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MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats

Background: Quinazoline α(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 recommend...

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Autores principales: Kubacka, Monika, Mogilski, Szczepan, Zadrożna, Monika, Nowak, Barbara, Szafarz, Małgorzata, Pomierny, Bartosz, Marona, Henryk, Waszkielewicz, Anna, Jawień, Wojciech, Sapa, Jacek, Bednarski, Marek, Knutelska, Joanna, Kotańska, Magdalena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157569/
https://www.ncbi.nlm.nih.gov/pubmed/34069933
http://dx.doi.org/10.3390/ph14050477
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author Kubacka, Monika
Mogilski, Szczepan
Zadrożna, Monika
Nowak, Barbara
Szafarz, Małgorzata
Pomierny, Bartosz
Marona, Henryk
Waszkielewicz, Anna
Jawień, Wojciech
Sapa, Jacek
Bednarski, Marek
Knutelska, Joanna
Kotańska, Magdalena
author_facet Kubacka, Monika
Mogilski, Szczepan
Zadrożna, Monika
Nowak, Barbara
Szafarz, Małgorzata
Pomierny, Bartosz
Marona, Henryk
Waszkielewicz, Anna
Jawień, Wojciech
Sapa, Jacek
Bednarski, Marek
Knutelska, Joanna
Kotańska, Magdalena
author_sort Kubacka, Monika
collection PubMed
description Background: Quinazoline α(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 α(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 α(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 α(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-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.
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spelling pubmed-81575692021-05-28 MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats Kubacka, Monika Mogilski, Szczepan Zadrożna, Monika Nowak, Barbara Szafarz, Małgorzata Pomierny, Bartosz Marona, Henryk Waszkielewicz, Anna Jawień, Wojciech Sapa, Jacek Bednarski, Marek Knutelska, Joanna Kotańska, Magdalena Pharmaceuticals (Basel) Article Background: Quinazoline α(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 α(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 α(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 α(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-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. MDPI 2021-05-18 /pmc/articles/PMC8157569/ /pubmed/34069933 http://dx.doi.org/10.3390/ph14050477 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kubacka, Monika
Mogilski, Szczepan
Zadrożna, Monika
Nowak, Barbara
Szafarz, Małgorzata
Pomierny, Bartosz
Marona, Henryk
Waszkielewicz, Anna
Jawień, Wojciech
Sapa, Jacek
Bednarski, Marek
Knutelska, Joanna
Kotańska, Magdalena
MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title_full MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title_fullStr MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title_full_unstemmed MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title_short MH-76, a Novel Non-Quinazoline α(1)-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats
title_sort mh-76, a novel non-quinazoline α(1)-adrenoceptor antagonist, but not prazosin reduces inflammation and improves insulin signaling in adipose tissue of fructose-fed rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157569/
https://www.ncbi.nlm.nih.gov/pubmed/34069933
http://dx.doi.org/10.3390/ph14050477
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