Salt‐Induced Increase in 20‐HETE Production Alters Vascular Function of Mesenteric Resistance Arteries of Dahl Salt‐Sensitive Rats

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).