Effects of BH4 and statins on erectile function in diabetic rats

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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.