Endothelium-Derived Hyperpolarizing Factor Mediates Bradykinin-Stimulated Tissue Plasminogen Activator Release in Humans

Abstract

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^-1·l^-1), and N^G-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 P₄₅₀-derived epoxides and is inhibited by K⁺_Ca channel blockade. Thus, BK stimulates both EDHF-dependent vasodilation and t-PA release.

Angiotensin-converting enzyme inhibitors attenuate propofol-induced pro-oxidative and antifibrinolytic effect in human endothelial cells

“…According to others, bradykinin-dependent t-PA release from the endothelium was solely mediated by EDHF signaling pathways, through a calcium and G protein-dependent way. 28 The authors emphasized the lack of contribution of NO to bradykinin-stimulated t-PA release. The in vitro results confirmed data in vivo that the dominant mechanism of profibrinolitic activity of ACE-Is is increasing t-PA concentration by bradykinin-EDHF stimulation and decreasing its degradation through PAI-1.…”

ACE2: The Major Cell Entry Receptor for SARS-CoV-2

“…By binding to bradykinin receptor-B2 (BRB2), BK and Lys-BK induce a local increase in nitric oxide production that has a potent vasodilator effect counterbalancing the vasopressor effect of the RAAS [71]. Moreover, BK positively regulates tissue plasminogen secretion (tPA) and, therefore, plays an important role in thrombus formation [72]. DEABK and LDEABK act on bradykinin receptor-B1 (BRB1) and have important role in the inflammation process [73,74].…”

Pathogenesis and preventive approach of hypercoagulopathy and microvascular thrombosis induced mortality from COVID-19

“…Bradykinin via bradykinin receptor-2 (abundantly expressed in endothelium) causes release of NO and prostacyclin to induce vasodilation (98) . Bradykinin has antithrombotic property by increasing tissue type plasminogen activator (99) . In COVD-19 victims there is degradation of bradykinin via Ag-II mediated hyperaldosteronism.…”