Journal
PHARMACEUTICALS
Volume 14, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/ph14050477
Keywords
adipose tissue; alpha 1-adrenoceptors antagonist; inflammation; adipocytokines; insulin resistance; obesity; metabolic syndrome; fructose-fed rats
Categories
Funding
- National Science Centre [DEC-2014/15/D/NZ7/01807]
- Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland [N42/DBS/000139]
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The study found that the non-quinazoline alpha(1)-adrenoceptor antagonist MH-76 can improve endothelial integrity, reduce adipose tissue inflammation and immune cell infiltration, and lower inflammatory cytokine levels in fructose-fed rats. In contrast, treatment with prazosin enhanced inflammatory effects in adipose tissue.
Background: Quinazoline alpha(1)-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 alpha(1)-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 alpha(1)-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 alpha(1)-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-alpha 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.
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