title: Effect of sulfaphenazole on tissue plasminogen activator release in normotensive subjects and hypertensive patients.
abstract: BACKGROUND
  A nitric oxide-independent response, possibly mediated by hyperpolarization, regulates vascular tone, acting as a compensatory mechanism in the presence of impaired nitric oxide availability. Cytochrome P450 2C9 (CYP 2C9) is a source of endothelium-derived hyperpolarizing factors and modulates tissue-type plasminogen activator (tPA) release from endothelial cells; however, no effect of hyperpolarization on fibrinolysis has been documented in humans. We aimed to assess the effect of sulfaphenazole, a specific CYP 2C9 inhibitor, on tPA release in normotensive subjects and patients with essential hypertension.
  
  
  RESULTS
  tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 microg x 100 mL(-1) x min(-1)) and acetylcholine (1.5 microg x 100 mL(-1) x min(-1)) infusions, with or without sulfaphenazole (0.03 microg x 100 mL(-1) x min(-1)). Bradykinin and acetylcholine infusions were repeated with N(G)-monomethyl-l-arginine (L-NMMA; 100 microg x 100 mL(-1) x min(-1)) and/or sulfaphenazole. tPA release by bradykinin and acetylcholine was higher in normotensive subjects than in patients with essential hypertension (P<0.01). Sulfaphenazole (P<0.01) blunted bradykinin-induced but not acetylcholine-induced tPA release in both groups. In normotensive subjects, L-NMMA infusion reduced tPA release (P<0.01). When L-NMMA was coinfused with sulfaphenazole, tPA release induced by bradykinin, but not by acetylcholine, was further reduced (P<0.01). In patients with essential hypertension, tPA release by both agonists was unaffected by L-NMMA, but only bradykinin-induced tPA release was blunted by sulfaphenazole, alone or with L-NMMA (P<001).
  
  
  CONCLUSIONS
  Sulfaphenazole inhibits bradykinin-induced tPA release, which suggests a modulatory role of CYP 2C9-derived endothelium-derived hyperpolarizing factors in tPA release in humans. In patients with essential hypertension, tPA release depends exclusively on endothelium-derived hyperpolarizing factor, which is an ineffective compensatory mechanism in the presence of impaired nitric oxide availability.
authors.affiliation: Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. c.giannarelli@int.med.unipi.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Giannarelli
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Ferdinando
authors.initials: F
authors.lastname: De Negri
authors.forename: Armando
authors.initials: A
authors.lastname: Magagna
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.forename: Antonio
authors.initials: A
authors.lastname: Salvetti
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors; D001794:Blood Pressure; D001920:Bradykinin / Q000008:administration & dosage; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005542:Forearm; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008833:Microcirculation; D008875:Middle Aged; D013426:Sulfaphenazole / Q000008:administration & dosage / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000187:drug effects / Q000378:metabolism*; D019323:omega-N-Methylarginine / Q000008:administration & dosage
chemical_list: D013426:Sulfaphenazole; D019323:omega-N-Methylarginine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D010959:Tissue Plasminogen Activator; D000109:Acetylcholine; D001920:Bradykinin