Central Inhibition of Bradykinin B1 Receptor Attenuates DOCA‐Salt Mediated Hypertension, Dysautonomia and Hypertrophy

We previously reported that DOCA‐salt hypertension is attenuated in bradykinin B1 receptor (B1R) knockout mice. To further examine the role of B1R, a specific antagonist R715 was used to inhibit B1R in the brain in wild‐type (WT) mice with or without DOCA‐salt hypertension. Autonomic function was analyzed using a pharmacological method (propranolol, 4 mg/kg, ip and atropine, 1 mg/kg, ip). Hypertrophy was assessed after 3 weeks using organ weight/tibia length. Compared to WT+DOCA, R715‐treated mice (70 µg/kg/day, icv) had a blunted hypertension (Telemetry; 143±2 vs. 122±4 mmHg, P <0.01) and an improved baroreflex gain (1.2±0.1 vs. 2.4±0.3 msec/mmHg, P <0.01). WT+DOCA mice dysautonomia, illustrated by reduced tachycardia to atropine (parasympathetic tone: +91±3 bpm) and increased bradycardia to propranolol (sympathetic tone: ‐145±21 bpm), was normalized in mice with R715 infusion (+174±15 and ‐81±9 bpm, respectively, p<0.05 vs. WT+DOCA), while urine norepinephrine levels were decreased (163±19 vs. 299±23 pg/ml, p<0.01). Moreover, DOCA‐salt treatment resulted in cardiac (7.2±0.2 vs. 9.2±0.3 mg/mm) and renal hypertrophy (9.7±0.3 vs. 21.1±0.7 mg/mm) in WT mice, which was significantly reduced in WT+DOCA+R715 mice (heart: 7.4±0.3 mg/mm; kidney: 18.1±0.9 mg/mm, P <0.01 vs. WT). In DOCA‐treated mice, expression of the pro‐inflammatory ADAM17 protein in the hypothalamus was increased by 2.4 fold (n=6, p<0.01), which was blunted by R715 infusion.Together, our data provide novel evidence to support the role of central B1R in dysautonomia, hypertension and organ damage in low‐renin hypertension. Funding: AHA 12EIA8030004 and 13POST16500025.