Kass David A, Takimoto Eiki, Nagayama Takahiro, Champion Hunter C
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.
Cardiovasc Res. 2007 Jul 15;75(2):303-14. doi: 10.1016/j.cardiores.2007.02.031. Epub 2007 Mar 2.
Nitric oxide regulation of the cardiovascular system involves both cGMP-dependent and independent mechanisms. The former directly interacts with the family of catabolic phosphodiesterases (PDEs) that control cGMP levels and thus distal effects such as protein kinase G stimulation. Growing evidence supports an important role of several PDEs, including PDE1, PDE2, and PDE5, in the regulation of cGMP in both vascular smooth muscle and cardiac myocytes. These PDEs have relatively little impact on resting function, but they can potently modulate acute contractile tone in cells stimulated by external agonists such as angiotensin or catecholamines. Regulation by PDEs is compartmentalized, with selective interactions occurring between a given source of cGMP and PDE hydrolysis. PDE1 and/or PDE5 are also reportedly up-regulated in chronic disease conditions such as atherosclerosis or cardiac pressure-load stress and heart failure as well as in response to long-term exposure to nitrates. Such up-regulation is thought to contribute to vascular and cardiac pathophysiology and to drug tolerance. Recent studies utilizing selective PDE5 inhibitors support significant cross-signaling with NO-cGMP synthetic pathways that may be particularly helpful in treating certain disease states.
一氧化氮对心血管系统的调节涉及cGMP依赖性和非依赖性机制。前者直接与控制cGMP水平的分解代谢磷酸二酯酶（PDEs）家族相互作用，从而产生诸如刺激蛋白激酶G等远端效应。越来越多的证据支持几种PDEs，包括PDE1、PDE2和PDE5，在血管平滑肌和心肌细胞中cGMP调节方面发挥重要作用。这些PDEs对静息功能影响相对较小，但它们能有效调节由血管紧张素或儿茶酚胺等外部激动剂刺激的细胞中的急性收缩张力。PDEs的调节是分区化的，特定的cGMP来源与PDE水解之间存在选择性相互作用。据报道，在诸如动脉粥样硬化、心脏压力负荷应激和心力衰竭等慢性疾病状态下，以及长期接触硝酸盐时，PDE1和/或PDE5也会上调。这种上调被认为会导致血管和心脏病理生理学以及药物耐受性。最近利用选择性PDE5抑制剂的研究支持与NO-cGMP合成途径存在显著的交叉信号传导，这可能对治疗某些疾病状态特别有帮助。
