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Central Inhibition of Bradykinin B1 Receptor Attenuates DOCA‐Salt Mediated Hypertension, Dysautonomia and Hypertrophy
Author(s) -
Sriramula Srinivas,
Lazartigues Eric
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.987.10
Subject(s) - endocrinology , medicine , propranolol , atropine , baroreflex , receptor antagonist , antagonist , chemistry , heart rate , receptor , blood pressure
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.