Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart

A. Farkas, Aasim Qureshi, Michael J. Curtis

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

1. Mibefradil was compared with (±)-verapamil for effects on ischaemia- and reperfusion-induced ventricular fibrillation (VF), and the role of ischaemia-selective L-channel block was examined. Langendorff perfused rat hearts (n = 12/group) were used. 2. Neither drug at up to 100 nM reduced the incidence of VF during 30 min regional ischaemia. 300 and 600 nM (±)-verapamil abolished VF (P <0.05); mibefradil was effective only at 600 nM (P <0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (±)-verapamil (P <0.05). Both drugs at ≥ 100 nM increased coronary flow (P <0.05) with a similar potency and maximum effectiveness. 3. In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affected ventricular contractility. With K+ raised to 6 mM, (±)-verapamil ≥ 30 nM reduced developed pressure (P <0.05); mibefradil did so only at 600 nM (P <0.05). With K+ raised to 10 mM the effects of (±)-verapamil were further increased (P <0.05) and mibefradil became active at ≥ 100 nM (P <0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (±)-verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each drug at ≥ 30 nM (P <0.05) indicating a marked vascular:myocardial selectivity. 4. In conclusion, mibefradil differed from (±)-verapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (±)-verapamil.

Original languageEnglish
Pages (from-to)41-50
Number of pages10
JournalBritish Journal of Pharmacology
Volume128
Issue number1
DOIs
Publication statusPublished - 1999

Fingerprint

Mibefradil
Verapamil
Ventricular Fibrillation
Reperfusion
Ischemia
Pharmaceutical Preparations
Blood Vessels
Incidence
Vasodilation
Hypotension
Cardiac Arrhythmias
Myocardium
Pressure

Keywords

  • ECG, electrocardiogram
  • VF, ventricular fibrillation
  • VPB, ventricular premature beat
  • VT, ventricular tachycardia

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{ccd7df9b3f9242c9b3f34ee1b153510e,
title = "Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart",
abstract = "1. Mibefradil was compared with (±)-verapamil for effects on ischaemia- and reperfusion-induced ventricular fibrillation (VF), and the role of ischaemia-selective L-channel block was examined. Langendorff perfused rat hearts (n = 12/group) were used. 2. Neither drug at up to 100 nM reduced the incidence of VF during 30 min regional ischaemia. 300 and 600 nM (±)-verapamil abolished VF (P <0.05); mibefradil was effective only at 600 nM (P <0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (±)-verapamil (P <0.05). Both drugs at ≥ 100 nM increased coronary flow (P <0.05) with a similar potency and maximum effectiveness. 3. In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affected ventricular contractility. With K+ raised to 6 mM, (±)-verapamil ≥ 30 nM reduced developed pressure (P <0.05); mibefradil did so only at 600 nM (P <0.05). With K+ raised to 10 mM the effects of (±)-verapamil were further increased (P <0.05) and mibefradil became active at ≥ 100 nM (P <0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (±)-verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each drug at ≥ 30 nM (P <0.05) indicating a marked vascular:myocardial selectivity. 4. In conclusion, mibefradil differed from (±)-verapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (±)-verapamil.",
keywords = "ECG, electrocardiogram, VF, ventricular fibrillation, VPB, ventricular premature beat, VT, ventricular tachycardia",
author = "A. Farkas and Aasim Qureshi and Curtis, {Michael J.}",
year = "1999",
doi = "10.1038/sj.bjp.0702778",
language = "English",
volume = "128",
pages = "41--50",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Inadequate ischaemia-selectivity limits the antiarrhythmic efficacy of mibefradil during regional ischaemia and reperfusion in the rat isolated perfused heart

AU - Farkas, A.

AU - Qureshi, Aasim

AU - Curtis, Michael J.

PY - 1999

Y1 - 1999

N2 - 1. Mibefradil was compared with (±)-verapamil for effects on ischaemia- and reperfusion-induced ventricular fibrillation (VF), and the role of ischaemia-selective L-channel block was examined. Langendorff perfused rat hearts (n = 12/group) were used. 2. Neither drug at up to 100 nM reduced the incidence of VF during 30 min regional ischaemia. 300 and 600 nM (±)-verapamil abolished VF (P <0.05); mibefradil was effective only at 600 nM (P <0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (±)-verapamil (P <0.05). Both drugs at ≥ 100 nM increased coronary flow (P <0.05) with a similar potency and maximum effectiveness. 3. In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affected ventricular contractility. With K+ raised to 6 mM, (±)-verapamil ≥ 30 nM reduced developed pressure (P <0.05); mibefradil did so only at 600 nM (P <0.05). With K+ raised to 10 mM the effects of (±)-verapamil were further increased (P <0.05) and mibefradil became active at ≥ 100 nM (P <0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (±)-verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each drug at ≥ 30 nM (P <0.05) indicating a marked vascular:myocardial selectivity. 4. In conclusion, mibefradil differed from (±)-verapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (±)-verapamil.

AB - 1. Mibefradil was compared with (±)-verapamil for effects on ischaemia- and reperfusion-induced ventricular fibrillation (VF), and the role of ischaemia-selective L-channel block was examined. Langendorff perfused rat hearts (n = 12/group) were used. 2. Neither drug at up to 100 nM reduced the incidence of VF during 30 min regional ischaemia. 300 and 600 nM (±)-verapamil abolished VF (P <0.05); mibefradil was effective only at 600 nM (P <0.05). Reperfusion-induced VF incidence was reduced only by 600 nM (±)-verapamil (P <0.05). Both drugs at ≥ 100 nM increased coronary flow (P <0.05) with a similar potency and maximum effectiveness. 3. In separate hearts perfused with Krebs' solution containing 3 mM K+ (the same as that used for arrhythmia studies) neither drug at up to 600 nM affected ventricular contractility. With K+ raised to 6 mM, (±)-verapamil ≥ 30 nM reduced developed pressure (P <0.05); mibefradil did so only at 600 nM (P <0.05). With K+ raised to 10 mM the effects of (±)-verapamil were further increased (P <0.05) and mibefradil became active at ≥ 100 nM (P <0.05). Likewise both drugs impaired diastolic relaxation, with raised K+ exacerbating the effects and (±)-verapamil being more potent and its effects more greatly exacerbated by K+. In contrast, when K+ was normal (3 mM), coronary flow was increased by each drug at ≥ 30 nM (P <0.05) indicating a marked vascular:myocardial selectivity. 4. In conclusion, mibefradil differed from (±)-verapamil in its myocardial effects only in terms of its lower potency. As mibefradil is the more potent T-channel blocker, the T-channel is unlikely to represent the molecular target for these effects. The K+ elevations that occur in the ischaemic milieu determine the ability of both drugs to block myocardial L-channels; this is sufficient to account for the drugs' actions on VF. Neither drug possesses sufficient selectivity for ischaemic myocardium versus blood vessels to permit efficacy (VF suppression without marked vasodilatation) and so inappropriate hypotension is likely to preclude the safe use of mibefradil (or similar analogue) in VF suppression, and explains the lack of clinical effectiveness of (±)-verapamil.

KW - ECG, electrocardiogram

KW - VF, ventricular fibrillation

KW - VPB, ventricular premature beat

KW - VT, ventricular tachycardia

UR - http://www.scopus.com/inward/record.url?scp=0032859737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032859737&partnerID=8YFLogxK

U2 - 10.1038/sj.bjp.0702778

DO - 10.1038/sj.bjp.0702778

M3 - Article

C2 - 10498833

AN - SCOPUS:0032859737

VL - 128

SP - 41

EP - 50

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 1

ER -