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Summary
Ruschitzka FT et al.  
Calcium antagonists and endothelial function

Journal of Clinical and Basic Cardiology 1999; 2 (2): 175-180

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Keywords: Endothelendothelin-1KalziumantagonistStickoxidcalcium antagonistendothelin-1endotheliumnitric oxide

Endothelial cells release numerous vasoactive substances, such as nitric oxide and endothelin-1. As endothelial dysfunction has been recognized as an early event in cardiovascular disease, modern therapeutic strategies in coronary artery disease should focus on preserving or restoring endothelial integrity. Calcium antagonists are widely used in the treatment of cardiovascular diseases. Three main chemical classes of calcium antagonists have been delineated: (1) phenylalkylamines (ie, verapamil, gallopamil), (2) dihydropyridines (ie, nifedipine as well as second generation dihydropyridines) and (3) benzothiazepines (ie, diltiazem). All drugs bind to different sites at the L-type calcium channel and thereby reduce the influx of extracellular calcium into the cell. Mibefradil also blocks T-type calcium channels and represents a new class of calcium channel blockers, but has been withdrawn from the market due to druginteraction The formation of NO from L-arginine by the enzyme NO synthase is associated with an increase in intracellular Ca2+. Although an increase in intracellular Ca2+ is probably most important for the release of NO, acute treatment with Ca2+ antagonists may directly stimulate NO release as well as facilitate the effects of NO at the level of vascular smooth muscle cells. Chronic treatment with Ca2+ antagonists was shown to prevent or restore decreased endothelium-dependent relaxations via increased NO production, augmented sensitivity of the vascular smooth muscle to endothelium-derived NO or potentiation of NO independent vasodilatory systems. Endothelins exert their biological effects via activation of specific membrane bound receptors that are coupled to G-proteins. Two types of endothelin receptors have been cloned, ie, ETA- and ETB- receptors. Calcium antagonists counteract the effects of ET-1 at the level of vascular smooth muscle by reducing Ca2+-inflow and facilitating the vasodilator effects of NO. As small vessels appear to be more dependent on extracellular Ca2+ than larger vessels, Ca2+ antagonists are preferentially effective in attenuating endothelin-induced vasoconstriction in the resistance circulation in vitro and in vivo. Ongoing clinical trials have to clarify whether these beneficial effects of Ca2+ antagonists on early endothelial dysfunction are associated with improvement of prognosis for our patients with cardiovascular disease. J Clin Basic Cardiol 1999; 2: 175-80.
 
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