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I K independent class III actions of MS‐551 compared with sematilide and dofetilide during reperfusion in anaesthetized rats
Author(s) -
Chen Jianguang,
Komori Sadayoshi,
Li Binghong,
Tamura Kohji,
Hashimoto Keitaro
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15762.x
Subject(s) - dofetilide , heart rate , qt interval , medicine , cardiology , anesthesia , ventricular fibrillation , hemodynamics , mean arterial pressure , blood pressure
1 The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS‐551, sematilide and dofetilide, were examined in the coronary artery, ligation‐reperfusion model of pentobarbitone‐anaesthetized rats, a species deficient in functional cardiac I K . MS‐551 is a non‐selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel ( I K ) blockers. 2 Before coronary ligation, 3 and 10 mg kg −1 MS‐551 decreased the heart rate by 6% ( P < 0.01) and 12% ( P < 0.01), and increased mean arterial pressure (MAP) by 14% ( P < 0.05) and 33% ( P < 0.01), respectively. Sematilide at 10 and 30 mg kg −1 also decreased the heart rate by 4% ( P < 0.01) and 9% ( P < 0.01), respectively, and the higher dose of 30 mg kg −1 decreased MAP by 29% ( P < 0.01). Dofetilide, 1 mg kg −1 , decreased the heart rate ( P < 0.01), but had no significant effect on MAP. 3 The QT interval was increased by 10% ( P < 0.01) and 31% ( P < 0.01), when 3 and 10 mg kg −1 MS‐551 were given. Sematilide and dofetilide had no effect on the QT interval. 4 Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS‐551 at 3 and 10 mg kg −1 , reduced the incidence of lethal VF to 50% and 20% ( P < 0.05). Neither dofetilide 1 mg kg −1 nor sematilide (10 and 30 mg kg −1 ) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion‐induced VT or the total incidence of VF. However, 10 mg kg −1 MS‐551 delayed the onset of reperfusion‐induced VF (27 ± 5 s compared with 12 ± 2 s of the control group, P < 0.05). 5 In conclusion, in rats which are deficient in cardiac I K MS‐551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than I K might participate in the defibrillatory effect of MS‐551. Sematilide and dofetilide, which are selective I K blockers, did not increase the QT interval nor did they show antiarrhythmic effects. Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.