Dahl salt-sensitive rats (SS) exhibit defects in the regulation of their renin-angiotensin system (RAS) that result in chronically low plasma renin activity (PRA) and low circulating ANG """""""" levels, even when they are normotensive and fed a normal salt (NS) diet (0.4% NaCI). Normotensive SS rats fed NS diet also exhibit an impaired response to vasodilator stimuli, which is strikingly similar to the endothelial dysfunction that has been show to be a predictor of adverse cardiovascular events, including death, in humans. This project will test the hypothesis that exposure to chronically low plasma ANG """""""" levels occurring as a result of defective regulation of the RAS in rats carrying the SS renin allele leads to impaired vascular relaxation. Recently, novel narrowed congenic rat strains have been developed that carry either the SS renin allele (impaired RAS regulation) or the Brown Norway (BN) renin allele (normal regulation of the RAS).
The specific aims of the project are to: 1) utilize SS rats and novel narrowed congenic rat strains showing differential regulation of the renin-angiotensin system to test the hypothesis that chronic exposure to low levels of circulating ANG """""""" contributes to impaired vascular relaxation in resistance arteries of normotensive SS rats maintained on NS diet;and 2), employ perturbations of circulating ANG """""""" levels and pharmacological approaches such as angiotensin converting enzyme (ACE) inhibition and chronic AT1 receptor blockade to directly evaluate the role of physiological levels ANG """""""" in maintaining normal vascular relaxation mechanisms in resistance arteries. These objectives will be accomplished by measuring vessel diameters and evaluating vessel responses to different endothelium-dependent vasodilator stimuli in SS rats and narrowed congenic rat strains either retaining the SS renin allele or carrying the normally functioning BN renin allele, which should restore normal regulation of the RAS and rescue normal vascular relaxation mechanisms in resistance arteries. These studies will not only enhance our understanding of the newly emerging role of ANG """""""" in regulating vascular reactivity under normal physiological conditions, but will also provide valuable knowledge concerning the mechanisms of the impaired reactivity of resistance vessels to vasodilator stimuli in SS rats, and the potential mechanisms of elevated vascular resistance and increased cardiovascular mortality in human salt-sensitive hypertension.

Public Health Relevance

Dahl salt-sensitive rats (SS) are a genetic rodent model of the salt-sensitive forms of hypertension that occur in many humans. These animals exhibit an inability to increase the levels of the hormone angiotensin II (ANG II) under normal physiological conditions (low salt diet and normal blood pressure). This project will test the hypothesis that chronic exposure of SS rats to low levels of ANG II in the blood lead to impaired regulation of the circulation, even in the absence of a high salt diet and elevated blood pressure. These studies should provide valuable knowledge concerning the potential mechanisms that underlie the development and maintenance of the elevated vascular resistance in salt-sensitive forms of hypertension occurring in humans, especially in many members of the African-American population, who exhibit salt-sensitive hypertension that bears striking similarities to the SS genetic model of hypertension.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hypertension and Microcirculation Study Section (HM)
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Thrasher, Terry N
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Medical College of Wisconsin
Schools of Medicine
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Lukaszewicz, Kathleen M; Paudyal, Mahesh P; Falck, John R et al. (2016) Role of vascular reactive oxygen species in regulating cytochrome P450-4A enzyme expression in Dahl salt-sensitive rats. Microcirculation 23:540-548
Beyer, Andreas M; Raffai, Gabor; Weinberg, Brian D et al. (2014) Amelioration of salt-induced vascular dysfunction in mesenteric arteries of Dahl salt-sensitive rats by missense mutation of extracellular superoxide dismutase. Am J Physiol Heart Circ Physiol 306:H339-47
Lukaszewicz, Kathleen M; Lombard, Julian H (2013) Role of the CYP4A/20-HETE pathway in vascular dysfunction of the Dahl salt-sensitive rat. Clin Sci (Lond) 124:695-700
Lukaszewicz, Kathleen M; Falck, John R; Manthati, Vijaya L et al. (2013) Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5(BN) consomic rats. Clin Sci (Lond) 124:333-42
Pavlov, Tengis S; Levchenko, Vladislav; O'Connor, Paul M et al. (2013) Deficiency of renal cortical EGF increases ENaC activity and contributes to salt-sensitive hypertension. J Am Soc Nephrol 24:1053-62
Durand, Matthew J; Lombard, Julian H (2013) Low-dose angiotensin II infusion restores vascular function in cerebral arteries of high salt-fed rats by increasing copper/zinc superoxide dimutase expression. Am J Hypertens 26:739-47
Priestley, Jessica R C; Buelow, Matthew W; McEwen, Scott T et al. (2013) Reduced angiotensin II levels cause generalized vascular dysfunction via oxidant stress in hamster cheek pouch arterioles. Microvasc Res 89:134-45
Beyer, Andreas M; Raffai, Gabor; Weinberg, Brian et al. (2012) Dahl salt-sensitive rats are protected against vascular defects related to diet-induced obesity. Hypertension 60:404-10
Raffai, Gabor; Durand, Matthew J; Lombard, Julian H (2011) Acute and chronic angiotensin-(1-7) restores vasodilation and reduces oxidative stress in mesenteric arteries of salt-fed rats. Am J Physiol Heart Circ Physiol 301:H1341-52
Durand, Matthew J; Lombard, Julian H (2011) Introgression of the Brown Norway renin allele onto the Dahl salt-sensitive genetic background increases Cu/Zn SOD expression in cerebral arteries. Am J Hypertens 24:563-8

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