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Hemodynamic actions and mechanisms of systemically administered α-MSH analogues in mice.
MedLine Citation:
PMID:  22982611     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
α-Melanocyte-stimulating hormone (α-MSH) regulates important physiological functions including energy homeostasis and inflammation. Potent analogues of α-MSH, [Nle(4), D-Phe(7)]-α-MSH (NDP-α-MSH) and melanotan-II (MT-II), are widely used in pharmacological studies, but the hemodynamic effects associated with their systemic administration have not been thoroughly examined. Therefore, we investigated the hemodynamic actions of these compounds in anesthetized and conscious C57Bl/6N mice using peripheral routes of administration. NDP-α-MSH and MT-II induced mild changes in blood pressure and heart rate in anesthetized mice compared to the effects observed in conscious mice, suggesting that anesthesia distorts the hemodynamic actions of α-MSH analogues. In conscious mice, NDP-α-MSH and MT-II increased blood pressure and heart rate in a dose-dependent manner, but the tachycardic effect was more prominent than the pressor effect. Pretreatment with the melanocortin (MC) 3/4 receptor antagonist SHU9119 abolished these hemodynamic effects. Furthermore, the blockade of β(1)-adrenoceptors with metoprolol prevented the pressor effect and partly the tachycardic action of α-MSH analogues, while the ganglionic blocker hexamethonium abrogated completely the difference in heart rate between vehicle and α-MSH treatments. These findings suggest that the pressor effect is primarily caused by augmentation of cardiac sympathetic activity, but the tachycardic effect seems to involve withdrawal of vagal tone in addition to sympathetic activation. In conclusion, the present results indicate that systemic administration of α-MSH analogues elevates blood pressure and heart rate via activation of MC(3/4) receptor pathways. These effects and the consequent increase in cardiac workload should be taken into account when using α-MSH analogues via peripheral routes of administration.
Authors:
Petteri Rinne; Sanna Tikka; Satu Mäkelä; Tomi Streng; Eriika Savontaus
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-9-11
Journal Detail:
Title:  Peptides     Volume:  -     ISSN:  1873-5169     ISO Abbreviation:  Peptides     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-9-17     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8008690     Medline TA:  Peptides     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Inc.
Affiliation:
Department of Pharmacology, Drug Development and Pharmaceutics, and Turku Center for Disease Modeling, University of Turku, Turku, Finland; Drug Discovery Graduate School, University of Turku. Electronic address: pperin@utu.fi.
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