Angiotensin converting enzyme inhibitor-calcium antagonist combination: an alliance for cardioprotection?

MECHANISMS OF ACTION IN SMOOTH MUSCLE: Calcium antagonists and angiotensin converting enzyme (ACE) inhibitors act synergistically in reducing blood pressure. Calcium antagonists counter an excess of calcium entry through the voltage-operated channels of the vascular smooth muscle. ACE inhibitors reduce the vasoconstrictive properties of local and circulating angiotensin II. In addition, they improve endothelium-dependent vasodilation by increasing the expression of endothelial inositol by a bradykinin-related mechanism. Thus, at the smooth muscle level, calcium antagonists cause dilation by reducing external calcium entry and ACE inhibitors cause dilation by reducing internal calcium cycling and improving nitric oxide production.

The two agents have synergistic antagonists exert a potent cardioprotective action; this effect requires prophylactic administration and relies on the ATP-sparing capacity of these drugs. Moreover, prophylactic administration of verapamil but not to other calcium antagonists in patients who have suffered an acute myocardial infarction reduces overall mortality, provided no overt heart failure is present. The molecular effect of ACE inhibitors on the ischaemic heart is less well known but seems to be related to a reduction in noradrenaline release or to an improvement in bradykinin; the effect is thus complementary to that of calcium antagonists.

There is evidence that ACE inhibitors may have additional cardioprotective properties in being able to improve coronary flow, prevent arrhythmias, reduce the toxicity of oxygen free radicals, improve myocardial energy metabolism and prevent remodelling of the heart. ACE inhibitors can also protect the ischaemic heart by inhibiting bradykinin breakdown and by interfering with the central and peripheral nervous and hormone systems such as the kallikrein-kinin, prostaglandin and sympathetic nervous systems. The administration of ACE inhibitors to patients with acute myocardial infarction failed to reduce mortality. However, prophylactic administration to patients with myocardial infarction and heart failure resulted in a significant reduction in mortality and in hospitalization for cardiac disease.

The combination of verapamil with an ACE inhibitor is promising not only for the treatment of hypertension, but also for ischaemic heart disease.