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(Stroke. 2001;32:2351.)
© 2001 American Heart Association, Inc.

Original Contributions

Endothelium-Derived Endothelin-1 Reduces Cerebral Artery Sensitivity to Nitric Oxide by a Protein Kinase C–Independent Pathway

Patricia Gilbert, BSc; Johanne Tremblay, PhD Eric Thorin, PhD

From Institut de cardiologie de Montréal, Centre de Recherche (P.G., E.T.), and Centre de Recherche de l’Hôtel-Dieu de Montréal, Montréal, Québec, Canada (J.T.).

Correspondence to Eric Thorin, PhD, Institut de cardiologie de Montréal, 500 rue Bélanger Est, Montréal, Québec, H1T 1C8 Canada.

Background and Purpose—— Nitric oxide (NO) reduces endothelin-1 (ET-1) production and blunts ET-1 dependent vasoconstriction. The direct effects of smooth muscle ET_A receptor stimulation on NO-mediated relaxation are unknown. We hypothesized that endothelium-derived ET-1 regulates vascular tone by reducing smooth muscle sensitivity to NO, possibly through activation of protein kinase C (PKC).

Methods—— Rings of rabbit middle cerebral artery were mounted on microvessel myographs to measure isometric tension. Dose-response curves to acetylcholine (ACh) and sodium nitroprusside (SNP; an NO donor) were obtained with or without ET-1 receptor blockade. Experiments were performed in the presence of indomethacin (10 µmol/L). Results are expressed as mean±SEM.

Results—— In depolarized conditions (40 mmol/L KCl physiological solution), ACh-induced relaxation was entirely NO-dependent, as indicated by its suppression by N-nitro-L-arginine (P<0.05). Arterial sensitivity (pD₂) to ACh (6.32±0.11, n=6) was increased (P<0.05) to 6.77±0.10 (n=6) by BQ123 (ET_A receptor antagonist, 5 µmol/L) but not by BQ788 (ET_B receptor antagonist, 5 µmol/L; 6.08±0.22, n=5). Consistent with this finding, blockade of ET_A receptors increased (P<0.05) vascular sensitivity to SNP (6.95±0.10, n=8), whereas BQ788 had no influence on arterial sensitivity to SNP (6.17±0.07, n=7) compared with control (6.43±0.13, n=11). In denuded arteries, the sensitivity to SNP (7.10±0.08, n=8) was reduced by exogenous ET-1 (6.51±0.35, n=7, P<0.05). Chelerythrine, a PKC inhibitor, did not alter smooth muscle sensitivity to NO, whereas phorbol 12-myristate 13-acetate, a PKC activator, strongly increased it.

Conclusions—— Blockade of ET_A but not ET_B receptors sensitizes vascular smooth muscle to exogenous and endothelium-derived NO. This suggests that ET-1 regulates smooth muscle sensitivity to NO by a PKC-independent pathway. This represents an alternative pathway by which NO and ET-1 interact to regulate vascular tone.

Key Words: acetylcholine • cerebral vessels • endothelins • endothelium, vascular • nitrates • nitric oxide

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