Abstract

Alterations in local blood flow control mechanisms may play a major role in the transition from an elevated cardiac output to a maintained elevation in vascular resistance in volume-expanded forms of hypertension. An enhanced constriction of arterioles, in response to increased O2, availability has been demonstrated in many forms of hypertension, but little is known regarding the mechanisms that mediate O2-induced constriction of microvessels. Cytochrome P450 (CYP450) 4A omega-hydroxylase, which catalyzes the formation of 20-HETE (a vasoconstrictor metabolite of arachidonic acid), may act as an 02 sensor in the microcirculation. This study investigates the role of CYP450 4A omega-hydroxylase and 20-HETE in mediating O2-induced constriction of arterioles in the microcirculation of the Dahl S rat, a genetic model of salt sensitive hypertension, and in SS.BN13 consomic rats, in which chromosome 13 of the normotensive Brown Norway rat is substituted into the Dahl S genetic background. The SS.BN13 consomic rats are 98% identical to the Dahl S rat genetically, but do not exhibit elevated blood pressure in response to high salt diet. The overall hypothesis to be tested is that the enhanced response of arterioles to elevated PO2 in Dahl S hypertensive rats is due to one or a combination of 3 factors: increased 20-HETE production, increased sensitivity of arterioles to the vasoconstrictor effects of 20-HETE, and/or altered expression of CYP450 4A omega-hydroxylase. The effect of 20-HETE inhibition, on arteriolar responses to elevated PO2 will be determined in the in situ cremaster muscle of Dahl S and SS.BN13 rats on high salt (HS) and low salt (LS) diets. Cytochrome P450-4A omega-hydroxylase isoforms in arterioles and parenchymal cells of Dahl S rats and SS.BN13 rats on high and low salt diets will be assessed by RT-PCR and Western blotting, and changes in 20-HETE production in response to elevated PO2 will be measured in arterioles and parenchymal cells. Arteriolar constriction in response to exogenous 20-HETE will also be compared in the in situ microcirculation of Dahl S rats and SS.BN13 rats on high salt and low salt diets for various periods of time. These studies should provide an increased understanding of how the mechanisms that regulate vascular tone during changes in 02 availability, are altered during hypertension and during increases in dietary salt intake

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072920-03
Application #
6881154
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Barouch, Winifred
Project Start
2003-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$327,548
Indirect Cost

  Institution

Name
Medical College of Wisconsin
Department
Physiology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226

  Publications

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
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
Drenjancevic-Peric, I; Jelakovic, B; Lombard, J H et al. (2011) High-salt diet and hypertension: focus on the renin-angiotensin system. Kidney Blood Press Res 34:1-11
Durand, Matthew J; Moreno, Carol; Greene, Andrew S et al. (2010) Impaired relaxation of cerebral arteries in the absence of elevated salt intake in normotensive congenic rats carrying the Dahl salt-sensitive renin gene. Am J Physiol Heart Circ Physiol 299:H1865-74
Durand, Matthew J; Raffai, Gábor; Weinberg, Brian D et al. (2010) Angiotensin-(1-7) and low-dose angiotensin II infusion reverse salt-induced endothelial dysfunction via different mechanisms in rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 299:H1024-33

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