Ruschitzka F T, Noll G, Lüscher T F
Cardiology, University Hospital Zürich, Switzerland.
J Cardiovasc Pharmacol. 1998;31 Suppl 2:S5-16. doi: 10.1097/00005344-199800002-00002.
An increasing body of evidence indicates that impairment of endothelial function is crucially involved in the pathogenesis of cardiovascular disease. Injury to the endothelium precipitates atherosclerosis by causing smooth-muscle cell migration and proliferation, induction of expression of growth factors, and impairment of plasma coagulation and endogenous fibrinolysis. Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are widely used in patients with cardiovascular disease and have beneficial vascular effects beyond blood pressure control alone. Both exhibit a synergistic hemodynamic profile. Whereas calcium antagonists dilate large conduit and resistance arteries, ACE inhibitors inhibit the renin-angiotensin system (RAS) and reduce sympathetic outflow. Certain calcium antagonists, such as verapamil and diltiazem, reduce heart rate, whereas dihydropyridines tend to increase it. In the blood vessel wall, the local vascular effects of ACE inhibitors and calcium antagonists are complementary. ACE inhibitors diminish transformation of angiotensin I (Ang I) into angiotensin II (Ang II) and prevent degradation of bradykinin [which stimulates nitric oxide (NO) and prostacyclin formation]. Calcium antagonists inhibit the effects of Ang I and endothelin-1 (ET-1) at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. The resistance circulation is particularly dependent on extracellular Ca2+, thereby explaining why nifedipine and verapamil effectively inhibit ET-induced vasoconstriction in vitro and in vivo. In hypertension, ACE inhibitors and calcium antagonists markedly improve structural changes and increase the media/lumen ratio in resistance arteries. Long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction in hypertensive animals. ACE inhibitors substantially reduce morbidity and mortality in patients with left ventricular dysfunction after myocardial infarction (MI). There is a strong trend indicating benefit with verapamil as well, but this is confined to patients with a normal left ventricular ejection fraction. Clinical studies have confirmed that calcium antagonists exhibit antiatherogenic properties. However, the clinical relevance of these findings has recently been disputed because short-acting dihydropyridines are reported to increase risk for MI. Because ACE inhibitors and calcium antagonists exhibit synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties, combination therapy provides a promising concept in patients with cardiovascular and renal disease.
越来越多的证据表明，内皮功能受损在心血管疾病的发病机制中起着关键作用。内皮损伤通过引起平滑肌细胞迁移和增殖、诱导生长因子表达以及损害血浆凝血和内源性纤维蛋白溶解，从而引发动脉粥样硬化。血管紧张素转换酶（ACE）抑制剂和钙拮抗剂广泛应用于心血管疾病患者，它们除了单独控制血压外，还具有有益的血管效应。两者都呈现出协同的血流动力学特征。钙拮抗剂可扩张大的传导动脉和阻力动脉，而ACE抑制剂则抑制肾素-血管紧张素系统（RAS）并减少交感神经流出。某些钙拮抗剂，如维拉帕米和地尔硫䓬，可降低心率，而二氢吡啶类则倾向于增加心率。在血管壁中，ACE抑制剂和钙拮抗剂的局部血管效应是互补的。ACE抑制剂减少血管紧张素I（Ang I）向血管紧张素II（Ang II）的转化，并防止缓激肽（刺激一氧化氮（NO）和前列环素形成）的降解。钙拮抗剂通过减少Ca2+内流并促进NO的血管舒张作用，在血管平滑肌水平抑制Ang I和内皮素-1（ET-1）的作用。阻力循环特别依赖细胞外Ca2+，这就解释了为什么硝苯地平和维拉帕米在体外和体内均能有效抑制ET诱导的血管收缩。在高血压患者中，ACE抑制剂和钙拮抗剂可显著改善结构变化并增加阻力动脉的中膜/管腔比值。维拉帕米和trandolapril的长期联合治疗在逆转高血压动物的内皮功能障碍方面特别有效。ACE抑制剂可大幅降低心肌梗死（MI）后左心室功能不全患者的发病率和死亡率。维拉帕米也有明显的有益趋势，但仅限于左心室射血分数正常的患者。临床研究证实钙拮抗剂具有抗动脉粥样硬化特性。然而，这些发现的临床相关性最近受到质疑，因为据报道短效二氢吡啶类会增加MI风险。由于ACE抑制剂和钙拮抗剂具有协同的血流动力学、抗增殖、抗血栓形成和抗动脉粥样硬化特性，联合治疗为心血管和肾脏疾病患者提供了一个有前景的概念。
