Abstract
Background: Quinazoline α1-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α1-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α1-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α1-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats. Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed. Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307. Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.
Highlights
Metabolic syndrome, an epidemic disorder of a global nature, is a cluster of risk factors that increase the likelihood of developing diabetes mellitus and cardiovascular disorders
In our previous study we showed that MH-76, in fructose-fed rats with metabolic syndrome, exerted antihypertensive effect, reversed endothelial dysfunction, decreased
In our previous study we showed that MH-76, in fructose-fed rats with metabolic syndrome, exerted antihypertensive effect, reversed endothelial dysfunction, decreased hyperglycemia and hypertriglyceridemia and reduced insulin resistance and abdominal adiposity
Summary
An epidemic disorder of a global nature, is a cluster of risk factors (i.e., abdominal adiposity, dyslipidemia, high blood pressure, insulin resistance and proinflammatory states) that increase the likelihood of developing diabetes mellitus and cardiovascular disorders. Adipose tissue releases free fatty acids that contribute to the development of insulin resistance in liver and muscles. Low-grade chronic inflammation affects local adipose physiology and exerts systemic detrimental effects on other tissues [1,4,7]. This is primarily due to macrophage infiltration as well as increased secretion of a large number of pro-inflammatory and decreased secretion of anti-inflammatory substances, like adipokines (adiponectin, resistin), hormones (leptin) and cyto- and chemokines Is a non-quinazoline α1 -adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity.
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