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Author Notes:

Correspondence to Irving H. Zucker, 985850 Nebraska Medical Center, Omaha, 68198-5850, NE. E-mail izucker@unmc.edu

The authors thank Mrs. Kaye L. Talbitzer, Ms. Johnnie F. Hackley, and Ms. Tara L. Rudebush, for their excellent technical assistance.

The opinions or assertions contained herein are the private views off the author and are not to be construed as official or as reflecting the views of the Department of the Army of the Department of Defense.

No conflicts of interest, financial or otherwise, are declared by the authors.


Research Funding:

This work was supported by National Institutes of Health National Heart, Lung, and Blood Institute (NIH NHLBI) grant P01 HL62222.

P.R. Pellegrino was partially supported by NIH NHLBI grant F30 HL118974 and American Heart Association (AHA) award 13PRE16210015.

A.M. Schiller was partially supported by AHA award 13PRE14700045.

K.K.V. Haack was partially supported by NIH NHLBI F32 HL116172.


  • Rho-associated kinases
  • RhoA GTP-binding protein
  • angiotensin II
  • baroreflex
  • cardiovascular diseases
  • hypertension
  • intraventricular infusions
  • Analysis of Variance
  • Angiotensin II
  • Animals
  • Baroreflex
  • Consciousness
  • Disease Models, Animal
  • Hypertension
  • Male
  • Rabbits
  • Random Allocation
  • Renin-Angiotensin System
  • Sympathetic Nervous System
  • rho-Associated Kinases

Central angiotensin-II increases blood pressure and sympathetic outflow via Rho kinase activation in conscious rabbits


Journal Title:



Volume 68, Number 5


, Pages 1271-1280

Type of Work:

Article | Post-print: After Peer Review


Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipump: AngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.

Copyright information:

© 2016 American Heart Association, Inc.

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