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¹ Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
² Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan
³ Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807-8555, Japan
⁴ Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan

CORRESPONDENCE Hiroaki Shimokawa: shimo{at}cardio.med.tohoku.ac.jp

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several relaxing factors, such as prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have previously demonstrated in animals and humans that endothelium-derived hydrogen peroxide (H₂O₂) is an EDHF that is produced in part by endothelial NO synthase (eNOS). In this study, we show that genetic disruption of all three NOS isoforms (neuronal [nNOS], inducible [iNOS], and endothelial [eNOS]) abolishes EDHF responses in mice. The contribution of the NOS system to EDHF-mediated responses was examined in eNOS^–/–, n/eNOS^–/–, and n/i/eNOS^–/– mice. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine of mesenteric arteries were progressively reduced as the number of disrupted NOS genes increased, whereas vascular smooth muscle function was preserved. Loss of eNOS expression alone was compensated for by other NOS genes, and endothelial cell production of H₂O₂ and EDHF-mediated responses were completely absent in n/i/eNOS^–/– mice, even after antihypertensive treatment with hydralazine. NOS uncoupling was not involved, as modulation of tetrahydrobiopterin (BH₄) synthesis had no effect on EDHF-mediated relaxation, and the BH₄/dihydrobiopterin (BH₂) ratio was comparable in mesenteric arteries and the aorta. These results provide the first evidence that EDHF-mediated responses are dependent on the NOSs system in mouse mesenteric arteries.

Abbreviations used: ACh, acetylcholine; BH₂, dihydrobiopterin; BH₄, tetrahydrobiopterin; Cu,Zn-SOD, copper, zinc-superoxide dismutase; DAHP, 2,4-diamino-6-hydroxypyrimidine; DCF, 2',7'-dichlorodihydro-fluorescein diacetate; DHE, dihydroethidium; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial NOS; GPx, glutathione peroxidase; GTPCH1, GTP cyclohydrolase-1; iNOS, inducible NOS; K_Ca, calcium-activated potassium; L-NNA, N-nitro-L-arginine; NO, nitric oxide; NOS; NO synthase; nNOS, neuronal NOS; PGI₂, prostacyclin; SNP, sodium nitroprusside; VSMC, vascular smooth muscle cell.

© 2008 Takaki et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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