Endogenous endothelin maintains coronary artery tone by endothelin type A receptor stimulation in patients undergoing coronary arteriography

Abstract

Objective-To examine the contribution of endothelin type A (ET A ) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans. Design-Controlled clinical study. Setting-Tertiary cardiovascular referral centre. Patients-14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years. Interventions-After diagnostic coronary arteriography, BQ-123 (a selective ET A receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone. Main outcome measures-Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments. Results-The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p < 0.05 v baseline). Coronary blood flow increased from 75 (10) to 92 (10) ml/min and coronary vascular resistance decreased from 1.99 (0.36) to 1.44 (0.22) mm Hg/ml/min after BQ-123 (both p < 0.05 v baseline). The response to BQ-123 of patients with and without coronary artery disease was similar. There was no eVect of saline in the controls. Conclusions-Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans by ET A receptor stimulation. The role of ET B receptors remains to be defined. (Heart 2000;84:176-182) Keywords: endothelins; arteries; blood flow; coronary circulation; angiographyThe endothelins are a family of 21 amino acid peptides with potent and characteristically sustained vasoconstrictor and vasopressor actions.1 Endothelin-1 (ET-1) is the predominant isopeptide generated by the vascular endothelium.2 ET-1 binds to at least two receptors. The ET A receptor appears to be the major one, causing vasoconstriction in arteries, while the ET B receptor mediates the release of endothelium dependent vasodilator substances and is also present in some resistance and capacitance arteries, where it can contribute to vasoconstriction.3 ET-1 may play a role in the pathophysiology of several conditions associated with vasoconstriction, including chronic heart failure, hypertension, Raynaud's disease, and renal failure.3 4 Recently described inhibitors of endothelin converting enzyme and endothelin receptor antagonists may therefore have therapeutic potential as vasodilator drugs in these conditions. Endogenous production of ET-1 contributes importantly to the maintenance of basal peripheral vascular tone 5 and blood pressure 6 in healthy volunteers, mainly through an eVect on ET A receptors. In contrast, the main eVect of endogenous ET-1 on ET B receptors in resistance arteries appears to be vasodilatation. ET-1 constricts human epicardi...

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

“…23,24 In one study, BQ-123 was only administered for 15 minutes, which likely underestimated its full effect. 23 We noted that ET A receptor blockade dilated epicardial arteries to Ϸ40% of the extent observed with the nitrovasodilator SNP.…”

“…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.…”

“…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.…”

Multiple Endothelial Biomarkers and Noninvasive Vascular Function in the General Population

“…Most of these blood biomarkers have been correlated with measures of vascular function in humans. [11][12][13][14][15] These circulating biomarkers represent diverse protective and vasoaggressive mechanisms. The natriuretic peptides MR-proANP and Nt-proBNP, as well as MR-proADM, effectively control blood pressure and plasma volume and have been shown to be indicators of cardiovascular risk and mortality in initially healthy individuals.…”

Endogenous Endothelin in Human Coronary Vascular Function

“…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.…”