Working under pressure: coronary arteries and the endothelin system

Abstract

Endogenous endothelin-1-dependent (ET-1) tone in coronary arteries depends on the balance between ET(A) and ET(B) receptor-mediated effects and on parameters such as receptor distribution and endothelial integrity. Numerous studies highlight the striking functional interactions that exist between nitric oxide (NO) and ET-1 in the regulation of vascular tone. Many of the cardiovascular complications associated with cardiovascular risk factors and aging are initially attributable, at least in part, to endothelial dysfunction characterized by a dysregulation between NO and ET-1. The contribution of the imbalance between smooth muscle ET(A/B) and endothelial ET(B) receptors to this process is poorly understood. An increased contribution of ET-1 that is associated with a proportional decrease in that of NO accompanies the development of coronary endothelial dysfunction, coronary vasospasm, and atherosclerosis. These data form the basis for the rationale of testing therapeutic approaches counteracting ET-1-induced cardiovascular dysfunction. It remains to be determined whether the beneficial role of endothelial ET(B) receptors declines with age and risk factors for cardiovascular diseases, revealing smooth muscle ET(B) receptors with proconstricting and proinflammatory activities.

Fig. 1

Schematization of the potential changes in the contribution of ET-1 to the regulation of the coronary arterial tone with age and clinical changes. We propose that ET-1 does not predominantly contribute to the constricting tone of the coronary circulation in young and healthy subjects, but rather to a mild dilatory tone through activation of endothelial ET_B receptors and the release of NO. With age and the associated cumulative mechanical stress-related damages induced by the cardiac cycles on the coronary circulation, endothelial damages lead to a reduction in NO and a rise in the contribution of constricting ET-1 through the activation of smooth muscle ET_A and ET_B receptors, leading, in turn, to a contractile tone. This change may be accelerated in the presence of risk factors for cardiovascular diseases.