Gene-targeted mice reveal a critical role for inducible nitric oxide synthase in vascular dysfunction during diabetes.

Abstract

Inducible nitric oxide synthase (iNOS) is a mediator of vascular dysfunction during inflammation. The purpose of this study was to test the hypothesis that vascular dysfunction during diabetes is dependent on expression of iNOS. Diabetes was produced in mice with streptozotocin (150 mg/kg IP). After 4 to 6 months of diabetes, vasomotor function was examined in vitro in carotid arteries from mice with targeted disruption of the gene for iNOS (iNOS-deficient mice) and from normal, wild-type (WT) mice. Contractile responses of carotid arteries to U46619, a thromboxane A2 analogue, were not altered by diabetes in WT mice. Responses to U46619 were increased in arteries from diabetic iNOS-deficient mice compared with diabetic WT and nondiabetic mice (iNOS-deficient and WT mice). These results indicate that expression of iNOS inhibits an increased vasoconstrictor response during diabetes. Arteries from nondiabetic WT mice relaxed 83+/-2% (mean+/-SE) in response to acetylcholine (1 micromol/L) compared with 58+/-6% in arteries from diabetic WT mice (P<0.05 versus nondiabetic mice). In contrast, relaxation of carotid arteries to acetylcholine was similar (81+/-4% versus 76+/-6%; P>0.05) in iNOS-deficient mice under nondiabetic and diabetic conditions, respectively. Thus, diabetes produced impairment of endothelium-dependent relaxation in arteries from WT but not iNOS-deficient mice. Endothelium-independent relaxation in response to nitroprusside was similar in arteries from all mice. These results provide the first direct evidence that impairment of endothelium-dependent relaxation during diabetes is dependent on expression of iNOS.