac output, and 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 greater than 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.(ABSTRACT TRUNCATED AT 250 WORDS)