Verapamil has antiarrhythmic effects that are mediated in brain through endogenous opioids.
The purpose of this study was to examine the hypothesis that the calcium channel blocker verapamil modulates catecholamine-induced arrhythmias in brain and to explore potential mechanisms of action. Wistar rats with catheters previously inserted in the lateral cerebral ventricle and femoral artery received verapamil 10 or 50 micrograms/kg or the diluent (intracerebroventricularly, i.c.v.) into the lateral cerebral ventricle. Epinephrine was infused to produce arrhythmias. Onset of ventricular arrhythmias, premature ventricular complexes (PVCs), occurred at a significantly (p < 0.05) higher epinephrine dose after the higher dose of verapamil. Development of fatal arrhythmias, mainly ventricular tachyarrhythmias, occurred at significantly (p < 0.05) higher epinephrine concentrations with verapamil 50 micrograms/kg i.c.v. as compared with controls. Comparison of the two enantiomers of verapamil (50 micrograms/kg i.c.v.) showed that S(-)verapamil had the same effect as the racemic mixture whereas R(+)verapamil was intermediate between the control and S(-)verapamil. The antiarrhythmic action of verapamil could not be explained by alteration of the blood pressure (BP) response to epinephrine. Endogenous opioids were implicated in this action of verapamil because the (-)enantiomer of naloxone, which is an opioid antagonist, significantly (p < 0.05) antagonized the antiarrhythmic effects of centrally administered verapamil to suppress epinephrine-induced arrhythmias. In contrast the (+)enantiomer of naloxone did not alter verapamil-induced increase in arrhythmia threshold. Pretreatment with pertussis toxin i.c.v. antagonized the effects of verapamil. Verapamil did not alter the cyclic AMP response to isoproterenol in lymphocytes isolated from Wistar rats not exposed to any other drugs.(ABSTRACT TRUNCATED AT 250 WORDS)
Rabkin
S W
SW
University of British Columbia, Vancouver, Canada.
D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000037:antagonists & inhibitors*; D019204:GTP-Binding Proteins / Q000502:physiology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D010566:Virulence Factors, Bordetella; D014700:Verapamil; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D004837:Epinephrine