Contribution of nitric oxide produced by inducible nitric oxide synthase to vascular responses of mesenteric arterioles in streptozotocin‐diabetic rats

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. Compared with age‐matched controls, the diabetic rats showed enhanced vascular sensitivity to phenylephrine, an α 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. 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. Immunostaining of the mesentery with a specific antibody for iNOS revealed iNOS in the microvessels of only the diabetic rats. These results suggest that constrictor responses to α 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.British Journal of Pharmacology (2004) 141 , 269–276. doi: 10.1038/sj.bjp.0705611