Abstract 082: Oral Minocycline Reduces Blood Pressure and Restores Autonomic Balance in Chronic Ang II-Infusion Rat Model of Hypertension
Introduction: We have established that microglial activation and dysfunctional autonomic nervous system (ANS) are associated with Ang II hypertension (HTN). The objective of this study was to test the hypothesis that oral delivery of minocycline (Mino), an anti-inflammatory antibiotic that crosses the blood brain barrier, would impact PVN microglia activation, improve autonomic function, and reverse HTN.
Methods: SD rats irradiated and reconstituted with donor eGFP bone marrow (BM) cells were infused with saline or 200ng/kg/min Ang II S.C. for 7 wks. Additionally, rats received vehicle or Mino (50 mg/kg) by oral gavage. MAP was measured weekly by telemetry (n=3/group) and tailcuff (n=9/group). Spectral analysis of telemetry BP signal was performed for ZT12-13 at 3 wks to reveal autonomic balance.
Results: Ang II increased MAP vs control (178±9 mmHg vs 104±2 mmHg; p<0.05), while a reduction was achieved by Mino (121±7 mmHg; p<0.05). Cardiac spontaneous baroreflex gain, measured by ΔsBRG(PI), was dampened in Ang II treated rats vs control (-0.51±0.09 ms/mmHg vs 0.21±0.23 ms/mmHg; p<0.05). This effect was attenuated by Mino treatment (-0.08±0.08 ms/mmHg; p<0.05). Vasomotor sympathetic tone (ΔLF[SBP]) and vasovagal balance (ΔLF[SBP]:HF[PI]) were increased in Ang II rats (1.0 ±0.48 mmHg2; 0.12±0.06 mmHg2/ms2, respectively; p<0.05), and were reversed by Mino (-0.83±0.45 mmHg2; -0.11±0.05 mmHg2/ms2, respectively; p<0.05). In contrast, no significant changes were observed in cardiac parasympathetic drive (ΔHF[PI]) and cardiac sympathetic tone (ΔLF[PI]:HF[PI]). Immunohistochemical analysis revealed 5.7 fold increase (p<0.05) in GFP+/Iba1+ cells in PVN of Ang II group vs control, indicating an increase in BM-derived microglia/macrophages. Treatment with Mino was associated with a 32% decrease in these cells. Blood CD4+8+ cells, indicative of peripheral inflammation, increased by ~29% in the Ang II group, and decreased in the Ang II/Mino group by 31% (p<0.05).
Conclusions: These observations demonstrate that oral Mino treatment inhibits microglia activation, attenuates autonomic dysfuction and peripheral inflammation that arrests the progression of HTN. This suggests that Mino might be an effective therapeutic agent to target neurogenic HTN.
Author Disclosures: M.M. Santisteban: None. J. Zubcevic: None. J. Marulanda-Carvajal: None. M. Zingler: None. M.K. Raizada: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2014 by American Heart Association, Inc.