Giannarelli Chiara, Virdis Agostino, De Negri Ferdinando, Magagna Armando, Duranti Emiliano, Salvetti Antonio, Taddei Stefano
Department of Internal Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy.
Circulation. 2009 Mar 31;119(12):1625-33. doi: 10.1161/CIRCULATIONAHA.108.782482. Epub 2009 Mar 16.
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.
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).
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.
一种不依赖一氧化氮的反应，可能由超极化介导，调节血管张力，在一氧化氮可用性受损时作为一种代偿机制发挥作用。细胞色素P450 2C9（CYP 2C9）是内皮源性超极化因子的来源，并调节组织型纤溶酶原激活物（tPA）从内皮细胞的释放；然而，超极化对人类纤溶作用的影响尚未见报道。我们旨在评估磺胺苯吡唑（一种特异性CYP 2C9抑制剂）对血压正常受试者和原发性高血压患者tPA释放的影响。
在56名血压正常受试者和57名原发性高血压患者的前臂微循环中，在输注缓激肽（0.015μg×100 mL⁻¹×min⁻¹）和乙酰胆碱（1.5μg×100 mL⁻¹×min⁻¹）时，测量tPA的释放，同时或不同时给予磺胺苯吡唑（0.03μg×100 mL⁻¹×min⁻¹）。在给予N(G)-单甲基-L-精氨酸（L-NMMA；100μg×100 mL⁻¹×min⁻¹）和/或磺胺苯吡唑的情况下，重复输注缓激肽和乙酰胆碱。血压正常受试者中缓激肽和乙酰胆碱诱导的tPA释放高于原发性高血压患者（P<0.01）。磺胺苯吡唑（P<0.01）使两组中缓激肽诱导的tPA释放减弱，但不影响乙酰胆碱诱导的tPA释放。在血压正常受试者中，输注L-NMMA可降低tPA释放（P<0.01）。当L-NMMA与磺胺苯吡唑联合输注时，缓激肽而非乙酰胆碱诱导的tPA释放进一步降低（P<0.01）。在原发性高血压患者中，两种激动剂诱导的tPA释放均不受L-NMMA影响，但只有缓激肽诱导的tPA释放可被磺胺苯吡唑单独或与L-NMMA联合使用减弱（P<0.01）。
磺胺苯吡唑抑制缓激肽诱导的tPA释放，这表明CYP 2C9衍生的内皮源性超极化因子在人类tPA释放中具有调节作用。在原发性高血压患者中，tPA释放完全依赖于内皮源性超极化因子，在一氧化氮可用性受损时这是一种无效的代偿机制。
