Testosterone protects rat hearts against ischaemic insults by enhancing the effects of α1‐adrenoceptor stimulation

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Abstract
Background and purpose: Testosterone alleviates symptoms in patients with ischaemic heart disease. Androgen receptors are present in the heart, and testosterone upregulates gene expression of cardiac β1‐adrenoceptors. We hypothesize that testosterone may confer cardioprotection by interacting with adrenoceptors.Experimental approach: In isolated perfused hearts and ventricular myocytes from orchidectomized rats without or with testosterone (200 μg/100 g) replacement, we first determined the effect of ischaemia/reperfusion in the presence of noradrenaline (10−7 M). Then we determined the contribution of interactions between testosterone and α1‐ or β1‐adrenoceptors in cardiac injury/protection (infarct size, release of lactate dehydrogenase, viability of myocytes, recovery of contractile function and incidence of arrhythmias) upon ischaemia/reperfusion by pharmacological manipulation using selective adrenoceptor agonists (α1‐adrenoceptor agonist: phenylephrine 10−6 M; non‐selective β‐adrenoceptor agonist: isoprenaline 10−7 M) and antagonists (α1: prazosin or benoxathian 10−6 M; β1: CGP 20712A 5 × 10−7 M). We also determined the expression of α1and β1‐adrenoceptor in the hearts from rats with and without testosterone.Key results: Testosterone reduced injury induced by ischaemia/reperfusion and noradrenaline. This was achieved by enhancing the beneficial effect of α1‐adrenoceptor stimulation, which was greater than the deleterious effect of β1‐adrenoceptor stimulation (also enhanced by testosterone). The effects of testosterone were abolished or attenuated by blockade of androgen receptors. Testosterone also enhanced the expression of α1Aand β1‐adrenoceptor.Conclusions and implications: Testosterone conferred cardioprotection by upregulating the cardiac α1‐adrenoceptor and enhancing the effects of stimulation of this adrenoceptor. The effect of testosterone was at least partly mediated by androgen receptors.British Journal of Pharmacology(2008)153, 693–709; doi:10.1038/sj.bjp.0707624; published online 24 December 2007