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Cardiovascular Research 2001 49(1):146-151; doi:10.1016/S0008-6363(00)00244-3
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Endothelin receptor blockade improves endothelial function in human internal mammary arteries

Subodh Vermaa, Fina Lovrena, Aaron S Dumonta, Kieren J Mathera, Andrew Maitlanda, Teresa M Kiesera, William Kidda, John H McNeillb, Duncan J Stewartc, Christopher R Trigglea and Todd J Andersona,*

aFaculty of Medicine, The University of Calgary, Calgary, Canada
bFaculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada
cFaculty of Medicine, The University of Toronto, Toronto, Canada

* Corresponding author. Division of Cardiology, Foothills Hospital, 1403-29th Avenue NW, Calgary, Alta, Canada T2N 2T9. Tel.: +1-403-670-1020; fax: +1-403-670-1592 todd.anderson{at}crha-health.ab.ca

Objective: Endothelial dysfunction, specifically endothelium-derived contracting factors have been implicated in the development of arterial conduit vasospasm. The potent vasoconstrictor endothelin-1 (ET-1) has received much attention in this regard. The present study was designed to evaluate the role of ET-1 in the development of endothelial dysfunction in human internal mammary arteries (IMA). To this aim, we examined the effects of specific and non-specific ET-receptor antagonists on endothelial function (assessed using acetylcholine (ACh)-induced vasodilation) in segments of IMA obtained during coronary artery bypass graft (CABG) surgery. Methods: Vascular segments of IMA were obtained from 51 patients undergoing elective coronary artery bypass graft (CABG) surgery and in vitro endothelium-dependent and -independent responses to ACh and sodium nitroprusside (SNP) were assessed. Isometric dose response curves (DRC) to ACh and SNP were constructed in pre-contracted rings in the presence and absence of bosentan (ETA/B receptor antagonist, 3 µM), BQ-123 (ETA antagonist, 1 µM) and BQ-788 (ETB antagonist, 1 µM) using the isolated organ bath apparatus. Percent maximum relaxation (%Emax) and sensitivity (pEC50) were compared between interventions. Results: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%Emax 43±4, pEC50 6.74±0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented (%Emax bosentan 60±3, BQ-123 56±4, BQ-788 53±5 vs. control 43±4, P<0.05) without affecting sensitivity. The effects of these antagonists were endothelium-specific since endothelium-independent responses to SNP remained unaltered. Furthermore, the beneficial effects were independently and maximally mediated by ETA and ETB receptors (%Emax BQ-123 56±4 vs. BQ-788 53±5 vs. bosentan 60±3, P>0.05). Conclusions: These data uncover, for the first time, beneficial effects of ET receptor blockade on endothelial-dependent vasorelaxation in human IMA.

KEYWORDS Endothelial function; Endothelins; Cardiovascular surgery; Vasoactive agents; Vasoconstriction/dilation


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