Vascular Reactivity to Phenylephrine Is Reciprocally Regulated by Carbon Monoxide and 20-Hydroxyeicosatetraenoic Acid of Vascular Origin
Carbon monoxide (CO) inhibits CYP-450 enzymes that synthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid that enhances vascular reactivity to phenylephrine (PE). This study examines the hypothesis that an interaction between CO and 20-HETE of vascular origin regulates the reactivity of rat renal interlobar arteries (ILA) to PE. ILA incubated (1h) in Krebs buffer released CO into the headspace (95±16 pmol/mg) and manufactured 20-HETE (18±2 ng/mg). Chromium mesoporphyrin (CrMP, 30 μM), an inhibitor of heme oxygenase-dependent CO synthesis, reduced (p<0.05) CO release (29±5 pmol/mg) but not 20-HETE production (15±4 ng/mg). In studies conducted on ILA mounted on a wire-myograph, CrMP caused a leftward shift in the PE concentration-response curve, decreasing the EC50 (0.27±0.03 to 0.12±0.05 μM, p<0.05) without affecting the maximal response. However, CrMP did not affect any aspect of the PE concentration-response relationship in ILA treated with dibromo-dodecenyl-methylsulfimide (DDMS, 30 μM), a 20-HETE synthesis inhibitor. Like CrMP, exogenous 20-HETE (10 μM) caused a leftward displacement of the PE concentration-response curve, decreasing (p<0.05) the EC50 from 0.29±0.01 to 0.07±0.01 μM. Superimposed treatment with exogenous CO (1 μM) shifted back to the right the PE concentration-response curve, increasing the EC50 to 0.31±0.03 μM (p<0.05). Exogenous CO had a similar effect in ILA treated with exogenous 20-HETE and DDMS in combination. These data suggest that CO of vascular origin inhibits vascular reactivity to PE via a mechanism independent of 20-HETE synthesis. However, vascular 20-HETE is a stimulatory regulator of vascular reactivity to PE and thus opposes at a functional level the inhibitory action of CO.