Modulation by Cytochrome P450-4A ω-Hydroxylase Enzymes of Adrenergic Vasoconstriction and Response to Reduced PO2 in Mesenteric Resistance Arteries of Dahl Salt-Sensitive Rats

Please cite this paper as: Raffai, Wang, Roman, Anjaiah, Weinberg, Falck and Lombard (2010). Modulation by Cytochrome P450‐4A ω‐Hydroxylase Enzymes of Adrenergic Vasoconstriction and Response to Reduced PO2 in Mesenteric Resistance Arteries of Dahl Salt‐Sensitive Rats. Microcirculation17(7), 525–535. Objective: This study evaluated the contribution of the 20‐HETE/cytochrome P450‐4A ω‐hydroxylase (CYP4A) system to the early development of salt‐induced vascular changes in Dahl salt‐sensitive (SS) rats. Methods: CYP4A expression and 20‐HETE production were evaluated and responses to norepinephrine, endothelin, and reduced PO2 were determined by video microscopy in isolated mesenteric resistance arteries from SS rats fed high salt (HS; 4% NaCl) diet for three days vs. low salt (LS; 0.4% NaCl) controls. Results: CYP4A enzyme inhibition with dibromododecenyl methylsulfimide (DDMS) selectively reduced norepinephrine sensitivity and restored impaired vasodilation in response to reduced PO2 in SS rats fed HS diet. In the presence of DDMS, vasodilatation to reduced PO2 was eliminated by indomethacin and unaffected by l‐NAME in rats fed LS diet, and eliminated by l‐NAME and unaffected by indomethacin in rats fed HS diet. The 20‐HETE agonist WIT003 restored norepinephrine sensitivity in DDMS‐treated arteries of HS‐fed rats. HS diet increased vascular 20‐HETE production and CYP4A protein levels by ∼24% and ∼31%, respectively, although these differences were not significant. Conclusions: These findings support the hypothesis that the 20‐HETE/CYP4A system modulates vessel responses to norepinephrine and vascular relaxation to reduced PO2 in mesenteric resistance arteries of SS rats fed HS diet.