Wilder, CDE;
Pavlaki, N;
Dursun, T;
Gyimah, P;
Caldwell-Dunn, E;
Ranieri, A;
Lewis, HR;
(2018)
Facilitation of ischaemia‐induced ventricular fibrillation by catecholamines is mediated by β1 and β2 agonism in the rat heart in vitro.
British Journal of Pharmacology
, 175
(10)
pp. 1669-1690.
10.1111/bph.14176.
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Abstract
BACKGROUND & PURPOSE: Antiarrhythmic β-blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesised that β-blockers do not prevent ventricular fibrillation (VF), but instead inhibit the ability of catecholamines to facilitate ischaemia-induced VF, limiting the scope of their usefulness. EXPERIMENTAL APPROACH: ECGs were analysed from ischaemic Langendorff-perfused rat hearts perfused with adrenoceptor antagonists and/or exogenous catecholamines (313 nM noradrenaline+75 nM adrenaline; CATs) in a blinded and randomised study. Ischaemic zone (IZ) size was deliberately made small or large. KEY RESULTS: In rat hearts with large IZs, ischaemia-induced VF incidence was high in controls. Atenolol, butoxamine and trimazosin had no effect on VF at concentrations with β1, β2or α1adrenoceptor specificity and selectivity, respectively (shown in separate rat aortae myography experiments). In hearts with small IZs and a low baseline incidence of ischaemia-induced VF, CATs, delivered to the uninvolved zone (UZ), increased ischaemia-induced VF incidence. This effect was not mimicked by atrial pacing, and hence not due to sinus tachycardia. However, the CATs-facilitated increase in ischaemia-induced VF was inhibited by atenolol and butoxamine (but not trimazosin), indicative of β1and β2but not α1adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). Furthermore, CATs did not facilitate VF in low-flow globally ischaemic hearts, which have no UZ. CONCLUSIONS AND IMPLICATIONS: Catecholamines facilitated ischaemia-induced VF when risk was low, acting via β1and β2adrenoceptors located in the UZ. There was no scope for facilitation when VF risk was high (large IZ), which may explain why β-blockers have equivocal effectiveness in humans.
| Type: | Article |
|---|---|
| Title: | Facilitation of ischaemia‐induced ventricular fibrillation by catecholamines is mediated by β1 and β2 agonism in the rat heart in vitro |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bph.14176 |
| Publisher version: | https://doi.org/10.1111/bph.14176 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Adrenaline, adrenergic, arrhythmia, myocardial ischaemia, noradrenaline, ventricular fibrillation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10044912 |
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