The present study tested the hypothesis that the Dahl SS (salt-sensitive) rat has vascular dysfunction due, in part, to the up-regulation of the CYP4A/20-HETE (cytochrome P450 ω-hydroxylase 4A)/20-hydroxyeicosatetraenoic acid) system. To assess the role of vascular 20-HETE, SS rats were compared with SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive BN (Brown Norway) introgressed on to the SS genetic background. Cerebral arteries from SS-5BN rats had less CYP4A protein than arteries from SS rats fed either NS (normal-salt, 0.4% NaCl) or HS (high-salt, 4.0% NaCl) diet. ACh (acetylcholine)-induced dilation of MCAs (middle cerebral arteries) from SS and SS-5BN rats was present in SS-5BN rats fed on either an NS or HS diet, but absent in SS rats. In SS rats fed on either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS (N-methyl-sulfonyl-12,12-dibromododec-11-enamide) or the 20-HETE antagonist 20-HEDE [20-hydroxyeicosa-6(Z),15(Z)-dienoic acid]. The restored response to ACh in DDMS-treated SS rats was inhibited by L-NAME (NGnitro-L-arginine methyl ester) and unaffected by indomethacin or MS-PPOH [N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide]. Vascular relaxation responses to the NO donor C5FeN6Na2O were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating that the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure of the VSMCs (vascular smooth muscle cells) to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats [evaluated semi-quantitatively by DHE (dihydroethidium) fluorescence] were lower than those in the arteries of SS rats. These findings indicate that SS rats have an up-regulation of the CYP4A/20-HETE pathway resulting in elevated ROS (reactive oxygen species) and reduced NO bioavailability causing vascular dysfunction.
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Research Article|
November 16 2012
Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats
Kathleen M. Lukaszewicz;
Kathleen M. Lukaszewicz
*Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
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John R. Falck;
John R. Falck
†Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, TX 75390, U.S.A.
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Vijaya L. Manthati;
Vijaya L. Manthati
†Department of Biochemistry, University of Texas Southwestern Medical School, Dallas, TX 75390, U.S.A.
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Julian H. Lombard
*Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, U.S.A.
Correspondence: Dr Julian H. Lombard (email jlombard@mcw.edu).
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Publisher: Portland Press Ltd
Received:
May 17 2012
Revision Received:
August 27 2012
Accepted:
September 03 2012
Accepted Manuscript online:
September 03 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2013 Biochemical Society
2013
Clin Sci (Lond) (2013) 124 (5): 333–342.
Article history
Received:
May 17 2012
Revision Received:
August 27 2012
Accepted:
September 03 2012
Accepted Manuscript online:
September 03 2012
Citation
Kathleen M. Lukaszewicz, John R. Falck, Vijaya L. Manthati, Julian H. Lombard; Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats. Clin Sci (Lond) 1 March 2013; 124 (5): 333–342. doi: https://doi.org/10.1042/CS20120232
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