Hemodynamic and Coronary Effects of the Endothelin Antagonist Bosentan in Patients With Coronary Artery Disease

Abstract

Background-Endothelin is a potent endothelium-derived vasoconstrictor peptide with proliferative properties. Elevated levels of the peptide occur in coronary artery disease; however, its pathophysiological role as a regulator of coronary tone and structure is uncertain. Endothelin-receptor antagonists are specific tools to clarify this issue and might be useful in the treatment of coronary artery disease. Methods and Results-In a double-blind, placebo-controlled randomized study, we investigated the effects of the ET A /ET B endothelin-receptor antagonist bosentan or placebo on systemic and coronary hemodynamics in 28 patients with angiographically documented stable coronary artery disease by quantitative coronary angiography and an intracoronary Doppler guidewire. Bosentan 200 mg IV decreased systolic blood pressure (PϽ0.05), whereas heart rate increased slightly (PϽ0.05). Coronary diameter increased, particularly in vessels with no or mild angiographic changes (PϽ0.01). Glycerol trinitrate did not further dilate these segments, whereas coronary diameter increased significantly after nitrate in the placebo group. The increase in coronary diameter after bosentan correlated inversely with plasma LDL-cholesterol levels (PϽ0.01) in both stenotic and angiographically normal coronary segments. Coronary flow velocity did not change. Bosentan was well tolerated. Conclusions-Endogenous endothelin exerts a vasoconstrictor tone in epicardial coronary arteries of patients with coronary artery disease, as evidenced by the vasodilation exerted by the combined ET A /ET B endothelin-receptor antagonist bosentan under acute conditions. Bosentan can safely be given to these patients. Hence, further long-term studies are necessary to determine the therapeutic potential of endothelin-receptor antagonists in patients with coronary artery disease. (Circulation. 1998;98:2235-2240.)

Coexpression of Endothelin-Converting Enzyme-1 and Endothelin-1 in Different Stages of Human Atherosclerosis

“…Indeed, it has recently been shown that endogenous ET-1 exerts a vasoconstrictor effect in the epicardial arteries of patients with coronary artery disease, as evidenced by the vasodilation through the ET-1 receptor antagonist bosentan. 20 Interestingly, in media subjacent to a CP, the number of ET-1 ϩ VSMCs is significantly lower than in media beneath a fatty streak lesion, and there is no significant difference between the number of ET-1 ϩ cells in media adjacent to AIF and media subjacent to a CP. This may be due to the medial atrophy with a reduction of the number of VSMCs, which is a common finding subjacent to advanced atherosclerotic plaques.…”

Endothelin Receptor Blockers in Cardiovascular Disease

“…Intravenous administration of bosentan to patients with angiographic stable coronary artery disease produced an increase in coronary diameter in those vessels with minimal angiographic changes. 60 The selective ET A receptor blocker BQ-123 given to patients with stable angina was shown to prevent distal coronary vasoconstriction after percutaneous transluminal coronary angioplasty. 61 …”

Endogenous Endothelin in Human Coronary Vascular Function

“…In contrast, combined ET AϩB receptor blockade results in both epicardial and microvascular coronary vasodilatation. 31 Thus, endogenous ET-1 has a role in the maintenance of resting coronary vasomotor tone. This reflects a net balance of ET A receptormediated vasoconstriction and ET B receptor-mediated vasodilatation, the latter acting exclusively in resistance vessels.…”

“…[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.…”