Impaired Endothelin Calcium Signaling Coupled to Endothelin Type B Receptors in Penile Arteries from Insulin-Resistant Obese Zucker Rats
Impaired Endothelin Calcium Signaling Coupled to Endothelin Type B Receptors in Penile Arteries from Insulin-Resistant Obese Zucker Rats
复制标题
胰岛素耐受性肥胖扎克大鼠阴茎动脉中与内皮素 B 型受体耦合的内皮素钙信号受损
DOI：
10.1111/jsm.12234
复制
发表时间：
2013-09-01
影响因子：
3.5
通讯作者：
Prieto, Dolores
中科院分区：
文献类型：
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作者：
Contreras, Cristina;Sanchez, Ana;Prieto, Dolores
前言勃起功能障碍被认为是亚临床血管疾病和内皮功能障碍的早期征兆，在糖尿病患者中非常普遍。目的研究内皮素（ET）-1的血管效应受损是否可能导致胰岛素抵抗大鼠阴茎动脉血管功能障碍。方法采用胰岛素抵抗大鼠模型，观察内皮素受体（ETA）和内皮素受体（ETB）拮抗剂对阴茎动脉细胞内Ca 2+浓度的影响，并观察内皮素受体（ET）-1（ET-1）对血管内皮功能的影响。结果ET-1受体拮抗剂对大鼠阴茎动脉细胞内Ca 2+浓度的影响不明显，而对血管内皮功能的影响不明显[Ca ~（2+）]（i）和对ET-1的收缩反应，主要结果检测胰岛素抵抗大鼠阴茎动脉内皮素1（ET-1）[Ca 2 +]（i）、血管收缩和ET受体表达的变化。结果胰岛素抵抗大鼠阴茎动脉内皮素1（ET-1）[Ca 2 +]（i）、血管收缩和ET受体表达的变化与胰岛素抵抗大鼠阴茎动脉内皮素1（ET-1）[Ca 2 +]（i）、血管收缩和ET受体表达的变化有关。与LZR相比，OZR诱导的血管收缩与阴茎动脉平滑肌[Ca 2 +]（i）的更高增加相关。内皮细胞的去除抑制和增强收缩的最低和最高剂量的ET-1，分别，主要是在OZR。选择性ETA受体拮抗剂BQ-123抑制LZR和OZR的ET-1收缩血管和[Ca ~（2+）]（i）反应。ETB受体拮抗剂BQ-788对正常血管作用不大，但能明显抑制ET-1引起的[Ca ~（2+）]（i）升高和OZR引起的血管收缩。ETA受体分布于阴茎动脉的平滑肌和内皮细胞，ETB受体分布于LZR和OZR的动脉内皮细胞，OZR的平滑肌细胞也有ETB受体的表达，OZR的两种受体的免疫组化染色均高于LZR。结论OZR的阴茎动脉内皮细胞ET-1 Ca 2+信号沿着ET受体表达的改变。因此，尽管ET-1收缩和相关的[Ca 2 +]（i）增加是由健康动脉中的平滑肌ETA受体介导的，但ETB受体有助于收缩并在胰岛素抵抗条件下与增强的ET-1 [Ca 2 +]（i）反应偶联。Contreras C，Sanchez A，Martinez P，Climent B，Benedito S，Garcia-Sacristan A，埃尔南德斯M，和Prieto D.胰岛素抵抗肥胖Zucker大鼠阴茎动脉中内皮素钙信号传导与内皮素B型受体偶联受损J Sex Med 2013;10：2141-2153.
Introduction Erectile dysfunction is considered as an early sign of subclinical vascular disease and endothelial dysfunction and a highly prevalent condition in diabetic patients.Aim The current study assessed whether impaired vascular effects of endothelin (ET)-1 may contribute to the vascular dysfunction of penile arteries from a rat model of insulin resistance.Methods The effect of ETA and ETB receptor antagonists was assessed on the intracellular Ca2+ [Ca2+](i) and contractile responses to ET-1 in penile arteries from obese Zucker rats (OZR) and lean Zucker rats (LZR), and ET receptor expression in the arterial wall was assessed by immunohistochemistry.Main Outcome Measure Changes in ET-1 [Ca2+](i) and vasoconstriction and ET receptor expression were evaluated in penile arteries from insulin-resistant rats.Results ET-1-induced vasoconstriction was associated with a higher increase in smooth muscle [Ca2+](i) in penile arteries from OZR compared with LZR. Removal of the endothelium inhibited and enhanced contractions to the lowest and highest doses of ET-1, respectively, mainly in OZR. The selective ETA receptor antagonist BQ-123 inhibited ET-1 vasoconstriction and [Ca2+](i) response in both LZR and OZR. The ETB receptor antagonist BQ-788 had little effect in healthy arteries but markedly inhibited ET-1-induced increases in [Ca2+](i) and vasoconstriction in arteries from OZR. ETA receptors were located on the smooth muscle and endothelium of penile arteries, whereas ETB receptors were found on the arterial endothelium in LZR and OZR, and also on the smooth muscle in OZR, immunostaining for both receptors being higher in OZR.Conclusion Penile arteries from OZR exhibit an impaired ET-1 Ca2+ signaling along with changes in the ET receptor profile. Thus, whereas ET-1 contraction and the associated [Ca2+](i) increase are mediated by smooth muscle ETA receptors in healthy arteries, ETB receptors contribute to contraction and are coupled to the augmented ET-1 [Ca2+](i) response under conditions of insulin resistance. Contreras C, Sanchez A, Martinez P, Climent B, Benedito S, Garcia-Sacristan A, Hernandez M, and Prieto D. Impaired endothelin calcium signaling coupled to endothelin type B receptors in penile arteries from insulin-resistant obese Zucker rats. J Sex Med 2013;10:2141-2153.