[Effect of palonidipine hydrochloride (TC-81), a new dihydropyridine derivative, on various myocardial ischemic models].
The antianginal effects of palonidipine, a novel 1,4-dihydropyridine derivative, and nifedipine on various myocardial ischemic models were compared. (1) Palonidipine at 0.5 mg/kg, p.o. significantly inhibited vasopressin-induced ST depression of ECG in Donryu rats. This activity was about 5 times more potent than that of nifedipine and was long-lasting. (2) Palonidipine at 1 mg/kg, i.d. significantly inhibited ST depression induced by isoproterenol in Wistar rats. This activity of TC-81 was more potent than that of nifedipine. (3) Palonidipine at 3 micrograms/kg, i.v. produced an increase in regional myocardial tissue blood flow in the ischemic region of chronic coronary artery occluded dogs. (4) In isolated dog coronary artery, palonidipine at a concentration of 10(-10) M or greater inhibited the amplitude of 3,4-DAP-induced cyclic contractions in a concentration-dependent manner. This activity was 10-30 times more potent than that of nifedipine. (5) An intracoronary injection of endothelin (30 pmol/kg) reduced the coronary blood flow, subepicardial tissue blood flow, and subepicardial pH in anesthetized dogs. The ST elevation of ECG over 0.1 mV also occurred in 8 of 10 cases. In all the cases, ventricular extrasystoles were noted, and 9 out of 10 animals died. Pretreatment with palonidipine (3 micrograms/kg, i.v.) inhibited endothelin-induced ischemic changes, with a potency greater than that of nifedipine. These results suggest that palonidipine may be useful for the therapy of angina-pectoris.
Kishimoto
T
T
Pharmaceutical Development Research Laboratories, Teijin, Ltd., Tokyo, Japan.
Okamiya
Y
Y
Aoki
K
K
Ota
M
M
Hoshina
K
K
Takeshita
T
T
D000787:Angina Pectoris / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C074351:TC 81; D009543:Nifedipine