Facilitation of ischaemia-induced ventricular fibrillation by catecholamines is mediated by β and β agonism in the rat heart in vitro.

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 -, β - or α - 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 - and β - but not α -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 - and β - 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.