Cardiovascular profile of the new dihydropyridine derivative S12968

The cardiovascular profile of S12968 was evaluated in anaesthetized pigs, using cumulative 15-min i.v. infusions of 1.25, 2.5, 5, 10 and 20 micrograms.kg-1.min-1 (n = 7) or equal volumes of its solvent (n = 7). S12968 decreased mean arterial blood pressure from 94 +/- 4 to 66 +/- 3 mm Hg (P less than 0.05) and cardiac output from 2.7 +/- 0.2 to 2.2 +/- 0.2 l.min-1 (P less than 0.05), had no effect on heart rate and left ventricular end-diastolic pressure, but decreased maxLVdP/dt (maximal rate of rise in left ventricular pressure) by up to 35 +/- 3% (P less than 0.05). With doses higher than 10 micrograms.kg-1.min-1 transmural left ventricular blood flow increased by up to 49 +/- 22% (P less than 0.05), favouring the subepicardium over the subendocardium. Myocardial oxygen consumption decreased by 22 +/- 7 and 32 +/- 8% (P less than 0.05) during infusion of 10 and 20 micrograms.kg-1.min-1, respectively. Heart rate, left ventricular end-diastolic pressure and arterial blood pressure were not affected, but maxLVdP/dt (partially) and cardiac output returned to pre-drug values a during a 60-min post-infusion period. In conclusion, S12968 exhibited a negative inotropic effect at low doses. However, with higher doses and after discontinuation of the infusion, vasodilatation occurred, while the negative inotropy disappeared. It is possible that an active metabolite, acting preferentially on the vasculature, was responsible for the vasodilatation.