Department of Cardiovascular Medicine, First Affiliated Hospital, Harbin Medical University, Harbin 150001, China.
Eur J Pharmacol. 2009 Oct 1;619(1-3):68-74. doi: 10.1016/j.ejphar.2009.07.023. Epub 2009 Aug 6.
The current study was designed to determine whether castration with or without testosterone replacement resulted in changes in cardiac sympathetic nerve activity in rats with heart failure induced by isoproterenol. At eight weeks post-castration, dysfunction of the cardiac sympathetic nerve system was aggravated as indicated by elevated plasma norepinephrine, reduced myocardial norepinephrine content and tyrosine hydroxylase (TH) protein. These effects of castration were reversed by testosterone replacement, as indicated by decreased plasma norepinephrine, increased myocardial norepinephrine and density of TH-labeled nerve fibers, as well as by an upregulated expression of myocardial TH protein. We also explored whether the neuroprotective effect of testosterone was influenced by the antiandrogen, flutamide. Interestingly, flutamide failed to block these testosterone-induced neuroprotective effects on the cardiac sympathetic nervous system in castrated rats with heart failure. These results provide the first evidence that endogenous testosterone deprivation in rats significantly worsened cardiac sympathetic function during pathophysiological changes associated with heart failure, and testosterone replacement reversed these adverse effects. These neuroprotective effects of testosterone, may, in part, be mediated through an upregulation in TH protein, but do not appear to involve the androgen receptor. Therefore, androgens may play an important role in modulating pathophysiological changes in the cardiac sympathetic nervous system that result from heart failure and our findings suggest the potential for beneficial effects of testosterone in the treatment of this condition.
本研究旨在确定去势伴或不伴睾酮替代治疗是否会导致异丙肾上腺素诱导心力衰竭大鼠心脏交感神经活性发生变化。去势 8 周后，血浆去甲肾上腺素升高，心肌去甲肾上腺素含量和酪氨酸羟化酶（TH）蛋白减少，表明心脏交感神经系统功能障碍加重。这些去势的影响可被睾酮替代逆转，表现为血浆去甲肾上腺素减少，心肌去甲肾上腺素和 TH 标记神经纤维密度增加，以及心肌 TH 蛋白表达上调。我们还探讨了抗雄激素氟他胺是否会影响睾酮的神经保护作用。有趣的是，氟他胺未能阻断心力衰竭去势大鼠中睾酮对心脏交感神经系统的这些神经保护作用。这些结果首次提供证据表明，内源性睾酮剥夺在与心力衰竭相关的病理生理变化期间显著加重大鼠心脏交感功能，而睾酮替代可逆转这些不利影响。睾酮的这些神经保护作用可能部分通过 TH 蛋白的上调介导，但似乎不涉及雄激素受体。因此，雄激素可能在调节心力衰竭引起的心脏交感神经系统的病理生理变化中发挥重要作用，我们的研究结果表明睾酮在治疗这种疾病方面具有潜在的有益作用。
