| Autor: |
Wilder, Catherine D. E., Pavlaki, Nikoleta, Dursun, Tutku, Gyimah, Paul, Caldwell‐Dunn, Ellice, Ranieri, Antonella, Lewis, Hannah R., Curtis, Michael J., Caldwell-Dunn, Ellice |
| Předmět: |
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| Zdroj: |
British Journal of Pharmacology; May2018, Vol. 175 Issue 10, p1669-1690, 22p, 1 Color Photograph, 1 Black and White Photograph, 1 Chart, 13 Graphs |
| Abstrakt: |
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 β1 -, β2 - or α1 - 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 β1 - and β2 - but not α1 -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 β1 - and β2 - 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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