Augmentation of endothelial function by endothelin antagonism in human saphenous vein conduits.
OBJECTIVE
Cerebral revascularization with saphenous vein (SV) conduits is used in the management of hard-to-treat lesions that require deliberate arterial occlusion and in selected patients with occlusive vascular disease. Endothelial dysfunction is thought to contribute to acute perioperative vasospasm and chronic graft atherosclerosis. In the present study the authors examined the contribution of the potent vasoconstrictor endothelin-1 (ET-1) to endothelial dysfunction in human SVs.


METHODS
The effects of an ET(A/B) receptor antagonist (bosentan), an ET(A) receptor antagonist (BQ-123), and an ET(B) receptor antagonist (BQ-788) on in vitro endothelium-dependent and -independent responses were studied in human SVs. Vascular segments were obtained in 34 patients who had undergone revascularization procedures, and isometric dose-response curves (DRCs) were constructed using the isolated tissue bath procedure as follows: 1) cumulative DRCs to norepinephrine; and 2) DRCs to acetylcholine (ACh) and sodium nitroprusside in the absence and presence of bosentan, BQ-123, or BQ-788. Maximal vasodilatory responses and sensitivity were compared between groups. In the presence of bosentan (Experiment 1) and BQ-123 or BQ-788 (Experiment 2), ACh responses were significantly augmented (percent maximum relaxation values: 7+/-2 [control] compared with 17+/-3 [bosentan], p < 0.002 [Experiment 1]; and 12+/-2 [control] compared with 29+/-2 [BQ-123] and 25+/-2 [BQ-788], p < 0.003 and p < 0.002, respectively [Experiment 2]). The sensitivity of SVs to ACh was unaffected by treatment. These beneficial effects were specific for the endothelium.


CONCLUSIONS
Blockade of ET receptors significantly improves endothelial function in SVs. Furthermore, these effects appear to be independently and maximally mediated by antagonism of either ET(A) or ET(B) receptors. Interventions aimed at improving endothelial function may serve to counter perioperative vasospasm and impede atherosclerosis in SVs used for revascularization procedures.
Dumont
A S
AS
Department of Neurological Surgery, University of Virginia, Charlottesville, USA. asd2f@virginia.edu
Lovren
F
F
McNeill
J H
JH
Sutherland
G R
GR
Triggle
C R
CR
Anderson
T J
TJ
Verma
S
S
D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D002548:Cerebral Revascularization; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; 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
D000959:Antihypertensive Agents; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D013449:Sulfonamides; C086539:BQ 788; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)