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J Am Coll Cardiol, 2006; 48:508-515, doi:10.1016/j.jacc.2006.04.074 (Published online 11 July 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HYPERTENSION

Identification of a Cytochrome P450 2C9-Derived Endothelium-Derived Hyperpolarizing Factor in Essential Hypertensive Patients

Stefano Taddei, MD*, Daniele Versari, MD, Alessandro Cipriano, MD, Lorenzo Ghiadoni, MD, PhD, Fabio Galetta, MD, Ferdinando Franzoni, MD, Armando Magagna, MD, Agostino Virdis, MD and Antonio Salvetti, MD

Department of Internal Medicine, University of Pisa, Pisa, Italy.

Manuscript received September 14, 2005; revised manuscript received March 27, 2006, accepted April 11, 2006.

* Reprint requests and correspondence: Dr. Stefano Taddei, Department of Internal Medicine, University of Pisa, Via Roma, 67, 56100 Pisa, Italy. (Email: s.taddei{at}med.unipi.it).

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 NG-monomethyl-L-arginine (L-NMMA) (100 µg/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-NMMA 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.

Abbreviations and Acronyms
  ACH = acetylcholine
  BDK = bradykinin
  BP = blood pressure
  COX = cyclooxygenase
  CYP 2C = cytochrome P450 epoxygenase
  EDHF = endothelium-derived hyperpolarizing factor
  EET = epoxyeicosatrienoic acid
  FBF = forearm blood flow
  L-NMMA = NG-monomethyl-L-arginine
  NO = nitric oxide
  SNP = sodium nitroprusside




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