Protective effect of bepridil against veratrine-induced contracture in rat atria.

Abstract

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.

• Authors: J Leboeuf, J Baissat, R Massingham
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 216 Issue 2 Pg. 183-9 (Jun 05 1992) ISSN: 0014-2999 [Print] Netherlands
• PMID: 1397005 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 11888CERM
• Tetrodotoxin
• Bepridil
• Veratrine
• Calcium

Topics

• Animals
• Bepridil (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Calcium (pharmacology)
• Cardiac Pacing, Artificial
• Heart Atria (drug effects)
• Heart Rate (drug effects)
• Male
• Muscle, Smooth, Vascular (drug effects)
• Myocardial Contraction (drug effects)
• Perfusion
• Rats
• Rats, Wistar
• Tetrodotoxin (pharmacology)
• Veratrine (pharmacology)