Effects of BH4 and statins on erectile function in diabetic rats

四氢生物蝶呤不仅是高苯丙氨酸血症的救援辅因子，也是与钙调蛋白类似的一氧化氮合酶。他汀类药物本质上是HMG-CoA还原酶抑制剂，被引入来降低血脂水平，表面上是为了预防冠心病(CVD)。他汀类药物通过上调内皮一氧化氮(NO)的产生来改善内皮功能，而一氧化氮的产生是通过抑制Rho GTP酶的异戊二烯基化而介导的。停用他汀类药物可抑制血管内皮细胞产生NO，并可能损害血管功能。我们已报道大鼠肾上腺髓质素(AM)诱导的血管扩张至少部分依赖于一氧化氮(NO)-cGMP。尽管众所周知，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过程中阴茎海绵体内压(ICP)的影响。大鼠左侧颈动脉插管监测平均动脉压(MAP)。在海绵体神经上放置双极电极。将针插入右侧海绵体，连接压力传感器监测颅内压。电刺激(ES)以电压依赖的方式增加颅内压。在ES期间，颅内压持续升高。灌胃给予BH4和他汀类药物可显著增强ES诱导的最大显影的ICPMAP和曲线下面积(ICPTRACE；AUC)的增加。静脉注射一氧化氮合酶抑制剂N(Omega)-硝基-L-精氨酸可显著降低BH_4或他汀类药物/AM/ES引起的颅内压升高。然而，在cGMP特异性磷酸二酯酶抑制剂E-4021的存在下，他汀类药物进一步增加了ICP/MAP和AUC。这些结果提示，NO-cGMP通路参与了这些一氧化氮合酶激活剂诱导的大鼠海绵体血管松弛的调节。

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.