Positive inotropic and vasodilatory actions of saterinone in vivo

Abstract

The cardiovascular actions of the newly developed inotropic and alpha 1-receptor blocking agent saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) was investigated in small laboratory animals in vivo. Saterinone caused a direct inotropic effect in pithed guinea pigs without affecting heart rate. In the same animal species saterinone competitively antagonized the pressor effects of phenylephrine at inotropic doses. In conscious rabbits saterinone exerted dose-dependent increase in left ventricular dP/dtmax and in heart rate, whilst reducing arterial blood pressure in the same dose range. The drug dose-dependently antagonized phenylephrine as evidence of its alpha 1-receptor blocking effects in the conscious rabbit. The duration of alpha 1-receptor blockade was longer than the duration of inotropic effects. The onset of inotropic and vascular effects of saterinone was found to be simultaneous, when the drug was slowly infused into the femoral vein of anesthetized cats. The saterinone dose which caused a significant inhibition of the pressor effects of phenylephrine (comparable to prazosin) still caused a reduction of femoral perfusion pressure and systemic blood pressure in anesthetized cats pretreated with phenoxybenzamine. Thus in contrast to prazosin, which was rendered ineffective after phenoxybenzamine, saterinone possesses an additional mechanism for vasodilation. Saterinone exhibited good oral efficacy in spontaneously hypertensive rats and in conscious cats, in which an oral dose of 10-30 mg/kg significantly reduced arterial blood pressure or increased left ventricular dP/dtmax, respectively. Thus saterinone exerts in vivo direct positive inotropic and vasodilating effects.(ABSTRACT TRUNCATED AT 250 WORDS)