Coronary Vasodilation and Improvement in Endothelial Dysfunction With Endothelin ET _A Receptor Blockade

Abstract

Abstract-The endothelium-derived peptide endothelin-1 (ET-1) causes vasoconstriction predominantly via smooth muscle ET A receptor activation. We hypothesized that ET A receptor inhibition would improve human coronary vascular function. We studied unobstructed coronary arteries of 44 patients with atherosclerosis or its risk factors. Epicardial diameter (D) Key Words: endothelin Ⅲ coronary circulation Ⅲ endothelial function Ⅲ atherosclerosis E ndothelin (ET), a powerful vasoconstrictor peptide, exists in 3 isoforms, ET-1, ET-2, and ET-3. 1,2 ET-1, the predominant isopeptide released from endothelial cells, is likely to be physiologically the most important in regulating vascular function via its action on 2 distinct receptor subtypes, ET A and ET B . 3 The ET A receptor has a high affinity for ET-1, is selectively expressed on vascular smooth muscle cells, and is the predominant ET receptor in the heart, 4,5 whereas the ET B receptor has equal affinity for all 3 isoforms of ET and is present on both endothelial and vascular smooth muscle cells. 6 ET-1, via stimulation of ET A receptors on vascular smooth muscle cells, activates phospholipase C, resulting in generation of inositol triphosphate, intracellular calcium accumulation, and vasoconstriction. 4,7,8 ET-1 levels are elevated in conditions associated with vascular endothelial dysfunction such as hyperlipidemia, hypertension, smoking, heart failure, and atherosclerosis, suggesting a possible pathophysiological role of ET-1 in these conditions. 9 -14 However, as ET-1 is preferentially secreted abluminally by the endothelial cells, circulating levels appear not to accurately reflect the vascular activity of ET-1, thus necessitating the use of selective antagonists to characterize its physiological effects. 15 ET A receptor antagonism vasodilates the forearm microcirculation of healthy volunteers and subjects with hypertension, heart failure, and hyperlipidemia, suggesting that endogenous ET-1 regulates resting peripheral vascular tone in humans. 16 -21 Endogenous ET-1 acting via the ET A receptor contributes toward the maintenance of coronary vasoconstrictor tone. [22][23][24] Although chronic ET A receptor blockade attenuated the progression of endothelial vasomotor dysfunction in animal models, 25,26 whether endogenous ET-1 contributes toward endothelial dysfunction in the human coronary circulation in vivo is unknown.We hypothesized that ET-1 activity may contribute to both the resting coronary vasomotor tone and the endothelial dysfunction observed in the coronary circulation of patients with atherosclerosis. Therefore, in this study, we investigated the effect of ET A receptor antagonism on coronary vasomotor function and on transcardiac ET-1 uptake in patients with and without coronary atherosclerosis.

The Endothelin System and Its Antagonism in Chronic Kidney Disease

“…Animal models of ED across a number of animal species have shown that antagonism of the ET system, predominantly with selective ET A receptor antagonists, improves NO-mediated endothelial function (78 -80), suggesting that ET-1, acting via ET A receptors, is involved in the pathogenesis of ED. Treatment with selective ET A receptor antagonism also improves endothelial function in the coronary vessels of patients with atherosclerosis, again suggesting that ET-1, acting via ET A receptors, is involved in the pathogenesis of ED in these patients (81).…”

Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors

“…9 ET-1 levels are elevated in patients with atherosclerosis, 10 and atherosclerotic coronary lesions exhibit enhanced ET-1-mediated vascular tone. 11,12 Risk factors for atherosclerosis are also associated with elevated plasma ET-1 levels. [13][14][15][16][17][18][19] Several studies have found that endogenous ET-1 causes vasoconstriction in the resistance vessels of subjects with hypertension.…”

Endogenous Endothelin in Human Coronary Vascular Function

“…This reflects a net balance of ET A receptormediated vasoconstriction and ET B receptor-mediated vasodilatation, the latter acting exclusively in resistance vessels. Furthermore, epicardial coronary endothelial dysfunction is improved by combined ET AϩB receptor blockade, as observed with ET A antagonism, 22 whereas selective ET B antagonism does not affect endothelial function. These effects were similar irrespective of angiographic CAD or specific risk factors.…”

“…Endogenous ET-1 is enhanced in hypertension, coronary artery disease (CAD), and heart failure, [15][16][17][18][19][20][21] with ET A receptor activation contributing to coronary constrictor tone and peripheral and coronary endothelial dysfunction via ET A receptor activation. [22][23][24][25][26][27] Differing effects of ET B receptor activation are observed in health and disease and in different vascular beds. 10,16 -19,28 -30 Combined ET AϩB antagonism causes coronary vasodilation, 31 but the effects on endothelial function and the specific role of ET B in coronary vasomotion remain unknown.…”