Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles

Abstract

Objectives We investigated the effect of suppressing plasma angiotensin II (ANG II) levels on arteriolar relaxation in the hamster cheek pouch. Methods Arteriolar diameters were measured via television microscopy during short-term (3–6 days) high salt (HS; 4% NaCl) diet and angiotensin converting enzyme (ACE) inhibition with captopril (100 mg/kg/day). Results ACE inhibition and/or HS diet eliminated endothelium-dependent arteriolar dilation to acetylcholine, endothelium-independent dilation to the NO donor sodium nitroprusside, the prostacyclin analogues carbacyclin and iloprost, and the KATP channel opener cromakalim; and eliminated arteriolar constriction during KATP channel blockade with glibenclamide. Scavenging of superoxide radicals and low dose ANG II infusion (25 ng/kg/min, subcutaneous) reduced oxidant stress and restored arteriolar dilation in arterioles of HS-fed hamsters. Vasoconstriction to topically-applied ANG II was unaffected by HS diet while arteriolar responses to elevation of superfusion solution PO2 were unaffected (5% O2, 10% O2) or reduced (21% O2) by HS diet. Conclusions These findings indicate that sustained exposure to low levels of circulating ANG II leads to widespread dysfunction in endothelium-dependent and independent vascular relaxation mechanisms in cheek pouch arterioles by increasing vascular oxidant stress, but does not potentiate O2- or ANG II-induced constriction of arterioles in the distal microcirculation of normotensive hamsters.

Amelioration of salt-induced vascular dysfunction in mesenteric arteries of Dahl salt-sensitive rats by missense mutation of extracellular superoxide dismutase

“…The dramatic increase in total SOD activity that we observed in ecSOD E124D rats fed HS diet supports the hypothesis that this mutation leads to compensatory responses to protect these vessels against the salt-induced vascular dysfunction and oxidant stress that occurs in mesenteric arteries of SpragueDawley rats (27,41), and multiple other vascular beds of animals (25,26,33) and humans (32). This compensatory response to upregulate SOD activity would, in turn, result in increased NO availability and would, therefore, have a protective effect on microvascular function that is normally compromised in SS rats (4 -10, 28).…”

“…Similar to the initial experiments [and contrary to studies in Sprague-Dawley rats (27,33), mice (25), hamsters (26), and humans (32)], endothelium-dependent dilation to ACh was unaffected by HS diet in arteries of the ecSOD E124D mutant rats (Fig. 3A).…”

“…However, contrary to our original hypothesis, endothelium-dependent vascular relaxation in response to ACh was unaffected by the ecSOD E124D mutation in mesenteric arteries of animals fed NS diet. Strikingly, and in contrast to multiple studies in rats (27,33), mice (25), hamsters (26), and humans (32), switching the animals to a HS diet actually unmasked a protective effect of the mutation on endothelium-dependent vasodilation. In the latter case, HS diet caused abrogated endothelium-dependent vasodilation to ACh in the SS parental strain, but not in the ecSOD E124D mutant rats.…”

Blood Pressure Reduction is Associated With the Changes in Oxidative Stress and Endothelial Activation in Hypertension, Regardless of Antihypertensive Therapy

“…In the ANGII infusion model of hypertension NAD(P)H oxidase has a central role in the development of increased blood pressure (BP) and impaired vascular function [2,9,12]. Conversely, suppression of ANGII during increased dietary salt intake or pharmacological inhibition of the renin-angiotensin system by ACE and AT 1 receptor blockers have been shown to increase vascular oxidative stress [13] by affecting superoxide dismutase (SOD) activity, leading to a similar increase of ROS levels [14,15]. In a recent study healthy normotensive volunteers subjected to a short period of high salt intake exhibited impaired endothelium dependent vasodilatation in response to reactive hyperaemia and acetylcholine infusion [16,17].…”

AT1 Receptors Prevent Salt-Induced Vascular Dysfunction in Isolated Middle Cerebral Arteries of 2 Kidney-1 Clip Hypertensive Rats

“…31 Consistent with the hypothesis that AT 1 receptor activation maintains antioxidant defenses are recent findings that losartan blocks the protective effect of ANG II infusion to reduce vascular superoxide levels and restore arteriolar dilation in hamsters fed an HS diet. 32 In this study, Cu/Zn SOD expression was significantly higher in arteries of 2K1C rats fed an HS diet vs. sham-operated controls fed an HS diet and was not downregulated by an HS diet in the 2K1C rats. Those observations are consistent with the hypothesis that earlier exposure to elevated PRA and ANG II in HS-fed 2K1C rats preserves vascular relaxation by preventing salt-induced downregulation of Cu/Zn SOD (and possibly other antioxidant enzymes).…”