title: Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.
abstract: Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.
authors.affiliation: Medicinal Research Laboratories II, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: W
authors.initials: W
authors.lastname: Uchida
authors.forename: K
authors.initials: K
authors.lastname: Shibasaki
authors.forename: M
authors.initials: M
authors.lastname: Asano
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000758:Anesthesia; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D009596:Nitrophenols / Q000494:pharmacology*; D014628:Vagotomy; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D009596:Nitrophenols; D014665:Vasodilator Agents; C064876:YM 16151-1; D001262:Atenolol; D009543:Nifedipine