Kinin B1 Receptor Antagonism Attenuates High Blood Pressure in Genetically Hypertensive Mice

Abstract

Cardiovascular disease (CVD) is the number one cause of death globally. Hypertension is the leading risk factor for the development of CVDs. There is ample evidence documenting the role of the kallikrein kinin system (KKS) in blood pressure regulation and the pathogenesis of hypertension. Kinins are vasoactive peptides that exert their regulatory effects through the activation of two receptor types, B1 and B2. The kinin B1 receptor (B1R) is an inducible G-protein coupled receptor that is markedly upregulated under inflammatory conditions. In the brain, we have shown that B1R is closely associated with microglia, the resident immune cells that mediate neuroinflammatory responses. Previously, we have reported that B1R expression is upregulated in cardiovascular regulatory regions of the brain in Angiotensin II-induced and deoxycorticosterone acetate (DOCA)-salt models of hypertension, suggesting a central role in blood pressure regulation. Due to its role in mediating inflammation and sympathetic activation, B1R may contribute to the elevated blood pressure seen in chronic neurogenic hypertension. Previous studies have reported that Schlager BPH/2J mice exhibit overactivation of the sympathetic nervous system, indicating they are a model of neurogenic hypertension. In this study, we hypothesized that pharmacological inhibition of B1R will reduce high blood pressure in the BPH/2J Schlager hypertensive mouse model by mitigating microglial activation. To investigate the role of B1R in chronic neurogenic hypertension, male BPH/2J hypertensive and BPN/3J normotensive mice were implanted with subcutaneous osmotic minipumps containing B1R antagonist, SSR240612 (5 mg/kg/day), or vehicle for 14 days. Mean arterial pressure (MAP) was measured by noninvasive tail-cuff plethysmography at baseline and following SSR240612 administration for 2 weeks. Tail-cuff recordings demonstrated a significant reduction in MAP in BPH/2J mice following SSR240612 treatment compared to baseline. Immunofluorescence staining revealed that microglia soma sizes increased in BPH/2J mice compared to BPN/3J, indicating an activated phenotype. Furthermore, B1R expression was colocalized with activated microglia in key cardiovascular regulatory regions. SSR240612 treatment attenuated this microglial activation, as indicated by reduced soma size and B1R immunoreactivity. Taken together, these findings suggest that central B1R contributes to persistent microglial activation and elevated blood pressure in chronic neurogenic hypertension. Our data provides novel evidence that blocking B1R can reduce chronic elevated blood pressure in genetically hypertensive mice, potentially through B1R mediated inflammatory mechanisms. This suggests that a B1R antagonist may serve as a potential therapeutic agent for the treatment of chronic neurogenic hypertension.