Modulation of Vascular O2 Responses by Cytochrome 450‐4A ω‐Hydroxylase Metabolites In Dahl Salt‐Sensitive Rats

Objective: This study evaluated the role of the 20‐HETE/cytochrome P450‐4A ω‐hydroxylase (CYP450‐4A) system in microvascular regulation in the skeletal muscle circulation following short‐term (three‐day) exposure to a high‐salt (HS) diet in Dahl salt‐sensitive (SS) rats. Methods: The effects of inhibiting CYP450‐4A on resting diameter, O₂‐induced constriction, and vasodilator responses to acetylcholine (ACh) and the nitric oxide (NO) donor, sodium nitroprusside (SNP), were evaluated in cremasteric arterioles of SS rats fed a low‐ (LS; 0.4% NaCl) or high‐salt (HS; 4% NaCl) diet for three days. Results: The HS diet upregulated CYP450‐4A mRNA expression and led to an enhanced constriction of arterioles in response to elevated PO₂ in SS rats, which could be blocked by inhibiting CYP450‐4A enzymes with dibromododecenyl methylsulfimide (DDMS). DDMS also inhibited resting tone significantly in SS rats fed the HS, but not the LS, diet, despite similar resting diameters and active tone in the two groups. Arteriolar dilations in response to ACh and SNP were similar in SS rats fed the LS vs. the HS diet and were unaffected by DDMS. Conclusions: These findings suggest that CYP450‐4A enzymes contribute to resting tone and to an enhanced response to elevated PO₂ in arterioles of Dahl‐SS rats fed the HS diet.