Diets with high salt content are common in Western society, and have long been implicated as a risk factor for hypertension. Historically, it has been believed that the high salt diet leads to an elevated blood pressure in salt sensitive individuals, and that this elevation in arterial pressure leads to pathological alterations in vessel function. However, recent studies suggest that elevated salt intake also affects vessel structure and reactivity in normotensive animals, and that these alterations are mediated via angiotensin II (ANG II) suppression. These novel and important observations have substantial clinical implications, since they demonstrate that the impaired vasodilator responses reported in many forms of salt sensitive hypertension may not depend on the elevation of blood pressure. This raises the possibility that, when combined with other predisposing factors, altered vascular reactivity with elevated salt intake could lead to the development of salt sensitive hypertension. This project will utilize isolated, cannulated resistance arteries and in situ microcirculatory preparations to test the central hypothesis that elevated salt intake per se leads to impaired vasodilator reactivity in arterioles and resistance arteries of normotensive animals, and that this effect is mediated via suppression of ANG II.
The specific aims of this study are: 1) to determine whether the impaired vascular relaxation occurring in response to high salt diet is due to alterations in the vascular smooth muscle cells, alterations in endothelial function, or both; 2) to evaluate the role of electrophysiological mechanisms in contributing to the impaired response to vasodilator stimuli in animals on a high salt diet; 3) to determine the role of ANG II and specific ANG II receptor subtypes in maintaining normal vasodilator responses in animals on a high salt diet. Elucidating the mechanism of the altered vascular reactivity that occurs in arterioles and resistance arteries of animals on a high salt diet can lead to an increased understanding of this novel role of ANG II in regulating vasodilator responses in the absence of the confounding effects of elevated arterial pressure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL065289-01
Application #
6159455
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
2000-09-20
Project End
2004-07-31
Budget Start
2000-09-20
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$286,625
Indirect Cost
Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Hoffmann, Brian R; Stodola, Timothy J; Wagner, Jordan R et al. (2017) Mechanisms of Mas1 Receptor-Mediated Signaling in the Vascular Endothelium. Arterioscler Thromb Vasc Biol 37:433-445
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
Priestley, Jessica R C; Kautenburg, Katie E; Casati, Marc C et al. (2016) The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction. Am J Physiol Heart Circ Physiol 310:H478-87
Frisbee, Jefferson C; Butcher, Joshua T; Frisbee, Stephanie J et al. (2016) Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol 310:H488-504
Raffai, Gábor; Lombard, Julian H (2016) Angiotensin-(1-7) Selectively Induces Relaxation and Modulates Endothelium-Dependent Dilation in Mesenteric Arteries of Salt-Fed Rats. J Vasc Res 53:105-118
Beyer, Andreas M; Fredrich, Katherine; Lombard, Julian H (2014) Response to ""Does angiotensin-dependent superoxide production help to prevent salt-induced endothelial dysfunction in 2 kidney-1 clip hypertensive rats?"". Am J Hypertens 27:640
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

Showing the most recent 10 out of 60 publications