Angiotensin II Infusion Alters Vascular Function in Mouse Resistance Vessels: Roles of O^–·2 and Endothelium

Abstract

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.

The physiological role of endoglin in the cardiovascular system

“…Moreover, the infusion of mice with angiopoietin II, characterized by a hyperproduction of O 2 Ϫ and ONOO Ϫ , causes an impairment in the NO-mediated component of endotheliumdependent relaxation in response to acetylcholine. This inhibitory effect is mediated by increased O 2 Ϫ and ONOO Ϫ in the VSMCs of mesenteric arteries (174), at variance with the increased endothelium-dependent vasodilatation of mesenteric arteries reported in Eng ϩ/Ϫ mice (160). Regarding muscular arteries that are involved in the hindlimb perfusion experiments of Eng ϩ/Ϫ animals (77), it has been reported that mice fed a high-salt diet show an increased generation of O 2 Ϫ in the skeletal muscle microcirculation and an impaired endothelium-dependent dilation through reduced NO bioavailability.…”

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

“…Kawazoe et al (1999) noted that suppression of rat mesenteric microcirculation in response to superfused ANG II was enhanced in the presence of NOS inhibition and was attenuated by treatment with SOD; superoxide production was increased by ANG II, suggesting that acute superoxide generation contributes to ANG II-induced vasoconstriction possibly via scavenging NO. ANG II infusion increased systolic blood pressure in mice, NADPH activity in mesenteric resistance vessels, and expression of p22phox mRNA; ANG II infusion enhanced the contractile response to ANG II, which was normalized by tempol and ebselen, a peroxynitrite scavenger (Wang et al, 2006). In addition, the endotheliumdependent ACh-induced relaxation was impaired in ANG-infused mice and was partially inhibited by L-NA in vessels from control mice but not those from ANGinfused mice; residual EDHF-like relaxation was not different between these groups.…”

Novel Nitric Oxide Synthase–Dependent Mechanism of Vasorelaxation in Small Arteries From Hypertensive Rats

“…10,[31][32][33][34][35] Studies that have assessed EDHF-and NOS-mediated dilation in mesenteric resistance arteries from hypertensive rats and mice report decreased NO and/or EDHF contributions to relaxation in mesenteric arteries. 12,[32][33][34][35] Although it is very difficult to compare these studies because of differences in experimental protocols and/or animal models, many of these studies observed an imbalance of the EDHF and/or NOS pathways in the vasodilator response. The present data demonstrate that there is a shift to the NOS pathway to maintain endothelium-dependent relaxation in mesenteric resistance arteries from hypertensive rats.…”

“…6 However, both unchanged and impaired ACh-induced vasorelaxation have been observed in small mesenteric arteries from DOCAsalt, 7,8 SHR, 9,10 and ANG rats 11 and mice. 12 Therefore, NO bioavailability in resistance arteries may be different than that observed in conduit vessels.…”