Endothelin receptor blockade improves endothelial function in human internal mammary arteries

Subodh Verma, Fina Lovren, Aaron S. Dumont, Kieren J. Mather, Andrew Maitland, Teresa M. Kieser, William Kidd, John H. McNeill, Duncan J. Stewart, Christopher Triggle, Todd J. Anderson

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

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 (ET(A/B) receptor antagonist, 3 μM), BQ-123 (ET(A) antagonist, 1 μM) and BQ-788 (ET(B) antagonist, 1 μM) using the isolated organ bath apparatus. Percent maximum relaxation (%E(max)) and sensitivity (pEC50) were compared between interventions. Results: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E(max) 43±4, pEC50 6.74±0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented (%E(max) 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 ET(A) and ET(B) receptors (%E(max) 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. (C) 2001 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)146-151
Number of pages6
JournalCardiovascular Research
Volume49
Issue number1
DOIs
Publication statusPublished - 2001
Externally publishedYes

Fingerprint

Endothelin Receptors
Mammary Arteries
Acetylcholine
Endothelium
Nitroprusside
Endothelin-1
Vasodilation
Coronary Artery Bypass
Transplants
Vasoconstrictor Agents
Baths
Blood Vessels
BQ 788
bosentan
cyclo(Trp-Asp-Pro-Val-Leu)

Keywords

  • Cardiovascular surgery
  • Endothelial function
  • Endothelins
  • Vasoactive agents
  • Vasoconstriction/dilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Verma, S., Lovren, F., Dumont, A. S., Mather, K. J., Maitland, A., Kieser, T. M., ... Anderson, T. J. (2001). Endothelin receptor blockade improves endothelial function in human internal mammary arteries. Cardiovascular Research, 49(1), 146-151. https://doi.org/10.1016/S0008-6363(00)00244-3

Endothelin receptor blockade improves endothelial function in human internal mammary arteries. / Verma, Subodh; Lovren, Fina; Dumont, Aaron S.; Mather, Kieren J.; Maitland, Andrew; Kieser, Teresa M.; Kidd, William; McNeill, John H.; Stewart, Duncan J.; Triggle, Christopher; Anderson, Todd J.

In: Cardiovascular Research, Vol. 49, No. 1, 2001, p. 146-151.

Research output: Contribution to journalArticle

Verma, S, Lovren, F, Dumont, AS, Mather, KJ, Maitland, A, Kieser, TM, Kidd, W, McNeill, JH, Stewart, DJ, Triggle, C & Anderson, TJ 2001, 'Endothelin receptor blockade improves endothelial function in human internal mammary arteries', Cardiovascular Research, vol. 49, no. 1, pp. 146-151. https://doi.org/10.1016/S0008-6363(00)00244-3
Verma, Subodh ; Lovren, Fina ; Dumont, Aaron S. ; Mather, Kieren J. ; Maitland, Andrew ; Kieser, Teresa M. ; Kidd, William ; McNeill, John H. ; Stewart, Duncan J. ; Triggle, Christopher ; Anderson, Todd J. / Endothelin receptor blockade improves endothelial function in human internal mammary arteries. In: Cardiovascular Research. 2001 ; Vol. 49, No. 1. pp. 146-151.
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abstract = "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 (ET(A/B) receptor antagonist, 3 μM), BQ-123 (ET(A) antagonist, 1 μM) and BQ-788 (ET(B) antagonist, 1 μM) using the isolated organ bath apparatus. Percent maximum relaxation ({\%}E(max)) and sensitivity (pEC50) were compared between interventions. Results: ACh caused dose-dependent endothelium-mediated relaxation in IMA ({\%}E(max) 43±4, pEC50 6.74±0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented ({\%}E(max) 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 ET(A) and ET(B) receptors ({\%}E(max) 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. (C) 2001 Elsevier Science B.V.",
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AU - Lovren, Fina

AU - Dumont, Aaron S.

AU - Mather, Kieren J.

AU - Maitland, Andrew

AU - Kieser, Teresa M.

AU - Kidd, William

AU - McNeill, John H.

AU - Stewart, Duncan J.

AU - Triggle, Christopher

AU - Anderson, Todd J.

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N2 - 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 (ET(A/B) receptor antagonist, 3 μM), BQ-123 (ET(A) antagonist, 1 μM) and BQ-788 (ET(B) antagonist, 1 μM) using the isolated organ bath apparatus. Percent maximum relaxation (%E(max)) and sensitivity (pEC50) were compared between interventions. Results: ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E(max) 43±4, pEC50 6.74±0.12). In the presence of bosentan, BQ-123 and BQ-788 ACh-induced relaxation was significantly augmented (%E(max) 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 ET(A) and ET(B) receptors (%E(max) 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. (C) 2001 Elsevier Science B.V.

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