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Salt‐Induced Increase in 20‐HETE Production Alters Vascular Function of Mesenteric Resistance Arteries of Dahl Salt‐Sensitive Rats
Author(s) -
Raffai Gabor,
Wang Jingli,
Falck John R.,
Roman Richard J.,
Lombard Julian H.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.976.7
Subject(s) - medicine , endocrinology , mesenteric arteries , vasodilation , vascular resistance , circulatory system , chemistry , bradykinin , norepinephrine , artery , dopamine , blood pressure , receptor
Cytochrome P450‐4A ω‐hydroxylase (CYP4A) enzymes and their metabolite, 20‐hydroxyeicosatetraenoic acid (20‐HETE) are potential contributors to inflammation and vascular alterations with elevated dietary salt and/or hypertension. This study evaluated the role of the 20‐HETE/CYP4A system in modulating salt‐induced changes in vascular reactivity in mesenteric resistance arteries from Dahl salt‐sensitive (SS) rats. High salt (HS; 4% NaCl) diet increased expression of mRNA for the 4A3 and 4A8 isoforms of CYP4A and increased 20‐HETE production by ~25% in mesenteric arteries of SS rats. In SS rats fed HS diet, CYP4A enzyme inhibition with dibromododecenyl methylsulfimide (DDMS) [30–50 μM]: 1) reduced norepinephrine sensitivity; 2) rescued impaired dilation in response to reduced PO 2 ; 3) switched the mechanism of hypoxic dilation from cyclooxygenase products to NO; and 4) selectively augmented vasodilation to the NO donor DETA NONOate. The 20‐HETE agonist 20‐OH‐5,14 HEDE (WIT003) [1μM] restored norepinephrine sensitivity and attenuated the restoration of hypoxic dilation in DDMS‐treated vessels of salt‐fed rats. These results suggest that the 20‐HETE/CYP4A system modulates both norepinephrine and NO sensitivity, suppresses hypoxic dilation, and could contribute to vascular inflammation and increased vascular resistance during the early stage of salt‐sensitive hypertension. (NIH #HL65289, #HL72920, #HL92026; #DK‐38226).