Kinin B1 receptor mediates acute cardiovascular and neural responses following cannabinoid receptor 1 activation in conscious male mice.

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.