Testosterone protects rat hearts against ischaemic insults by enhancing the effects of α 1 ‐adrenoceptor stimulation

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 β 1 ‐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 α 1 ‐ or β 1 ‐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 (α 1 ‐adrenoceptor agonist: phenylephrine 10 −6   M ; non‐selective β‐adrenoceptor agonist: isoprenaline 10 −7   M ) and antagonists (α 1 : prazosin or benoxathian 10 −6   M ; β 1 : CGP 20712A 5 × 10 −7   M ). We also determined the expression of α 1 and β 1 ‐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 α 1 ‐adrenoceptor stimulation, which was greater than the deleterious effect of β 1 ‐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 α 1A and β 1 ‐adrenoceptor. Conclusions and implications: Testosterone conferred cardioprotection by upregulating the cardiac α 1 ‐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