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Is there a rationale for combining angiotensin-converting enzyme inhibitors and calcium antagonists in cardiovascular
1Cardiovascular Research University Hospital, Zurich, Switzerland.
Insights
Combining angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists offers synergistic benefits for cardiovascular disease, improving endothelial function and reducing risks. This therapy shows promise in managing conditions like coronary artery disease.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Endothelial Function
Background:
- Coronary artery disease is a leading cause of death, driven by multifactorial pathophysiologies including endothelial dysfunction.
- Endothelial cells regulate vascular tone and cell trafficking via substances like nitric oxide (NO), a vasodilator with antiatherogenic properties.
- Vasoconstrictors such as angiotensin II and endothelin-1 counterbalance NO's effects, contributing to disease progression.
Purpose of the Study:
- To investigate the synergistic vascular effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists in cardiovascular disease.
- To evaluate the potential of combination therapy in reversing endothelial dysfunction and improving hemodynamic parameters.
Main Methods:
- The study reviews the mechanisms of action for ACE inhibitors and calcium antagonists on the renin-angiotensin system, bradykinin, and calcium ion influx.
- It examines the synergistic effects of these drug classes on vascular smooth muscle, endothelial function, and hemodynamic parameters.
- Evidence from animal models (hypertensive animals) and clinical observations (post-myocardial infarction patients) is considered.
Main Results:
- ACE inhibitors reduce angiotensin II production and enhance bradykinin, while calcium antagonists block calcium influx, counteracting vasoconstrictors.
- Combination therapy, exemplified by verapamil and trandolapril in hypertensive animals, effectively reverses endothelial dysfunction.
- ACE inhibitors reduce morbidity/mortality in left ventricular dysfunction; verapamil benefits secondary prevention in patients with normal ejection fraction.
Conclusions:
- Long-term combination therapy with ACE inhibitors and calcium antagonists demonstrates synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties.
- This combined approach holds significant potential for beneficial effects in managing cardiovascular diseases.
- The complementary actions of these drug classes offer a promising strategy for cardiovascular disease treatment.
Abstract:
Coronary artery disease and its sequelae remain the most important cause of morbidity and mortality in Western countries. Because the pathophysiologic characteristics of coronary artery disease are multifactorial, impairment of endothelial function featuring enhanced vasoconstriction, increased platelet vessel wall interaction, adherence of monocytes, migration and proliferation of vascular smooth muscle cells are crucially involved. Endothelial cells release numerous vasoactive substances regulating function of vascular smooth muscle and trafficking blood cells such as nitric oxide (NO), which is a potent vasodilator also inhibiting cellular growth and migration. In addition, NO possesses antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors such as angiotensin II and endothelin-1. In the blood vessel wall, the local vascular effects of angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists are synergistic. ACE inhibitors diminish the conversion of angiotensin I into angiotensin II and the inactivation of bradykinin. Calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of NO. In hypertensive animals, long-term combination therapy with verapamil and trandolapril is particularly effective in reversing endothelial dysfunction. Further, ACE inhibitors and calcium antagonists exert beneficial vascular and complementary hemodynamic effects. Whereas ACE inhibitors inhibit the renin-angiotensin system and reduce sympathetic outflow, calcium antagonists dilate large conduit and resistance arteries. Because small vessels appear to be more dependent on extracellular Ca2+ than larger vessels, nifedipine and verapamil effectively inhibit endothelin-induced vasoconstriction in vitro and in vivo in the resistance circulation. Long-term treatment with ACE inhibitors substantially reduces morbidity and mortality rates in patients with left ventricular dysfunction after myocardial infarction; beneficial effects of verapamil in secondary prevention are confined to patients with normal left ventricular ejection fraction. In summary, long-term combination therapy of ACE inhibitors and calcium antagonists might provide beneficial effects in cardiovascular disease because they exert synergistic hemodynamic, antiproliferative, antithrombotic, and antiatherogenic properties.