Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.