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CARDIOVASCULAR

Neuronal Nitric-Oxide Synthase Inhibition Facilitates Adrenergic Neurotransmission in Rat Mesenteric Resistance Arteries

Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama, Japan (Y.H., N.H., J.H., S.A., F.T., H.K.); Department of Hospital Pharmacy, Okayama University Hospital of Medicine and Dentistry, Shikata-cho, Okayama, Japan (H.N., Y.G.); and Centre for Integrated Research in Science, Shimane University, Enya-cho, Izumo, Japan (Y.K.)

The effects of nonselective nitric-oxide synthase (NOS) inhibitors [N--nitro-L-arginine methyl ester (L-NAME) and N--nitro-L-arginine (L-NNA)] and specific neuronal NOS (nNOS) inhibitor [vinyl-L-N-5-(1-imino-3-butenyl)-L-ornithine (L-VNIO)] on adrenergic nerve-mediated vasoconstriction were studied in rat perfused mesenteric vascular beds without endothelium. Perfusion of L-NAME, L-NNA, or L-VNIO markedly augmented vasoconstrictor responses to periarterial nerve stimulation (PNS; 2-8 Hz) without affecting vasoconstriction induced by exogenously injected norepinephrine (NE). Addition of L-arginine, a precursor for the synthesis of nitric oxide (NO), reversed the augmentation of the PNS response by L-NAME. The PNS (8 Hz)-evoked NE release in the perfusate was increased by L-NAME perfusion. In preparations treated with capsaicin [a depleter of calcitonin gene-related peptide (CGRP)-containing nerves], L-NAME did not augment vasoconstrictor responses to PNS or NE injection. Combined perfusion of CGRP(8-37) (a CGRP receptor antagonist) and L-NAME induced additive augmentation of the vasoconstrictor response to PNS but did not affect the response to NE injection. In preparations with active tone produced by methoxamine and in the presence of guanethidine, L-NAME perfusion did not affect the vasodilator response induced by PNS. Immunostaining of the mesenteric artery showed the presence of nNOS-like immunopositive nerve fibers, which were absent in arteries pretreated with capsaicin. These findings suggest that NO, which is released from perivascular capsaicin-sensitive nerves, presynaptically inhibits neurogenic NE release to modulate adrenergic neurotransmission.

Address correspondence to: Dr. Hiromu Kawasaki, Department of Clinical Pharmaceutical Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan. E-mail: kawasaki{at}pheasant.pharm.okayama-u.ac.jp

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