Endothelin receptor blockade improves endothelial function in human internal mammary arteries.
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 microM), BQ-123 (ET(A) antagonist, 1 microM) and BQ-788 (ET(B) antagonist, 1 microM) using the isolated organ bath apparatus. Percent maximum relaxation (%E(max)) and sensitivity (pEC(50)) were compared between interventions.


RESULTS
ACh caused dose-dependent endothelium-mediated relaxation in IMA (%E(max) 43+/-4, pEC(50) 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.
Verma
S
S
Faculty of Medicine, The University of Calgary, Calgary, Canada.
Lovren
F
F
Dumont
A S
AS
Mather
K J
KJ
Maitland
A
A
Kieser
T M
TM
Kidd
W
W
McNeill
J H
JH
Stewart
D J
DJ
Triggle
C R
CR
Anderson
T J
TJ
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology; D001807:Blood Vessel Prosthesis; D000077300:Bosentan; D001026:Coronary Artery Bypass; D046508:Culture Techniques; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D008323:Mammary Arteries / Q000503:physiopathology* / Q000637:transplantation; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D013449:Sulfonamides; D014665:Vasodilator Agents; C086539:BQ 788; D000109:Acetylcholine; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)