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(Circulation. 2009;119:1625-1633.)
© 2009 American Heart Association, Inc.

Hypertension

Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients

Chiara Giannarelli, MD, PhD; Agostino Virdis, MD; Ferdinando De Negri, MD; Armando Magagna, MD; Emiliano Duranti, BSc; Antonio Salvetti, MD; Stefano Taddei, MD

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

Correspondence to Chiara Giannarelli, MD, Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. E-mail c.giannarelli{at}int.med.unipi.it

Received March 25, 2008; accepted January 30, 2009.

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.

Methods and Results— tPA release was measured in the forearm microcirculation of 56 normotensivesubjects and 57 patients with essential hypertension after bradykinin (0.015 µg · 100 mL^–1 · min^–1) and acetylcholine (1.5 µg · 100 mL^–1 · min^–1) infusions, with or without sulfaphenazole (0.03 µg · 100 mL^–1 · min^–1). Bradykinin and acetylcholine infusions were repeated with N^G-monomethyl-L-arginine (L-NMMA; 100 µg · 100 mL^–1 · 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 119: 1553-1555. [Extract] [Full Text]

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				N. J. Brown and M. Pretorius Letter by Brown and Pretorius Regarding Article, "Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients" Circulation, November 10, 2009; 120(19): e159 - e159. [Full Text] [PDF]

				C. Giannarelli, A. Virdis, F. De Negri, A. Magagna, E. Duranti, A. Salvetti, and S. Taddei Response to Letter Regarding Article, "Effect of Sulfaphenazole on Tissue Plasminogen Activator Release in Normotensive Subjects and Hypertensive Patients" Circulation, November 10, 2009; 120(19): e160 - e160. [Full Text] [PDF]