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.

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.