Bassenge E
Institute of Applied Physiology, University of Freiburg, Germany.
Cardiovasc Drugs Ther. 1994 Aug;8(4):601-10. doi: 10.1007/BF00877414.
The endogenous nitrovasodilator endothelium-derived nitric oxide (EDNO) is continuously synthetized enzymatically by NO synthase from L-arginine and is released from endothelial cells. Enhanced, superimposed EDNO release can be stimulated by various local and circulating factors, such as bradykinin, ATP, etc., but also most importantly by viscous drag-induced shear stress of the bloodstream acting on the endothelial lining. Thus luminal release suppresses leukocyte adhesion (expression of adhesion molecules), platelet activation, platelet adhesion, and platelet aggregation, and abluminal release counteracts myogenic and neurogenic coronary constrictor tone, thereby increasing myocardial perfusion and dilating large coronary artery calibers. Thus endothelial impairment and denudation (hypercholesterolemia, atheromatosis, balloon catheter interventions) favor excessive constrictor tone and myocardial ischemia. Under these conditions EDNO can be supplemented by compounds (e.g., nitroglycerin, isosorbide dinitrate) converted by biological systems into NO. In addition, it can be supplemented by compounds that even spontaneously release NO (e.g., sydnonimines such as SIN-1 and sodium nitroprusside). EDNO and exogenously supplemented NO stimulate soluble guanylyl cyclase, increase cGMP levels, and bring about vascular relaxation, particularly in those still compliant sections in which EDNO production is impaired and cGMP levels are thus diminished. Exogenous nitrovasodilators are preferentially converted (in the presence of cysteine) enzymatically in large coronary arteries, improving coronary conductance, and in the venous bed (preload reduction), resulting in an improved O2 supply/demand ratio. During chronic, continuous application, neurohormonal counterregulation and diminished enzymatic biotransformation into NO may reduce their effectiveness, resulting in tolerance, particularly in the most sensitive vascular sections, such as veins and coronary arteries. This drawback can be overcome by applying spontaneously NO-releasing compounds, intermittent therapy, or intermittent interposition of other vasodilator principles.
内源性硝基血管扩张剂内皮衍生一氧化氮（EDNO）由一氧化氮合酶从L-精氨酸中持续酶促合成，并从内皮细胞释放。多种局部和循环因子，如缓激肽、ATP等，都能刺激EDNO释放增强、叠加释放，但最重要的是血流作用于内皮的粘性阻力诱导的剪切应力。因此，管腔内释放可抑制白细胞粘附（粘附分子表达）、血小板活化、血小板粘附和血小板聚集，而管腔外释放可抵消肌源性和神经源性冠状动脉收缩张力，从而增加心肌灌注并扩张大冠状动脉口径。因此，内皮损伤和剥脱（高胆固醇血症、动脉粥样硬化、球囊导管介入）有利于过度的收缩张力和心肌缺血。在这些情况下，EDNO可由生物系统转化为NO的化合物（如硝酸甘油、异山梨醇二硝酸酯）补充。此外，它还可由甚至能自发释放NO的化合物（如西地那非，如SIN-1和硝普钠）补充。EDNO和外源性补充的NO刺激可溶性鸟苷酸环化酶，增加cGMP水平，并导致血管舒张，特别是在那些仍有顺应性的节段，其中EDNO生成受损，cGMP水平因此降低。外源性硝基血管扩张剂在大冠状动脉中优先（在有半胱氨酸存在的情况下）酶促转化，改善冠状动脉传导，并在静脉床（降低前负荷），从而改善氧供需比。在慢性、持续应用过程中，神经激素的反调节和酶促生物转化为NO的减少可能会降低其有效性，导致耐受性，特别是在最敏感的血管节段，如静脉和冠状动脉。通过应用自发释放NO的化合物、间歇治疗或间歇插入其他血管扩张原理，可以克服这一缺点。
