Combination of ACE inhibitors and calcium antagonists: a logical approach

Abstract

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.