title: Baseline blood flow and bradykinin-induced vasodilator responses in the human forearm are insensitive to the cytochrome P450 2C9 (CYP2C9) inhibitor sulphaphenazole.
abstract: A substantial portion of the vasodilator response elicited by bradykinin in the human forearm is unaffected by the combined inhibition of nitric oxide (NO) synthases and cyclo-oxygenases. The cytochrome P450 (CYP) 2C9 inhibitor sulphaphenazole was recently identified as a potent inhibitor of NO- and prostacyclin (PGI2)-independent relaxation in porcine coronary arteries. The aim of the present study was to determine the effect of sulphaphenazole on basal and bradykinin-induced NO/PGI2-independent changes in the forearm blood flow (FBF) of healthy subjects. Eleven healthy male volunteers participated in this placebo-controlled study. Test agents were infused into the brachial artery and FBF was measured by bilateral venous occlusion plethysmography. Sulphaphenazole (0.02-2 mg/min) alone did not affect basal blood flow. Inhibition of the NO synthases by NG-monomethyl-L-arginine (L-NMMA; 4 micromol/min) and cyclo-oxygenases by ibuprofen (1200 mg, orally) reduced FBF to 48 +/- 7% in the absence and 50 +/- 8% in the presence of sulphaphenazole (2 mg/min; P=not significant). After pretreatment with L-NMMA (16 micromol/min) and ibuprofen (1200 mg, orally), sulphaphenazole (6 mg/min) did not substantially inhibit bradykinin-induced vasodilation. We conclude that CYP2C9-derived metabolites (i) are not involved in the regulation of baseline blood flow, and (ii) do not mediate bradykinin-induced NO/PGI2-independent vasorelaxation in the human forearm. However, determining the contribution of this enzyme to regulation of blood flow in pathological conditions associated with endothelial dysfunction requires further studies.
authors.affiliation: Division of Nephrology, Carl Gustav Carus University Hospital, Technical University Dresden, Dresden, Germany. passauer@rcs.urz.tu-dresden.de
authors.forename: Jens
authors.initials: J
authors.lastname: Passauer
authors.forename: Eckhart
authors.initials: E
authors.lastname: Büssemaker
authors.forename: Grit
authors.initials: G
authors.lastname: Lässig
authors.forename: Frank
authors.initials: F
authors.lastname: Pistrosch
authors.forename: Joachim
authors.initials: J
authors.lastname: Fauler
authors.forename: Peter
authors.initials: P
authors.lastname: Gross
authors.forename: Ingrid
authors.initials: I
authors.lastname: Fleming
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D001920:Bradykinin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065729:Cytochrome P-450 CYP2C9; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010991:Plethysmography; D012039:Regional Blood Flow / Q000187:drug effects; D013426:Sulfaphenazole / Q000097:blood / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D014665:Vasodilator Agents; D013426:Sulfaphenazole; D019323:omega-N-Methylarginine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D019001:Nitric Oxide Synthase; D001189:Aryl Hydrocarbon Hydroxylases; D001920:Bradykinin; D007052:Ibuprofen