Interactions of a new beta-blocker, celiprolol, with the calcium antagonists, diltiazem and nifedipine, on atrioventricular conduction.
The influence of a new beta-blocker, celiprolol, on the direct dromotropic effects of the Ca antagonists, diltiazem and nifedipine, on atrioventricular (AV) conduction was estimated in the canine isolated, blood-perfused AV node preparation. Diltiazem (1-10 micrograms) and nifedipine (0.3-3 micrograms) injected i.a. into the AV node artery dose dependently prolonged the atrio-His (AH) interval (5-39 msec and 7-51 msec) in the AV mode preparation. When celiprolol (1 and 10 mg/kg) was given i.v. in the support dog, the AH interval in the AV node preparation was transiently shortened and then maintained constant as a control. These doses of i.v. celiprolol completely abolished the isoproterenol-induced decrease in the AH interval (28 msec at 0.03 microgram, i.a.) and AV nodal tachycardia. In the presence of celiprolol, the same doses of i.a. diltiazem and nifedipine increased the AH interval by the same amounts (6-43 msec and 8-53 msec) as the control. The incidence of second degree AV conduction block produced by diltiazem (2 in 5 AV node preparations at 10 micrograms) and nifedipine (2 in 6 preparations at 3 micrograms) was not changed by celiprolol. In the second experiments, diltiazem (30-300 micrograms/kg) and nifedipine (3-30 micrograms/kg), given i.v. in an open-chest in situ vagotomized dog, dose dependently increased AV conduction time (AVCT; 2-30 msec and 1-12 msec). Celiprolol 1 and 10 mg/kg i.v., which suppressed the isoproterenol-induced decrease in AVCT (32 msec at 0.3 mu/kg i.v.) and AV nodal tachycardia (4 in 6 in situ hearts), potentiated the prolongation of AVCT by the same doses of diltiazem (11-50 msec) and nifedipine (3-40 msec). The incidence of second degree AV conduction block produced by i.v., diltiazem (1 in 5 in situ hearts at 300 micrograms/kg) and nifedipine (0 in 6 in situ hearts at 30 micrograms/kg) was aggravated (4 in 5 and 3 in 6 in situ hearts) after i.v. celiprolol. These results indicate that although celiprolol does not affect the direct negative dromotropic effects of the Ca antagonists, AV block could easily be produced when celiprolol eliminates tonic adrenergic influences in vivo.
Motomura
S
S
Department of Pharmacology, Hirosaki University School of Medicine, Japan.
Hashimoto
K
K
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002036:Bundle of His / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D017272:Celiprolol / Q000008:administration & dosage / Q000494:pharmacology*; D004110:Diltiazem / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D006327:Heart Block; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009543:Nifedipine / Q000008:administration & dosage / Q000494:pharmacology*; D014628:Vagotomy
D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D017272:Celiprolol; D004110:Diltiazem; D009543:Nifedipine