Yohimbine Promotes Cardiac NE Release and Prevents LPS-Induced Cardiac Dysfunction via Blockade of Presynaptic α(2A)-Adrenergic Receptor

Myocardial depression is an important contributor to mortality in sepsis. We have recently demonstrated that α(2)-adrenoceptor (AR) antagonist, yohimbine (YHB), attenuates lipopolysaccharide (LPS)-induced myocardial depression. However, the mechanisms for this action of YHB are unclear. Here, we demonstrated that YHB decreased nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) levels in the myocardium and plasma, attenuated cardiac and hepatic dysfunction, but not kidney and lung injuries in endotoxemic mice. Immunohistochemical analysis revealed that cardiac α(2A)-AR was mostly located in sympathetic nerve presynaptic membrane; YHB decreased cardiac α(2A)-AR level and promoted cardiac norepinephrine (NE) release in endotoxemic mice. Reserpine that exhausted cardiac NE without markedly decreasing plasma NE level abrogated the inhibitory effects of YHB on cardiac TNF-α and iNOS expression as well as cardiac dysfunction, but not the suppressive effects of YHB on plasma TNF-α and NO elevation in LPS-challenged mice. Furthermore, both reserpine and YHB significantly inhibited LPS-induced myocardial apoptosis. α(1)-AR, β(2)-AR, but not β(1)-AR antagonists reversed the inhibitory effect of YHB on LPS-stimulated myocardial apoptosis. However, β(1)-AR antagonist attenuated LPS-caused cardiomyocyte apoptosis, partly abolished the protective effect of YHB on the left ventricular ejection fraction in endotoxemic mice. Altogether, these findings indicate that YHB attenuates LPS-induced cardiac dysfunction, at least in part, through blocking presynaptic α(2A)-AR and thus increasing cardiac NE release. YHB-elevated cardiac NE improves cardiac function via suppressing cardiac iNOS and TNF-α expression, activating β(1)-AR and inhibiting cardiomyocyte apoptosis through α(1)- and β(2)-AR in endotoxemic mice. However, cardiac β(1)-AR activation promotes LPS-induced cardiomyocyte apoptosis.