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Anti-Inflammatory Effects of Angiotensin Receptor Blockers in the Brain and the Periphery

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Abstract

In addition to regulating blood pressure, Angiotensin II (Ang II) exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT1 receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Ang II receptor blockers (ARBs) decreases hypertension-related vascular inflammation in peripheral organs. In rodent models of genetic hypertension, ARBs reverse the inflammation in the cerebral microcirculation. We hypothesized that ARBs could be effective in inflammatory conditions beyond hypertension. Our more recent studies, summarized here, indicate that this is indeed the case. We used the model of systemic administration of the bacterial endotoxin lipopolysaccharide (LPS). LPS produces a robust initial inflammatory reaction, the innate immune response, in peripheral organs and in the brain. Pretreatment with the ARB candesartan significantly diminishes the response to LPS, including reduction of pro-inflammatory cytokine release to the general circulation and decreased production and release of the pro-inflammatory adrenal hormone aldosterone. In addition, the ARB very significantly decreased the LPS-induced gene expression of pro-inflammatory cytokines and microglia activation in the brain. Our results demonstrate that AT1 receptor activity is essential for the unrestricted development of full-scale innate immune response in the periphery and in the brain. ARBs, due to their immune response-limiting properties, may be considered as therapeutically useful in a number of inflammatory diseases of the peripheral organs and the brain.

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Abbreviations

Ang II:

Angiotensin II

AT1 :

Angiotensin II receptor type 1

COX-2:

Cyclooxygenase 2

ICAM-1:

Intercellular adhesion molecule 1

IκBα:

Nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor, alpha

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

iNOS:

Inducible nitric oxide synthase

LBP:

LPS binding protein

MAPKs:

Mitogen-activated protein kinases

MCP-1:

Monocyte chemotactic protein-1

NFκB:

Nuclear factor κB

PGE2 :

Prostaglandin E2

PLA2 :

Phospholipase A2

ROS:

Reactive oxygen species

sCD14:

Soluble CD14

TLR-4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor alpha

VCAM-1:

Vascular cell adhesion molecule 1

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Acknowledgments

This research was supported by the Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, USA.

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  1. Department of Health and Human Services, Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bldg. 10, Room 2D-57, Bethesda, MD, 20892, USA

    Julius Benicky, Enrique Sánchez-Lemus, Jaroslav Pavel & Juan M. Saavedra

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  1. Julius Benicky
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  2. Enrique Sánchez-Lemus
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Correspondence to Juan M. Saavedra.

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Benicky, J., Sánchez-Lemus, E., Pavel, J. et al. Anti-Inflammatory Effects of Angiotensin Receptor Blockers in the Brain and the Periphery. Cell Mol Neurobiol 29, 781–792 (2009). https://doi.org/10.1007/s10571-009-9368-4

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