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BDNF/TrkB Antagonism Attenuates the Hypertensive and Sympatho‐excitatory Response to ICV Administration of Angiotensin II in Male Sprague‐Dawley Rats
Author(s) -
Becker Bryan K,
Wang Hanjun,
Zucker Irving H
Publication year - 2016
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.30.1_supplement.757.10
Subject(s) - medicine , endocrinology , angiotensin ii , tropomyosin receptor kinase b , heart rate , mean arterial pressure , antagonist , blood pressure , neurotrophic factors , receptor
Exaggerated sympathetic tone is associated with increased central angiotensin II (Ang II) signaling in cardiovascular disease states such as chronic heart failure and hypertension. Recent studies by us and others have explored the association between increased Ang II and brain‐derived neurotrophic factor (BDNF) in mediating sympatho‐excitation; however, the direct association between Ang II signaling and BDNF has not yet been established in vivo. We hypothesized that central blockade of the BDNF receptor, TrkB, attenuates Ang II‐induced increased sympathetic tone. We employed a model of neurogenic hypertension through ICV infusion of Ang II (20 ng/min) with or without the TrkB antagonist, ANA‐12, (100 ng/h) via osmotic minipump for 12 days in male, Sprague‐Dawley rats implanted with radiotelemetry. Hemodynamic measurements were taken in conscious, freely moving rats. Ang II infusion evoked an immediate and sustained increase in mean arterial pressure (MAP) (+34.1 ± 1.4 mmHg at day 7 post infusion; p<0.05 relative to baseline; n=4). Ang II + ANA‐12 attenuated the increase in MAP (+12.9 ± 8.0 mmHg relative to baseline, p<0.05 relative to Ang II treatment via RM‐ANOVA; n=4). Heart rate increased in both groups (+40.0 ± 4.4 bpm Ang II; +15.6 ± 7.3 bpm Ang II + ANA‐12; no group interaction via RM‐ANOVA). ANA‐12 alone or vehicle had no effect on MAP or heart rate (n=4/group). Following the 12 days of infusion, acute anesthetized experiments were conducted to evaluate renal sympathetic nerve activity (RSNA) and baroreflex sensitivity (BRS). Ang II decreased BRS relative to vehicle (1.5 ± 0.2 vs. 2.8 ± 0.2 % RSNA/mmHg max gain; p<0.05). ANA‐12 attenuated this blunted BRS (2.8 ± 0.5 % RSNA/mmHg max gain; p<0.05 vs Ang II). Ang II increased resting RSNA relative to vehicle (34.1 ± 2.5 vs. 15.0 ± 1.9 % Max; p<0.05). ANA‐12 attenuated this increase in RSNA (16.0 ± 2.5 % Max; p<0.05). We conclude that the sympatho‐excitatory response to central Ang II involves concurrent BDNF/TrkB signaling. Further work investigating the specific sites of interaction between Ang II and BDNF in mediating sympatho‐excitation will be important in defining precise mechanisms. Support or Funding Information NIH P01‐HL62222; NIH 1F31‐HL126286Change in MAP following ICV Ang II, Ang II+ANA‐12, ANA‐12, or vehicle. δ, p<0.05 relative to baseline (days −3 to −1); *, p<0.05 vs. vehicle; #, p<0.05 vs. Ang II; n=4/group; RM‐ANOVA