Yohimbine Promotes Cardiac NE Release and Prevents LPS-Induced Cardiac Dysfunction via Blockade of Presynaptic α2A-Adrenergic Receptor

Abstract

Myocardial depression is an important contributor to mortality in sepsis. We have recently demonstrated that α2-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 α2A-AR was mostly located in sympathetic nerve presynaptic membrane; YHB decreased cardiac α2A-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. α1-AR, β2-AR, but not β1-AR antagonists reversed the inhibitory effect of YHB on LPS-stimulated myocardial apoptosis. However, β1-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 α2A-AR and thus increasing cardiac NE release. YHB-elevated cardiac NE improves cardiac function via suppressing cardiac iNOS and TNF-α expression, activating β1-AR and inhibiting cardiomyocyte apoptosis through α1- and β2-AR in endotoxemic mice. However, cardiac β1-AR activation promotes LPS-induced cardiomyocyte apoptosis.

Montelukast attenuates lipopolysaccharide-induced cardiac injury in rats

“…There is good evidence that overproduction of TNF-a is involved in the development of LPS-induced organ dysfunction. 35 In the present study, LPS caused the appearance of some TNF-aimmunstained areas in the myocardiocytes reflecting severe inflammatory response. MNT (20 mg/kg) treatment resulted in absence of positive staining by TNF-a, reflecting the absence of inflammatory response, while treatment of LPS rats with MNT (10 mg/kg) revealed a mild cardiac affection.…”

Dexmedetomidine protects against acute kidney injury through downregulating inflammatory reactions in endotoxemia rats

“…Rats were pretreated with DEX (10 µg/kg; Jiangsu Hengrui Medicine Co., Ltd., Lianyungang, Jiangsu, China) 10 min before LPS injection (15). A unique α-2-adrenergic receptor antagonist, YOH (1 mg/kg; Sigma Aldrich), was injected intraperitoneally 30 min before DEX exposure (16). All the rats were sacrificed 4 h later.…”

Extending In Silico Mechanism-of-Action Analysis by Annotating Targets with Pathways: Application to Cellular Cytotoxicity Readouts

“…Implication of ADRA receptors in apoptotic mechanisms is indeed supported by literature: Brimonidine, an ADRA2 agonist, has a protective action against apoptosis induced by glutamate and H 2 O 2 in spiral ganglion neurons, which can be reversed by the ADRA2 antagonist yohimbine [113]. On the other hand, yohimbine has been associated with protection from myocardial apoptosis in mice presenting cardiac dysfunction through multiple mechanisms involving inhibition of ADRA2 [114]. Although these two pieces of evidences might seem contrasting, the different tissues in which the measurements were carried out Table 5.…”