Blockade of AT₁ receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats

Abstract

Previous studies have demonstrated activation of the local renin-angiotensin system in hindlimb unweighting (HU) rat vasculature. The present study intended to identify the effects of blockade of angiotensin II (ANG II) type 1 (AT(1)) receptors with losartan on vascular reactivity, nitric oxide synthase (NOS) expression, and superoxide anion (O(2)(*-)) levels in 3-wk HU rat cerebral and carotid arteries. Three weeks later, vasoconstriction, vasodilatation, endothelial NOS (eNOS) and inducible NOS (iNOS) protein, as well as O(2)(*-) levels in rat cerebral and carotid arteries were examined. We found that HU enhanced maximal response to KCl/5-hydroxytryptamine (P < 0.01) in basilar arteries and KCl/phenylephrine (P < 0.05) in common carotid arteries from HU rats. Acetylcholine induced concentration-dependent vasodilatation in all the artery rings, but with significantly smaller amplitude in basilar (P < 0.01) and common carotid (P < 0.05) arteries from HU rats than those from control rats. Chronic treatment with losartan partially restored response to vasoconstrictors and acetylcholine-induced vasodilatation in basilar (P < 0.01) and common carotid (P < 0.05) arteries from losartan-treated HU rats. Furthermore, iNOS content in cerebral arteries and eNOS/iNOS content in carotid arteries were significantly (P < 0.01) increased in HU rats. Meanwhile, HU increased O(2)(*-) levels in all the layers of these arteries. However, losartan restored NOS content and O(2)(*-) levels toward normal. These results suggested that the HU-induced enhancement of vasoconstriction and reduction in endothelium-dependent relaxation involved alterations in O(2)(*-) and NOS content through an ANG II/AT(1) receptor signaling pathway.

NAD(P)H oxidase inhibiting with apocynin improved vascular reactivity in tail-suspended hindlimb unweighting rat

“…Furthermore, O 2 ·− contributes to compensatory upregulated expression of eNOS and iNOS in hypertensive rats [14], and it appears that the primary source of O 2 ·− within arteries is nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase. Interestingly, we have detected excessive O 2 ·− production in 21-day HU rat cerebral and carotid arteries by morphology [19], but whether excessive O 2 ·− production participates in endothelium-dependent relaxation is unclear. Thus, our first goal was to clarify whether NAD(P)H oxidase inhibition with apocynin, a specific inhibitor of NAD(P)H oxidase, could prevent enhanced vascular response to vasoconstrictors and impaired endotheliumdependent relaxation in HU rat cerebral and carotid arteries.…”

“…HU+APO and CON+APO rats received distilled water containing apocynin at 50 mg/kg/day by gavage, and the rats of the other groups received equal volume of vehicles (distilled water). The HU technique described in detail previously [18,19] was used to simulate microgravity in rats.…”

“…Therefore, impaired endotheliumdependent relaxation in the settings of microgravity or simulated microgravity may be the result of decreased bioactive NO or decreased response of vascular smooth muscles to NO. Our previous work [19] found that 21-day HU upregulated expression of endothelial NO synthase (eNOS) in cerebral arteries and inducible NO synthase (iNOS) in cerebral and carotid arteries. In addition, vascular response to sodium nitroprusside, which induced endothelium-independent relaxation, seemed to be similar between control and HU rats in cerebral arteries [19], which raise the possibility that decreased bioactive NO may be the underlying cause of impaired endothelium-dependent relaxation in HU rat arteries.…”

“…Studies in animals and humans have demonstrated that adaptive changes in vascular function are involved in the occurrence of post-flight orthostatic intolerance [18]. Enhanced arterial vasoconstriction and myogenic tone development [4,15,20], as well as impaired endothelium-dependent relaxation [19] of cerebral and carotid arteries have been reported before in spite of contrary results [12]. It is now well known that endothelium-dependent relaxation is produced mainly by nitric oxide (NO).…”

Losartan increases NO release in afferent arterioles during regression ofl-NAME-induced renal damage

“…Interestingly, a similar response to losartan was observed in arteries from hindlimb unweighted rats, a model of microgravity exposure. During this special type of cardiovascular stress, losartan restored the general vasoreactivity, ACh-induced vasorelaxation, and increased eNOS protein expression (26), indicating improved NOS function.…”