Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice.
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 (H(2)O(2)) 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 H(2)O(2) 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 (BH(4)) synthesis had no effect on EDHF-mediated relaxation, and the BH(4)/dihydrobiopterin (BH(2)) 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.
Takaki
Aya
A
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Morikawa
Keiko
K
Tsutsui
Masato
M
Murayama
Yoshinori
Y
Tekes
Ender
E
Yamagishi
Hiroto
H
Ohashi
Junko
J
Yada
Toyotaka
T
Yanagihara
Nobuyuki
N
Shimokawa
Hiroaki
H
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology / Q000379:methods; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms
D020033:Protein Isoforms; D001708:Biopterins; D006861:Hydrogen Peroxide; D019001:Nitric Oxide Synthase; C003402:sapropterin; D000109:Acetylcholine