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

Abstract

SUMMARYIn addition to regulating blood pressure, Angiotensin II exerts powerful pro-inflammatory effects in hypertension through stimulation of its AT 1 receptors, most clearly demonstrated in peripheral arteries and in the cerebral vasculature. Administration of Angiotensin 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 AT 1 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.

Lower Frequency of Antidepressant Use in Patients on Renin-Angiotensin-Aldosterone System Modifying Medications

“…Blockade of angiotensin II (AT) receptors prevents the HPA axis response to isolation stress and prevents the formation of stress-induced gastric ulcers in experimental animals (Saavedra et al 2005). The anti-inflammatory effects of ARBs may block the production of pro-inflammatory cytokines in the brain (Benicky et al 2009;Pavel et al 2008), thereby linking blockade of the RAAS system with cytokine theories of depression (Dinan 2009;Schiepers et al 2005).…”

Mouse TU tagging: a chemical/genetic intersectional method for purifying cell type-specific nascent RNA

“…To test the ability of TU tagging to identify newly induced transcripts, we assayed the spleen endothelial gene expression response to lipopolysaccharide (LPS) injection. This assay is ideal because several innate immune response genes are known to be induced by LPS injection (Buttini and Boddeke 1995;Qin et al 2007;Benicky et al 2009), and microarray data exist for spleen transcriptomes following LPS injection (Hammer et al 2006). We injected 4TU into Tie2:Cre; CA>GFPstop>UPRT adult mice and subsequently injected half of these mice with LPS after 1 h; 3 h later, we collected intact spleen tissue from both LPSinjected and uninjected mice (Fig.…”

The neuroinflammatory hypothesis of delirium

“…So, considerable interest exists whether the evidence reviewed in this paper can bring new approaches for the prevention and management of delirium. In this regard, some agents with anti-inflammatory action were useful to reduce LPS-induced microglial/astrocyte activation, production of pro-inflammatory mediators and facilitating recovery from neurobehavioural symptoms [11,56,84,118]. Likewise, in models of experimental sepsis there is evidence that blockage of C5a, a small peptide derived from complement activation, can prevent BBB breakdown [45].…”