Contribution of nitric oxide produced by inducible nitric oxide synthase to vascular responses of mesenteric arterioles in streptozotocin-diabetic rats.
1. The functional changes in mesenteric arterioles of streptozotocin-induced diabetes were investigated by intravital microscopy. The mesentery was exteriorized from anesthetized rats, spread in a chamber, and superfused with Tyrode solution. All drugs tested were applied to the superfusing Tyrode solution. 2. Compared with age-matched controls, the diabetic rats showed enhanced vascular sensitivity to phenylephrine, an alpha(1)-adrenoceptor agonist. The preincubation of the mesentery with N(G)-nitro-l-arginine (l-NNA), a nitric oxide synthase (NOS) inhibitor, shifted the phenylephrine-concentration-response curves to the left in both the diabetic and control rats. Even in the presence of l-NNA, the sensitivity to phenylephrine was higher in the diabetic rats than in the control. 3. Acetylcholine relaxed the mesenteric arterioles in both groups, but to a significantly greater extent in the control than in the diabetic rats. However, the l-NNA-induced constriction of arterioles did not differ significantly between the groups. In contrast, the amplitude of the constrictions of mesenteric arterioles induced by S-ethylisothiourea, an inducible NOS (iNOS) inhibitor, was significantly greater in the diabetic rats than in the control. 4. Immunostaining of the mesentery with a specific antibody for iNOS revealed iNOS in the microvessels of only the diabetic rats. 5. These results suggest that constrictor responses to alpha(1)-adrenoceptor stimulation are sensitized in the mesenteric arterioles of STZ-diabetic rats, and that iNOS expressed in the arteriolar smooth muscle plays a role in suppressing the basal tone and the reactivity of the arterioles in STZ-diabetic rats.
Ishikawa
Tomohisa
T
Department of Cellular and Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka City, Shizuoka 422-8526, Japan. ishikat@u-shizuoka-ken.ac.jp
Kohno
Fumika
F
Kawase
Ryosuke
R
Yamamoto
Yuri
Y
Nakayama
Koichi
K
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat