Protective effect of bepridil against veratrine-induced contracture in rat atria.
In isolated stimulated rat atria, superfusion with veratrine caused a marked contracture (VIC) which was absent in calcium-free medium and which was inhibited by tetrodotoxin (IC50VIC of 1.38 microM). Lowering the extracellular calcium concentration from 2.5 to 0.5 or 0.1 mM reduced the veratrine-induced contracture and delayed its onset. Superfusion of bepridil (1-10 microM) for 60 min before and during veratrine exposure markedly slowed the onset of contracture, reduced the maximum response (IC50VIC = 2.11 microM) and facilitated recovery upon washout of the alkaloid. The direct negative inotropic effect (NIE) of bepridil (IC50NIE = 10.96 microM) resulted in an VIC/NIE ratio of 5.19 for this drug. The protective effects of bepridil were rate-independent and were not modified by the presence of atropine (1.4 microM) and propranolol (0.3 microM) in the medium. Diltiazem, verapamil and nifedipine only reduced veratrine-induced contracture at concentrations much higher than those producing a negative inotropic effect, giving them negative NIE/VIC ratios of 0.31, 0.08 and 0.08 respectively. Like bepridil, flunarizine had a positive NIE/VIC ratio (15.87, IC50VIC = 3.71 microM). The lack of effect of the quaternary derivative of bepridil CERM 11888 indicated that intracellular sites of action may be involved in the activity of bepridil on veratrine-induced contracture. Given that veratrine-induced changes may mimic some of the pathological changes occurring in ischaemia, the results suggest that bepridil and flunarizine may be more effective than L-type, slow calcium ion-channel blockers in protecting against calcium overload during ischaemia and reperfusion injury.
Leboeuf
J
J
RL-CERM, Department of Pharmacology, Riom, France.
Baissat
J
J
Massingham
R
R
D000818:Animals; D015764:Bepridil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D002118:Calcium / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology; D014702:Veratrine / Q000494:pharmacology*
C049474:11888CERM; D013779:Tetrodotoxin; D015764:Bepridil; D014702:Veratrine; D002118:Calcium