Angiotensin II infusion alters vascular function in mouse resistance vessels:: Roles of O2•- and endothelium

We hypothesized that prolonged angiotensin II (AngII) infusion would alter vascular reactivity by enhancing superoxide anion (O-2(-)) generation. Male C57BL/6 mice were infused with AngII at 400 ng/kg/min (n = 16, AngII mice) or vehicle ( n = 16, sham mice) for 2 weeks via subcutaneous osmotic minipumps. Contraction and relaxation of mesenteric resistance vessels (MRVs) were assessed using a Mulvany-Halpern myograph. AngII infusion increased systolic blood pressure, MRV NADPH oxidase activity and expression of p22(phox) mRNA. Contraction to norepinephrine was unchanged, but AngII infusion increased contractile responses to AngII (41 +/- 5 vs. 10 +/- 4%, p < 0.001) and endothelin-1 (ET-1; 95 +/- 10 vs. 70 +/- 9%, p < 0.05), which was normalized by tempol (10(-4) M, a stable membrane-permeable superoxide dismutase mimetic) and ebselen [10(-5) M, a peroxynitrite ( ONOO-) scavenger]. Endothelium removal enhanced MRV contraction to AngII and ET-1 in sham mice but blunted these contractile responses in AngII mice. Relaxation to ACh was impaired in AngII mice (60.1 +/- 8.8 vs. 83.2 +/- 3.5%, p < 0.01), which normalized by tempol, whereas relaxation to sodium nitroprusside was similar in both groups. N-nitro-L-arginine (NNLA, a nitric oxide synthase inhibitor), partially inhibited acetylcholine relaxation of vessels from sham mice but not from AngII mice. The residual endothelium-dependent hyperpolarizing-factor-like relaxation was not different between groups. In conclusion, the AngII slow pressor response in mouse MRVs consisted of specific contractile hyperresponsiveness and impairment in the NO-mediated component of endothelium-dependent relaxation, which was mediated by O-2(-) and ONOO- in the vascular smooth muscle cell.