Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients.
OBJECTIVE
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 mug/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.
Taddei
Stefano
S
Department of Internal Medicine, University of Pisa, Pisa, Italy. s.taddei@med.unipi.it
Versari
Daniele
D
Cipriano
Alessandro
A
Ghiadoni
Lorenzo
L
Galetta
Fabio
F
Franzoni
Ferdinando
F
Magagna
Armando
A
Virdis
Agostino
A
Salvetti
Antonio
A
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001205:Ascorbic Acid / Q000494:pharmacology; D001685:Biological Factors / Q000096:biosynthesis / Q000097:blood*; D001920:Bradykinin / Q000494:pharmacology; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004338:Drug Combinations; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D009599:Nitroprusside / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013426:Sulfaphenazole / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D001685:Biological Factors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013426:Sulfaphenazole; D009599:Nitroprusside; D019323:omega-N-Methylarginine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000109:Acetylcholine; D001205:Ascorbic Acid; D001920:Bradykinin