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Combination of ACE inhibitors and calcium antagonists: a logical approach
F T Ruschitzka1, G Noll, T F Lüscher
1Cardiology, University Hospital Zürich, Switzerland.
Insights
Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists offer synergistic vascular benefits beyond blood pressure control. Combination therapy shows promise for cardiovascular and renal diseases by improving endothelial function and reducing atherosclerosis.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Endothelial Function
Background:
- Endothelial dysfunction is a key factor in cardiovascular disease and atherosclerosis development.
- Angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are established cardiovascular therapies.
- These drug classes possess vascular effects independent of blood pressure reduction.
Purpose of the Study:
- To explore the complementary vascular effects of ACE inhibitors and calcium antagonists.
- To evaluate the potential of combination therapy for cardiovascular and renal diseases.
Main Methods:
- Review of existing evidence on the mechanisms of action of ACE inhibitors and calcium antagonists.
- Analysis of their effects on vascular smooth muscle, endothelial function, and hemodynamic parameters.
- Examination of preclinical and clinical data on combination therapy outcomes.
Main Results:
- ACE inhibitors reduce angiotensin II formation and preserve bradykinin, promoting nitric oxide release.
- Calcium antagonists inhibit calcium influx, counteracting vasoconstrictors like endothelin-1 and enhancing nitric oxide effects.
- Combination therapy demonstrates synergistic improvements in vascular structure, endothelial function, and antiatherogenic properties.
Conclusions:
- ACE inhibitors and calcium antagonists have complementary local vascular actions.
- Combination therapy exhibits synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic effects.
- Combined use offers a promising therapeutic strategy for cardiovascular and renal conditions.
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.