Introgression of the Brown Norway Renin Allele Onto the Dahl Salt-Sensitive Genetic Background Increases Cu/Zn SOD Expression in Cerebral Arteries

Elevated superoxide levels in the vasculature reduce the bio-availability of nitric oxide (NO) and cause endothelial dysfunction, which can lead to the onset and progression of cardiovascular disease.1 Vascular tone in the larger arteries of the cerebral circulation is strongly influenced by NO under resting conditions.2 Therefore, increased levels of superoxide can result in the loss of NO-dependent vasodilation, cause vasoconstriction, and adversely affect blood flow regulation in the brain.3 Sprague-Dawley (SD) rats that are fed a short-term high salt (HS) diet have severe endothelial dysfunction and increased levels of reactive oxygen species in multiple vascular beds.4-6 Accumulating evidence has shown that the endothelial dysfunction are that occurs in middle cerebral arteries (MCAs) of SD rats that are fed a HS-diet is a consequence of salt-induced suppression of the renin-angiotensin system (RAS), because chronic infusion of a subpressor dose of angiotensin II (ANG II) (5 ng/ kg/ min) sufficient to return plasma levels of ANG II to normal salt (NS) control values also restores normal vascular relaxation mechanisms in MCAs and prevents downregulation of the crucial antioxidant enzyme Cu/Zn superoxide dismutase (SOD).4,7 The Dahl salt-sensitive (SS) rat is a well-accepted animal model of salt -sensitive, low-renin hypertension similar to that of commonly observed in the African American population.8 When maintained on a NS diet, the Dahl SS rat is normotensive, but similar to HS-fed SD rats, has vascular dysfunction caused by chronically low activity of the RAS because intravenous infusion of a subpressor dose of ANG II restores endothelial function to normal.9,10 Chronically treating Dahl SS rats with the SOD mimetic tempol also restores the vasodilator response to acetylcholine (ACh) in isolated MCAs.11 The Ren1-BN congenic rat (which has the Brown Norway (BN) renin allele introgressed onto the Dahl SS genetic background through marker-assisted breeding) provides a unique animal model to test the relationships between suppressed RAS activity, vascular oxidative stress, and endothelial dysfunction in the large cerebral arteries because previous studies have shown that introgressing the renin allele from the BN rat onto the Dahl SS genetic background not only restores normal activity of the RAS10,12 but also restores NO-dependent vasodilatation in MCAs of the congenic animals.11 The goal of this study was to determine whether superoxide levels are lower in cerebral arteries of Ren1-BN congenic rats compared to those of parental Dahl SS rats. To determine the potential causes of increased vascular superoxide levels in cerebral arteries of the Dahl SS rat, we also evaluated the contributions of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase (XO) to vascular superoxide production, and the relative expression of SOD enzymes in the larger cerebral arteries (MCAs, posterior cerebral arteries, basilar arteries, and arteries from the Circle of Willis) of Dahl SS and Ren1-BN congenic rats.