Ayaz M. Rahman a , Jonathan R. Murrow a , Muhiddin A. Ozkor a , Nino Kavtaradze a , Ji Lin b , Christine De Staercke c , W. Craig Hooper c , Amita Manatunga b , Salim Hayek a , Arshed A. Quyyumi a , *
04 June 2014
Aims: Bradykinin (BK) stimulates tissue plasminogen activator (t-PA) release from human endothelium. Although BK stimulates both nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) release, the role of EDHF in t-PA release remains unexplored. This study sought to determine the mechanisms of BK-stimulated t-PA release in the forearm vasculature of healthy human subjects. Methods: In 33 healthy subjects (age 40.3 ± 1.9 years), forearm blood flow (FBF) and t-PA release were measured at rest and after intra-arterial infusions of BK (400 ng/min) and sodium nitroprusside (3.2 mg/min). Measurements were repeated after intra-arterial infusion of tetraethylammonium chloride (TEA; 1 µmol/min), fluconazole (0.4 µmol·min<sup>-1</sup>·l<sup>-1</sup>), and N<sup>G</sup>-monomethyl-<smlcap>L</smlcap>-arginine (<smlcap>L</smlcap>-NMMA, 8 µmol/min) to block nitric oxide, and their combination in separate studies. Results: BK significantly increased net t-PA release across the forearm (p < 0.0001). Fluconazole attenuated both BK-mediated vasodilation (-23.3 ± 2.7% FBF, p < 0.0001) and t-PA release (from 50.9 ± 9.0 to 21.3 ± 8.9 ng/min/100 ml, p = 0.02). TEA attenuated FBF (-14.7 ± 3.2%, p = 0.002) and abolished BK-stimulated t-PA release (from 22.9 ± 5.7 to -0.8 ± 3.6 ng/min/100 ml, p = 0.0002). <smlcap>L</smlcap>-NMMA attenuated FBF (p < 0.0001), but did not inhibit BK-induced t-PA release (nonsignificant). Conclusion: BK-stimulated t-PA release is partly due to cytochrome P<sub>450</sub>-derived epoxides and is inhibited by K<sup>+</sup><sub>Ca</sub> channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.