Departamento de Fisiología, Facultad de Farmacia, Universidad de Valencia, Valencia, Spain.
Pharmacol Res. 2010 Jan;61(1):62-70. doi: 10.1016/j.phrs.2009.06.008. Epub 2009 Jun 30.
Cardiovascular disease is the major cause of morbidity and mortality in diabetic patients, which in turn is also associated with low levels of serum testosterone. The working hypothesis was that diabetes might modify the mechanisms involved in the vascular actions of testosterone in isolated rabbit carotid arteries. Testosterone (10(-8)-3x10(-4)M) induced a concentration-dependent relaxation of precontracted carotid arteries, which was higher in diabetic than in control rabbits. In control rabbits neither endothelium removal nor the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine (l-NOArg, 10(-5)M) modified the relaxant action of testosterone, and the cyclooxygenase (COX) inhibitor indomethacin (10(-5)M) enhanced this relaxation. In contrast, in diabetic rabbits endothelium removal, l-NOArg (10(-5)M) or indomethacin (10(-5)M) inhibited the testosterone induced relaxation. In arteries from diabetic rabbits, eNOS, iNOS and COX-2 expression and testosterone induced release of prostacyclin resulted enhanced in comparison with arteries from control rabbits. Testosterone (10(-4)M) strongly inhibited CaCl(2) (10(-5)-3x10(-2)M) concentration-related contractions of the carotid artery both in control and diabetic rabbits. These results suggest that testosterone relaxes the rabbit carotid artery by blocking the extracellular calcium entry. Diabetes enhances the vasodilator response of the rabbit carotid artery to testosterone by a mechanism that at least includes an increased modulatory activity of the endothelial nitric oxide and an augmented release of COX-2 vasodilator, prostacyclin rather than the absence of COX-1 vasoconstrictor, thromboxane A(2). The hypotestosteronemia observed in diabetic rabbits could be a consequence of the increased expression of iNOS and could contribute to the hyperreactivity of the rabbit carotid artery to testosterone.
心血管疾病是糖尿病患者发病率和死亡率的主要原因，而糖尿病患者的血清睾丸酮水平也较低。研究假设是糖尿病可能会改变血管中睾丸酮作用的相关机制，而这种作用在兔颈动脉中可以被分离出来。在预收缩的兔颈动脉中，睾丸酮（10(-8)-3x10(-4)M）浓度依赖性地诱导舒张，而糖尿病兔的舒张程度高于对照组。在对照组中，去除血管内皮或一氧化氮合酶（NOS）抑制剂 N(G)-硝基-L-精氨酸（l-NOArg，10(-5)M）均不改变睾丸酮的舒张作用，而环氧化酶（COX）抑制剂吲哚美辛（10(-5)M）增强了这种舒张作用。相反，在糖尿病兔中，去除血管内皮、l-NOArg（10(-5)M）或吲哚美辛（10(-5)M）抑制了睾丸酮诱导的舒张。与对照组相比，糖尿病兔的动脉内皮型一氧化氮合酶（eNOS）、诱导型一氧化氮合酶（iNOS）和 COX-2 的表达以及睾丸酮诱导的前列环素释放增强。在对照组和糖尿病兔中，睾丸酮（10(-4)M）均强烈抑制了颈动脉的钙离子依赖性收缩，浓度范围为 10(-5)-3x10(-2)M。这些结果表明，睾丸酮通过阻断细胞外钙离子内流来舒张兔颈动脉。糖尿病通过增加内皮一氧化氮的调节活性和增强 COX-2 血管舒张性前列腺素的释放来增强兔颈动脉对睾丸酮的血管舒张反应，而不是 COX-1 血管收缩性血栓素 A2 的缺失。糖尿病兔的低睾丸酮血症可能是 iNOS 表达增加的结果，并可能导致兔颈动脉对睾丸酮的高反应性。
