Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD) in Pharmacy

Copyright Statement

All rights reserved. This publication is intended for use solely by faculty, students, and staff of Nova Southeastern University. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, now known or later developed, including but not limited to photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author or the publisher.

Department

College of Pharmacy

First Advisor

Michelle A Clark

Publication Date / Copyright Date

2017

Publisher

Nova Southeastern University

Abstract

BACKGROUND: Spontaneously hypertensive rats (SHRs), an essential hypertension model, are characterized by pro-inflammatory states in brainstems. While Angiotensin (Ang) II, via activation of glial Ang Type 1 receptors (AT1Rs), has been shown to trigger a significant upsurge in pro-inflammatory cytokines, activation of astroglial Cannabinoid Type 1 Receptors (CB1Rs), elicits a potent anti-inflammatory response in the brain. Both brainstem AT1Rs and CB1Rs have also been reported to alter cardiovascular parameters in SHRs. Evidence of crosstalk between CB1Rs and AT1Rs has also emerged, further highlighting a need to understand their signaling interaction in cardiovascular diseases. APPROACH: The purpose of this study was twofold- first, to investigate the downstream consequences of AT1R and CB1R activation in astrocytes under early hypertensive and normotensive conditions, and second, to explore potential crosstalk mechanisms between the two receptors. The proposed studies were carried out in brainstem and cerebellar astrocytes isolated from SHRs and their normotensive controls, the Wistar rats. Alterations in activation patterns of Mitogen activated protein kinases (MAPKs), and/or the levels of the total and inactive (phosphorylated) forms of the receptor, especially CB1R in the latter case, in SHR astrocytes, were employed as indices of receptor functionality. Additionally, changes in the levels of pro- and/or anti-inflammatory cytokines in response to Ang II and CB1R agonist, both alone and in combination, were also employed to assess the immunomodulatory effects of the two systems in SHR and Wistar rat astrocytes. RESULTS: Altered neuroinflammatory states were observed in brainstem astrocytes, but not cerebellar astrocytes of SHRs when compared to Wistar rats. While Ang II triggered potent activation of MAPKs and elicited prominent pro-inflammatory effects in brainstem astrocytes of both models, its activation in cerebellar astrocytes resulted in an increase in both pro- and anti-inflammatory states in both models. A reduction in CB1R expression, and CB1R-mediated anti-inflammatory effects were observed in brainstem astrocytes of SHRs when compared to Wistar rats. Although CB1R expression in cerebellar astrocytes was similar in both models, its downstream effects were partially reduced in cerebellar astrocytes of SHRs when compared to Wistar rats. While CB1R activation diminished Ang II-mediated pro-inflammatory effects in brainstem astrocytes of Wistar rats, its effects were not abated in SHRs. Interestingly, Ang II not only reduced CB1R expression in brainstem astrocytes of SHRs, but also triggered phosphorylation of CB1Rs in cerebellar astrocytes of both models. CONCLUSION: A dysregulated neuroinflammatory status, along with a dampened brainstem astroglial endocannabinoid tone, could well be important factors in the etiology of hypertension. Since AT1R activation results in downregulation and phosphorylation of CB1Rs, counteracting the effects of renin angiotensin system (RAS) could serve as a viable strategy to indirectly elevate/preserve the basal endocannabinoid tone. This is especially applicable to hypertension, which is characterized by hyperactivity of the RAS and a potential dysregulation of the endocannabinoid system.

Disciplines

Pharmacy and Pharmaceutical Sciences

Keywords

Biological sciences, Angiotensin, Astroglia, Brainstem, Cannabinoid type 1 receptor, Hypertension, SHR

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