Department of Urology and Pharmacology, Health Sciences Center, Tulane University, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
Curr Pharm Des. 2010 May;16(14):1619-33. doi: 10.2174/138161210791164162.
Nitric oxide (NO)-sensitive soluble guanylyl cyclase (sGC) is the receptor that catalyzes the formation of the intracellular messenger cyclic guanosine monophosphate (cGMP). Binding of the physiological activator, NO, to the reduced heme moiety of sGC increases the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP) and engages crucial effector systems such as protein kinases, phosphodiesterases, and ion channels. The development of compounds that activate sGC independent of NO release has therapeutic implications. Recent studies have demonstrated the potential use of heme-dependent sGC stimulators (e.g. YC-1, BAY 41-2272, BAY 41-8543, BAY 63-2521, CFM-1571 and A-350619) and heme-independent sGC activators (e.g. BAY 58-2667, HMR-1766, S-3448, A-778935) in the treatment of cardiovascular diseases. Erectile dysfunction (ED) affects millions of men. Phosphodiesterase (PDE)-5 inhibitors, produce an NO-dependent increase in intracellular cGMP concentration, have been a successful approach in the treatment of ED. However, >30% of men with ED do not respond to PDE-5 inhibitor therapy, implying that endogenous NO production may be impaired to such an extent that inhibition of cGMP degradation produces no significant therapeutic advantage. Endogenous NO released from nitrergic nerves in the corpora cavernosa is significantly decreased in various conditions (e.g. diabetes, aging, and hypertension) and have reduced activation of the NO-sGC-cGMP pathway. It is conceivable that sGC stimulators and/or activators may be more effective than PDE5 inhibitors in the treatment of ED in such circumstances by improving NO-sGC-cGMP signaling and erectile function. This novel drug therapy approach for the treatment of ED shows promise.
一氧化氮（NO）-敏感的可溶性鸟苷酸环化酶（sGC）是催化细胞内信使环鸟苷酸（cGMP）形成的受体。NO 与 sGC 还原血红素部分结合，增加鸟苷三磷酸（GTP）转化为环鸟苷酸（cGMP），并激活关键效应系统，如蛋白激酶、磷酸二酯酶和离子通道。开发独立于 NO 释放激活 sGC 的化合物具有治疗意义。最近的研究表明，血红素依赖性 sGC 刺激剂（如 YC-1、BAY 41-2272、BAY 41-8543、BAY 63-2521、CFM-1571 和 A-350619）和血红素非依赖性 sGC 激活剂（如 BAY 58-2667、HMR-1766、S-3448、A-778935）在心血管疾病治疗中的潜在用途。勃起功能障碍（ED）影响着数以百万计的男性。磷酸二酯酶（PDE）-5 抑制剂通过增加细胞内 cGMP 浓度来产生 NO 依赖性作用，已成为治疗 ED 的成功方法。然而，>30%的 ED 男性对 PDE-5 抑制剂治疗无反应，这意味着内源性 NO 产生可能受损到抑制 cGMP 降解不会产生显著治疗优势的程度。在各种情况下（如糖尿病、衰老和高血压），海绵体中的 nitrergic 神经释放的内源性 NO 显著减少，并减少了 NO-sGC-cGMP 途径的激活。可以想象，在这种情况下，sGC 刺激剂和/或激活剂可能比 PDE5 抑制剂更有效，通过改善 NO-sGC-cGMP 信号转导和勃起功能来治疗 ED。这种治疗 ED 的新型药物治疗方法有很大的应用前景。
