Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs.

The effects of (7,8-dimethoxy 3-[3-([(1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl]methylamino) - propyl]1,3,4,5-tetrahydro-2H-benzapin 2-one hydrochloride) (S 16257), a new bradycardic agent acting through inhibition of the hyperpolarization-activated I(f) current in the sino-atrial node, on arterial blood pressure, cardiac output, left ventricular pressure and dP/dt, epicardial coronary artery diameter and coronary blood flow velocity were investigated at graded doses (0.1 to 1 mg/kg) and compared to those of propranolol (1 mg/kg) and saline in chronically instrumented conscious dogs. At rest, S 16257 induced a dose-dependent bradycardia that was significant at 0.5 (-16% +/- 3%) and 1 mg/kg (-23% +/- 3%). At 0.5 mg/kg, S 16257 decreased both resting HR and treadmill exercise-induced tachycardia to a similar extent as propranolol. However, in contrast to propranolol, S 16257 (0.5 mg/kg) did not affect the increase in mean coronary blood flow velocity and the decrease in coronary vascular resistance observed during a control exercise performed under saline. In addition, S 16257 did not affect resting epicardial coronary artery diameter and only attenuated its increase during exercise, whereas propranolol reduced it at rest and maintained a significant constriction of these large vessels throughout the exercise period. Propranolol, but not S 16257, decreased left ventricular dP/dt at each stage of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)