S 16257, or (7,8-dimethoxy3-(3-[(1S) (4,5 dimethoxybenzocyclobutan-1-yl) methyl] methylamino] propyl] 1,3,4,5-tetrahydro-2H-benzazepin 2-one) hydrochloride, inhibits the hyperpolarizing-activated I f current in cardiac sinoatrial node cells and thus reduces heart rate (HR) * . We compared the coronary and systemic hemodynamic effects of graded doses of S 16257 to those of saline (control) and propranolol (1 mg/kg), in 12 conscious dogs instrumented for the measurement of arterial (aortic catheter) and left ventricular pressures (Konigsberg gauge), cardiac output (CO) (electromagnetic flow probe), left circumflex coronary artery diameter (CD) (ultrasonic crystals) and blood flow velocity (CBFv) (doppler flow probe). At rest, S 16257 induced a dose-dependent bradycardia which was significant at 0.5 (16+/-3%) and 1 mg/kg (-23+/-3%) (all p<0.01). At 0.5 mg/kg, S 16257 decreased both resting HR and treadmill exercise-induced tachycardia to a similar extent as propranolol. However, S 16 257 (0.5 mg/kg) did not affect the increases in CBFv, CD, CO, and dP/dt observed during the control exercise. These coronary and systemic hemodynamic effects of S 16257 were in sharp contrast to those of propranolol which reduced exercise-induced increases in CBFv, CO, dP/dt and which aboveall reduced CD at rest and maintained a significant constriction of the epicardial coronary vessels throughout the exercise period. All the coronary and systemic hemodynamic effects associated with S 16257 were secondary to the reduction in HR since they were abolished by atrial pacing. Thus, S 16257 is a new potent and selective bradycardic agent which clearly differs from propranolol in that it does not display any intrinsic negative inotropic effect and any vasoconstrictor effect at the level of large and small coronary arteries in resting and exercised conscious dogs.