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Facilitation of ischaemia‐induced ventricular fibrillation by catecholamines is mediated by β 1 and β 2 agonism in the rat heart in vitro
Author(s) -
Wilder Catherine D E,
Pavlaki Nikoleta,
Dursun Tutku,
Gyimah Paul,
CaldwellDunn Ellice,
Ranieri Antonella,
Lewis Hannah R,
Curtis Michael J
Publication year - 2018
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/bph.14176
Subject(s) - medicine , atenolol , cardiology , ischemia , ventricular fibrillation , ventricular tachycardia , anesthesia , blood pressure
Background and Purpose Antiarrhythmic β‐blockers are used in patients at risk of myocardial ischaemia, but the survival benefit and mechanisms are unclear. We hypothesized 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 (CATs: 313 nM noradrenaline + 75 nM adrenaline) in a blinded and randomized 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 did not affect VF at concentrations with β 1 ‐, β 2 ‐ or α 1 ‐ adrenoceptor specificity and selectivity (confirmed in separate rat aortae myography experiments). In hearts with small IZs and 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, 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 β 1 ‐ and β 2 ‐ but not α 1 ‐adrenoceptor involvement (confirmed by immunoblot analysis of downstream phosphoproteins). 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 β 1 ‐ and β 2 ‐ adrenoceptors 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.