Bradycardic effects of AQ-A 39 (falipamil) in situ and in isolated, blood-perfused dog hearts. Comparison with alinidine and verapamil.
The cardiovascular effects of a specific bradycardic agent, AQ-A 39, were investigated in intact donor dogs and isolated and cross-perfused dog heart preparations. Intravenous administration of AQ-A 39 (10-1000 micrograms/kg) to the donor dog caused a dose-dependent heart rate decrease in the donor dog and a decreased atrial rate in the isolated atrium perfused by the donor's blood. The arterial blood pressure of the donor dog and contractile force of the atrial preparation were unchanged or slightly decreased. The direct injection of AQ-A (1-300 micrograms) into the sinus node artery of the isolated atrium caused dose-dependent negative chronotropic and slight, transient positive inotropic responses. Alinidine and verapamil caused marked negative chronotropic and inotropic responses. The negative chronotropic effect of AQ-A 39 was not modified by atropine. However, it was enhanced slightly but significantly by propranolol, indicating that AQ-A 39-induced bradycardia was antagonized partly by beta-adrenoceptor function. These results confirmed that AQ-A 39 selectively reduced sinus rate by a direct action on the sinus node. Furthermore, the potency of the bradycardiac action, compared with the decrease in contractility, was greater than for alinidine or verapamil. AQ-A 39 (300 micrograms) tended to depress norepinephrine (NE)-induced positive chronotropic but not inotropic effects in isolated atria. By contrast, verapamil (3-10 micrograms) significantly depressed the NE-induced positive inotropic but not the chronotropic effect, and propranolol (10 micrograms) suppressed both cardiac effects of NE. These data suggest that the AQ-A 39-induced, selective attenuation of the NE-induced chronotropic effect is not due to either calcium channel blockade or beta-adrenoceptor antagonism.
Ogiwara
Y
Y
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto, Japan.
Furukawa
Y
Y
Akahane
K
K
Haniuda
M
M
Chiba
S
S
D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D006325:Heart Atria; D006339:Heart Rate / Q000187:drug effects*; D054833:Isoindoles; D009200:Myocardial Contraction / Q000187:drug effects; D010797:Phthalimides / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology*
D002317:Cardiovascular Agents; D054833:Isoindoles; D010797:Phthalimides; D014700:Verapamil; C022192:alinidine; D003000:Clonidine; C030532:falipamil