Theobald Drew, Ahmed Syed Anees, Abdel-Rahman Abdel A, Sriramula Srinivas
Department of Pharmacology and Toxicology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
Physiol Rep. 2025 Sep;13(18):e70579. doi: 10.14814/phy2.70579.
The cannabinoid receptor 1 (CB1R) regulates cardiovascular functions and is activated by agonists such as WIN55,212-2. While CB1R activation is known to influence blood pressure and oxidative stress both centrally and peripherally, the downstream mechanisms remain unclear. The kinin B1 receptor (B1R), induced by stress and inflammation, may function as a signaling partner for CB1R. This study investigated whether CB1R-mediated effects require B1R activation. Wild-type (WT) and B1R knockout (B1RKO) mice were treated with WIN55,212-2 acutely. In WT mice, WIN55,212-2 increased blood pressure, CB1R and B1R expression, and oxidative stress in the brain and heart, while these effects were absent in B1RKO mice. In vitro, H9c2 cardiomyocytes, human cardiac fibroblasts, and primary neurons were treated with WIN55,212-2 with or without a B1R antagonist. WIN55,212-2 increased CB1R and B1R expressions, and oxidative stress in all cell types and reduced mitochondrial membrane potential in H9c2 cells. In neurons, WIN55,212-2-induced mitochondrial and oxidative stress responses were attenuated by B1R inhibition. These findings reveal that CB1R activation acutely engages B1R signaling to drive pressor responses, oxidative stress, and mitochondrial dysfunction, positioning B1R as a critical downstream effector of CB1R. Targeting B1R may represent a novel strategy to mitigate cannabinoid-induced oxidative stress and cardiovascular effects.
大麻素受体1（CB1R）调节心血管功能，并被WIN55,212-2等激动剂激活。虽然已知CB1R激活在中枢和外周都会影响血压和氧化应激，但其下游机制仍不清楚。由应激和炎症诱导的缓激肽B1受体（B1R）可能作为CB1R的信号传导伙伴发挥作用。本研究调查了CB1R介导的效应是否需要B1R激活。对野生型（WT）和B1R基因敲除（B1RKO）小鼠进行WIN55,212-2急性处理。在WT小鼠中，WIN55,212-2升高了血压、CB1R和B1R的表达，并增加了大脑和心脏中的氧化应激，而这些效应在B1RKO小鼠中不存在。在体外，对H9c2心肌细胞、人心脏成纤维细胞和原代神经元用WIN55,212-2进行处理，同时添加或不添加B1R拮抗剂。WIN55,212-2增加了所有细胞类型中CB1R和B1R的表达以及氧化应激，并降低了H9c2细胞中的线粒体膜电位。在神经元中，B1R抑制减弱了WIN55,212-2诱导的线粒体和氧化应激反应。这些发现表明，CB1R激活通过急性激活B1R信号传导来驱动升压反应、氧化应激和线粒体功能障碍，将B1R定位为CB1R的关键下游效应器。靶向B1R可能是减轻大麻素诱导的氧化应激和心血管效应的一种新策略。
