Introgression of Brown Norway CYP4A Genes onto the Dahl Salt-Sensitive Background Restores Vascular Function in SS-5^BN Consomic Rats

Authors

Kathleen M. Lukaszewicz, Marquette UniversityFollow
John R. Falck, University of Texas Southwestern Medical Center at DallasFollow
Vijaya L. Manthati, University of Texas
Julian H. Lombard, Medical College of Wisconsin

Document Type

Article

Language

eng

Publication Date

3-2013

Publisher

Portland Press Unlimited

Source Publication

Clinical Science

Source ISSN

0143-5221

Abstract

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-5^BN 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-5^BN 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-5^BN rats was present in SS-5^BN 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 (N^Gnitro-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-5^BN 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-5^BN 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.

Comments

Accepted version. Clinical Science, Vol. 124, No. 5 (March 2013): 333-342. DOI. © 2013 Portland Press. Used with permission.

Recommended Citation

Lukaszewicz, Kathleen M.; Falck, John R.; Manthati, Vijaya L.; and Lombard, Julian H., "Introgression of Brown Norway CYP4A Genes onto the Dahl Salt-Sensitive Background Restores Vascular Function in SS-5^BN Consomic Rats" (2013). Physical Therapy Faculty Research and Publications. 142.
https://epublications.marquette.edu/phys_therapy_fac/142