Reduced Angiotensin II and Oxidative Stress Contribute to Impaired Vasodilation in Dahl Salt-Sensitive Rats on Low-Salt Diet

Abstract

Abstract-This study investigated the role of impaired angiotensin II (Ang II) modulation in contributing to reduced vascular relaxation in isolated middle cerebral arteries (MCA) (100 to 200 m in diameter) of normotensive Dahl salt-sensitive (SS) rats maintained on low salt (LS) diet (0.4% NaCl) for 9 to 10 weeks. MCA from SS rats on LS diet (nϭ6 to 9) constricted in response to reduction of perfusate and superfusate PO 2 to 35 to 40 mm Hg or acetylcholine (ACh). Vasodilator responses to reduced PO 2 and ACh were restored in SS.13 BN consomic rats that are 98% genetically identical to SS rats, but exhibit normal regulation of their renin-angiotensin system (RAS). This restored dilation could be prevented by feeding SS.13 BN rats high-salt (HS) diet (4% NaCl) for 3 days to suppress Ang II. A continuous intravenous infusion of a subpressor dose (3 ng/kg per minute) of Ang II for 3 days restored vasodilator responses to ACh and reduced PO 2 in SS.13 BN rats on HS diet and in SS rats on LS diet. Superoxide scavenging with tempol (100 mol/L) restored vasodilator responses to ACh and reduced PO 2 in MCA of SS rats on LS diet, but did not affect vasodilator responses in MCA of SS.13 BN rats on LS diet. These data indicate that exposure to chronically low Ang II levels leads to impaired vascular relaxation in SS rats, even when the animals are on LS diet and normotensive. This impaired relaxation appears to be mediated by increased levels of oxidative stress in the arteries. Key Words: angiotensin II Ⅲ endothelium Ⅲ muscle, smooth, vascular Ⅲ oxygen Ⅲ vasodilation D ahl salt-sensitive (SS) rats exhibit impaired regulation of their plasma renin activity 1-3 and are presumably exposed to chronically low levels of angiotensin II (Ang II). SS.13 BN consomic rats are produced by substituting chromosome 13 of the Brown Norway rat containing a normally functioning renin gene into the genetic background of the SS rat. SS.13 BN rats are 98% genetically identical to the SS rat 4 but are able to regulate their renin-angiotensin system (RAS) normally and do not show the extreme hypertension exhibited by SS rats when they are fed high-salt (HS) diet. 2 A recent study demonstrated a striking impairment of vascular relaxation mechanisms in middle cerebral arteries (MCA) of SS rats, even when the rats are on a low-salt (LS) diet and are normotensive. 5 Impaired vascular relaxation in SS rats on LS diet appeared to be caused by chronic exposure to low Ang II levels, because normal vasodilator responses were restored in SS.13 BN consomic rats that show normal regulation of the RAS. 5 This restored dilation in SS.13 BN rats could be eliminated by feeding the animals HS diet to suppress plasma Ang II or by blocking the AT 1 receptor with losartan when the rats were on LS diet. 5 The potential link between impaired vascular relaxation and low Ang II levels in SS rats on LS diet is consistent with existing studies demonstrating that Ang II suppression with HS diet leads to striking impairments of vascular reactivity in normotensive Sprague-D...

Restoration of normal vascular relaxation mechanisms in cerebral arteries by chromosomal substitution in consomic SS.13BNrats

“…The studies of Katusic and Vanhoutte (27) and Cosentino et al (6) suggest that the latter alteration can lead to an impaired balance between vasodilator and vasoconstrictor factors, similar to that observed in the present study. The latter hypothesis is consistent with the results of a recent study (12) demonstrating that superoxide scavenging with Tempol restores vasodilator responses to ACh (and hypoxia) in MCA of SS rats fed a low-salt diet.…”

“…These observations provide further support for the hypothesis that the RAS plays an important role in maintaining normal vascular relaxation mechanisms in resistance arteries (11,12,34,52).…”

Mechanism of Differential Cardiovascular Response to Propofol in Dahl Salt-Sensitive, Brown Norway, and Chromosome 13-Substituted Consomic Rat Strains: Role of Large Conductance Ca2+ and Voltage-Activated Potassium Channels

“…One explanation could be an impaired renin-angiotensin system in SS rats. Compared with BN rats that carry a normal renin gene on chromosome 13, renin activity and angiotensin II (Ang II) levels tend to be reduced in SS rats relative to BN and other strains (Cowley et al, 2001;Drenjancevic-Peric and Lombard, 2005). Low levels of circulating Ang II could potentially be responsible for the enhanced activity of mesenteric BK channel in SS rats.…”

Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension

“…The SS rat, which mimics many aspects of progressive salt-sensitive human hypertension, has provided key insights and been used to identify a number of mechanisms and pathways which are believed to contribute to this form of hypertension. These include oxidative stress in the kidney (32, 95, 119, 139, 160 185,186), brain (54,78,82), and vasculature (48,96,109). Importantly, among these mechanisms is also the infiltration of immune cells into the kidney and related inflammatory responses that contribute significantly to ROS production, renal dysfunction, and hypertension (38 -40, 121, 123).…”