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

Article

关键词: ENDOTHELIUM-DEPENDENT VASODILATION;    NITRIC-OXIDE PATHWAY;    HYPERPOLARIZING FACTOR;    CYTOCHROME P4502C9;    CORONARY-ARTERIES;    EPOXYEICOSATRIENOIC ACIDS;    IMPAIRED CAPACITY;    EUROPEAN-SOCIETY;    INHIBITION;    BRADYKININ;   

DOI  :  10.1161/CIRCULATIONAHA.108.782482

来源: SCIE

【 摘 要 】

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 mu g . 100 mL(-1) . min(-1)) and acetylcholine (1.5 mu g . 100 mL(-1) . min(-1)) infusions, with or without sulfaphenazole (0.03 mu g . 100 mL(-1) . min(-1)). Bradykinin and acetylcholine infusions were repeated with N(G)-monomethyl-L-arginine (L-NMMA; 100 mu g . 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. (Circulation. 2009; 119: 1625-1633.)

【 授权许可】

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