Department of Anesthesiology, Pharmacology & Therapeutics, D Department of Chemistry, University of British Columbia (UBC), Vancouver, Canada; Centre for Heart Lung Innovation, University of British Columbia (UBC), Vancouver, Canada.
Research Center of the Centre Hospitalier Universitaire de Sherbrooke, Québec, Canada.
Eur J Pharmacol. 2024 Aug 15;977:176663. doi: 10.1016/j.ejphar.2024.176663. Epub 2024 May 28.
We have documented profound release of nitric oxide (NO) and endothelium-derived hyperpolarization factor (EDHF) by angiotensin II (ANGII) receptor 1 (AT1) blocker (ARB) losartan and its unique metabolite EXP3179, a pleiotropic effect that may help rationalize the protective properties of ARBs. Since blood pressure (BP) lowering by ARBs likely require an ANGII-dependent switch from AT1 to ANGII receptor 2 (AT2) signaling, a receptor known to stimulate endothelial NO release, we investigated the contribution of AT1 and AT2 to losartan and EXP3179's endothelial function-activating properties.
Two AT1 ligands were used in an attempt to block the AT1-dependent endothelium-enhancing effects of EXP3179. AT2-null mice were used to evaluate the acute ex vivo and chronic in vivo effects of EXP3179 (20μM) and losartan (0.6 g/l), respectively, on endothelial function, BP and aortic stiffness.
Ex vivo blockade of AT1 receptors did not attenuate EXP3179's effects on NO and EDHF-dependent endothelial function activation. We observed significant reductions in PE-induced contractility with EXP3179 in both WT and AT2 knockout (KO) aortic rings. In vivo, a 1-month chronic treatment with losartan did not affect pulse wave velocity (PWV) but decreased PE-induced contraction by 74.9 % in WT (p < 0.0001) and 47.3 % in AT2 KO (p < 0.05). Presence of AT2 was critical to losartan's BP lowering activity.
In contrast to BP lowering, the endothelial function-enhancing effects of losartan and EXP3179 are mostly independent of the classic ANGII/AT1/AT2 pathway, which sheds light on ARB pleiotropism.
我们已经记录到血管紧张素 II (ANGII) 受体 1 (AT1) 阻滞剂（ARB）氯沙坦及其独特代谢物 EXP3179 可显著释放一氧化氮 (NO) 和内皮衍生超极化因子 (EDHF)，这是一种多效性效应，可能有助于合理说明 ARB 的保护特性。由于 ARB 降低血压可能需要依赖 ANGII 的从 AT1 到 ANGII 受体 2 (AT2) 信号的转换，而 AT2 受体已知可刺激内皮细胞释放 NO，因此我们研究了 AT1 和 AT2 对氯沙坦和 EXP3179 激活内皮功能的特性的贡献。
使用两种 AT1 配体试图阻断 EXP3179 对 AT1 依赖性的内皮增强作用。使用 AT2 基因敲除 (KO) 小鼠分别评估 EXP3179 (20μM) 和氯沙坦 (0.6g/l) 的急性离体和慢性体内对内皮功能、血压和主动脉僵硬度的影响。
体外阻断 AT1 受体不能减弱 EXP3179 对 NO 和 EDHF 依赖性内皮功能激活的作用。我们观察到 EXP3179 可显著降低 WT 和 AT2 KO 主动脉环中 PE 诱导的收缩性。在体内，用氯沙坦进行为期 1 个月的慢性治疗并未影响脉搏波速度 (PWV)，但使 WT 组的 PE 诱导收缩减少了 74.9% (p < 0.0001)，使 AT2 KO 组减少了 47.3% (p < 0.05)。AT2 的存在对于氯沙坦的降压作用至关重要。
与降低血压相反，氯沙坦和 EXP3179 增强内皮功能的作用主要独立于经典的 ANGII/AT1/AT2 途径，这揭示了 ARB 的多效性。
