The antianginal effects of
YM-16151-4, a combined
calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in various experimental angina models and compared with those of
nifedipine and
propranolol. In anesthetized dogs,
YM-16151-4 (0.3 and 1 mg/kg intravenously, i.v.) increased coronary blood flow and reduced myocardial oxygen consumption (MVO2). In isolated dog coronary arteries,
YM-16151-4 concentration-dependently inhibited 3,4-diaminopyridine-induced rhythmic contractions with an IC50 value of 91 nM. In anesthetized rats,
YM-16151-4 also inhibited the ST-segment depression induced by
vasopressin (0.5 U/kg i.v.) with an ED50 value of 29 mg/kg orally, (p.o.).
Nifedipine was also effective in these models, but
propranolol was not. In addition,
YM-16151-4 (0.3 mg/kg i.v.) inhibited the ST-segment elevation in the epicardial ECG induced by coronary artery occlusion in anesthetized dogs.
Propranolol (1 mg/kg i.v.) also inhibited this elevation, but
nifedipine (0.003 mg/kg i.v.) did not. In anesthetized dogs, furthermore, the prolongation of PQ-interval induced by
YM-16151-4 was almost the same as that induced by
propranolol. These results demonstrate that
YM-16151-4, in contrast to
nifedipine and
propranolol, is fully effective in these various types of angina models. Thus,
YM-16151-4 is expected to prove a valuable antianginal agent in treatment of various types of
angina pectoris, with these antianginal effects resulting from the sum of its
calcium entry blocking and beta 1-adrenoceptor blocking activities.