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Effects of BH4 and statins on erectile function in diabetic rats

BH4和他汀类药物对糖尿病大鼠勃起功能的影响

基本信息

批准号：
14571487
负责人：
NISHIMATSU Hiroaki
金额：
$ 2.18万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571487/
关键词：
rat vivo model cavernous function nitric oxide synthase co-factor of NOS tetrahydrobiopterin statins NO合成蛋白臭化ビオプリテン NOS活性

项目摘要

Tetrahydrobiopterin is not only known as the rescue cofactor of as the co-factor of Hyperphenylalaninemia, also nitiric oxide synthase, like calmodulin. The statin drugs are essentially the HMG-CoA reductase inhibitors, which were introduced to lower serum lipid levels, ostensibly to prevent coronary heart disease (CVD). Statins improve endothelial function by upregulating endothelial nitric oxide (NO) production that is mediated by inhibiting the isoprenylation of rho GTPase. Withdrawal of statin treatment could suppress endothelial NO production and may impair vascular function. We have reported that adrenomedullin (AM)-induced vasodilation is at least in part nitric oxide (NO)-cGMP-dependent in the rat. Although it is well known that NO is much involved in the erectile function, it is controversial as to whether AM influences the erectile function. Thus, we examined the effects of BH4 and statins on intracavernous pressure (ICP) during penile erection. The left carotid artery of rats was cannulated to monitor of mean arterial pressure (MAP). Bipolar electrodes were positioned on the cavernous nerve. The right cavernous body was cannulated with a needle connected to a pressure transducer to monitor ICP. Electrical stimulation (ES) increased ICP in a voltage-dependent manner. Elevation of ICP continued during ES. The administarion of BH4 and statins by gavage significantly potentiated ES-induced increases in both maximal developed ICP/MAP and area under the curve (ICP trace ; AUC). Since BH4 slightly lowered MAP, ICP was normalized by MAP.i.v administration of N(omega)-nitro-L-arginine, a NO synthase inhibitor, markedly decreased BH4 or statin/AM/ES-induced ICP elevation. However, in the presence of E-4021, a cGMP-specific phosphodiesterase inhibitor, Statins further increased both ICP/MAP and AUC. These results suggest that a NO-cGMP pathway is involved in the regulation of these NOS activating drug-induced rat cavernous vasorelaxation.

四氢生物蝶呤不仅是高苯丙氨酸血症的辅助因子，也是一氧化氮合酶，如钙调蛋白。他汀类药物本质上是HMG-CoA还原酶抑制剂，用于降低血脂水平，表面上是为了预防冠心病（CVD）。他汀类药物通过抑制rho GTPase异戊二烯化介导的内皮细胞一氧化氮（NO）的产生，从而改善内皮功能。停用他汀类药物可抑制内皮细胞NO生成，损害血管功能。我们报道了肾上腺髓质素（AM）诱导的血管舒张在大鼠中至少部分依赖于一氧化氮(NO)- cgmp。虽然众所周知NO与勃起功能密切相关，但AM是否影响勃起功能仍存在争议。因此，我们研究了BH4和他汀类药物对阴茎勃起时海绵内压（ICP）的影响。取大鼠左颈动脉插管，监测平均动脉压（MAP）。双极电极放置在海绵状神经上。用一根连接压力传感器的针对右侧海绵体插管以监测颅内压。电刺激（ES）以电压依赖的方式增加ICP。ES期间ICP持续升高。灌胃给药BH4和他汀类药物可显著增强es诱导的最大发展ICP/MAP和曲线下面积（ICP trace； AUC）的增加。由于BH4轻微降低了MAP，因此通过给予NO合成酶抑制剂N(omega)-硝基- l -精氨酸（N(omega)-硝基- l -精氨酸）显著降低BH4或他汀类药物/AM/ es诱导的ICP升高，使MAP正常化。然而，当cgmp特异性磷酸二酯酶抑制剂E-4021存在时，他汀类药物进一步增加了ICP/MAP和AUC。提示NO-cGMP通路参与了NOS激活药物诱导的大鼠海绵体血管舒张的调控。