Boerrigter Guido, Burnett John C
Cardiorenal Research Laboratory, Mayo Clinic, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Cardiovasc Drug Rev. 2007 Spring;25(1):30-45. doi: 10.1111/j.1527-3466.2007.00003.x.
The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5'-guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular regulation by promoting vasodilation and inhibiting vascular smooth muscle cell growth, platelet aggregation, and leukocyte adhesion. In pathophysiological states with endothelial dysfunction this signaling pathway is impaired. Activation of sGC has traditionally been achieved with nitrovasodilators; however, these drugs are associated with the development of tolerance and potentially deleterious cGMP-independent actions. In this review the actions of BAY 41-2272, the prototype of a new class of NO-independent sGC stimulators, in cardiovascular disease models is discussed. BAY 41-2272 binds to a regulatory site on the alpha-subunit of sGC and stimulates the enzyme synergistically with NO. BAY 41-2272 had antihypertensive actions and attenuated remodeling in models of systemic arterial hypertension. It also unloaded the heart in experimental congestive heart failure. BAY 41-2272 reduced pulmonary vascular resistance in acute and chronic experimental pulmonary arterial hypertension. Furthermore, BAY 41-2272 inhibited platelet aggregation in vitro and leukocyte adhesion in vivo. These findings make direct sGC stimulation with BAY 41-2272 a promising new therapeutic strategy for cardiovascular diseases and warrant further studies. Finally, the significance of the novel NO- and heme-independent sGC activator BAY 58-2667, which activates two forms of NO-insensitive sGC, is briefly discussed.
一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）途径在心血管调节中发挥着重要作用，它可促进血管舒张，并抑制血管平滑肌细胞生长、血小板聚集和白细胞黏附。在内皮功能障碍的病理生理状态下，该信号通路会受损。传统上，sGC的激活是通过硝基血管扩张剂实现的；然而，这些药物会导致耐受性的产生以及潜在的有害非cGMP依赖性作用。在这篇综述中，将讨论新型非NO依赖性sGC刺激剂的原型BAY 41-2272在心血管疾病模型中的作用。BAY 41-2272与sGCα亚基上的一个调节位点结合，并与NO协同刺激该酶。BAY 41-2272在系统性动脉高血压模型中具有降压作用并减轻了重塑。它还能在实验性充血性心力衰竭中减轻心脏负担。BAY 41-2272可降低急性和慢性实验性肺动脉高压中的肺血管阻力。此外，BAY 41-2272在体外可抑制血小板聚集，在体内可抑制白细胞黏附。这些发现使得用BAY 41-2272直接刺激sGC成为一种有前景的心血管疾病新治疗策略，值得进一步研究。最后，还简要讨论了新型非NO和血红素依赖性sGC激活剂BAY 58-2667的意义，它可激活两种形式的对NO不敏感的sGC。
