OBJECTIVES We assessed the role of cytochrome P450 2C9 (CYP 2C9)-derived endothelium-derived hyperpolarizing factor (EDHF) in the forearm microcirculation of essential hypertensive patients (EH) by utilizing sulfaphenazole (SUL), a selective CYP 2C9 inhibitor. BACKGROUND In EH patients, EDHF acts as a compensatory pathway when nitric oxide (NO) availability is reduced. Cytochrome P450 2C9 is a possible source of EDHF. METHODS In 36 healthy subjects (normotensive [NT]) and 32 hypertensive patients (HT), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intraarterial acetylcholine (ACH) and bradykinin (BDK), repeated during N-G-monomethyl-L-arginine (L-NMMA) (100 mu g/100 ml/min) or SUL (0.03 mg/100 ml/min). In HT, the effect of SUL on ACH and BDK was repeated during vitamin C (8 mg/100 ml/min). Sodium nitroprusside (SNP) was utilized as control. RESULTS In NT, vasodilation to ACH and BDK was blunted by L-NMMA and not changed by SUL. In contrast, in HT responses to ACH and BDK, reduced compared with NT, were resistant to L-NMMA. In these patients, SUL blunted vasodilation to ACH and to a greater extent the response to BDK. When retested with vitamin C, SUL was no longer effective on both endothelial agonists. In 2 final groups of normotensive control subjects, vasodilation to ACH or BDK residual to cyclooxygenase and L-NMNIA blockade was further inhibited by simultaneous SUL infusion. Response to SNP, similar between NT and HT, was unaffected by SUL. CONCLUSIONS Cytochrome P450 epoxygenase-derived EDHF acts as a partial compensatory mechanism to sustain endothelium-dependent vasodilation in HT, particularly the BDK-mediated response, when NO activity is impaired because of oxidative stress.
|Autori:||Taddei S; Versari D; Cipriano A; Ghiadoni L; Galetta F; Franzoni F; Magagna A; Virdis A; Salvetti A.|
|Titolo:||Identification of a cytochrome P450-2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients|
|Anno del prodotto:||2006|
|Digital Object Identifier (DOI):||10.1016/j.jacc.2006.04.074|
|Appare nelle tipologie:||1.1 Articolo in rivista|