Document Detail

Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats.
MedLine Citation:
PMID:  16274849     Owner:  NLM     Status:  MEDLINE    
In the present studies, we used a non-selective melanocortin MC3/4 receptor agonist (HP228) and a novel selective melanocortin MC4 receptor (MC4-R) agonist (MK-cpd1) to study the cardiovascular, temperature, locomotor and feeding responses to melanocortin receptor stimulation in comparison to sibutramine in rats instrumented with a telemetry transmitter. Moreover, norepinephrine turnover rates in heart and brown adipose tissue were determined. HP228 (1, 3 and 10mg/kg, i.p.) reduced 24h food intake dose-dependently and increased heart rate and mean arterial pressure (maximal differences: +60+/-8beats/min and +8+/-1mmHg, means+/-S.E.M., p<0.001 and p<0.01, respectively). After 10mg/kg HP228 showed a three-fold increase in norepinephrine turnover in the heart. The selective MC4-R agonist MK-cpd1 tended to decrease 24h food intake only at the highest dose tested (10mg/kg, i.p., p=0.06) and increased both heart rate (+17+/-4 and +22+/-5beats/min at 3 and 10mg/kg, p<0.01) and mean arterial pressure (+4+/-1mmHg at 10mg/kg, p<0.05). Sibutramine reduced food intake at all doses tested (1, 3 and 10mg/kg, i.p.). It did not change mean arterial pressure significantly, and increased heart rate only at the highest dose tested (+36+/-6beats/min, p<0.05). If also observed in humans, the pharmacological profile of MC4-R agonists would not offer a significant therapeutic advantage over currently used appetite suppressants such as sibutramine.
Ulrich Nordheim; Janet R Nicholson; Karol Dokladny; Patrick Dunant; Karl G Hofbauer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-11-07
Journal Detail:
Title:  Peptides     Volume:  27     ISSN:  0196-9781     ISO Abbreviation:  Peptides     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-01-31     Completed Date:  2006-05-25     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8008690     Medline TA:  Peptides     Country:  United States    
Other Details:
Languages:  eng     Pagination:  438-43     Citation Subset:  IM    
Chair for Applied Pharmacology, Biozentrum/Pharmazentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
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MeSH Terms
Body Temperature
Cardiovascular Physiological Phenomena / drug effects*
Cyclobutanes / administration & dosage,  pharmacology*
Feeding Behavior / drug effects
Oligopeptides / administration & dosage,  pharmacology*
Rats, Sprague-Dawley
Receptor, Melanocortin, Type 4 / drug effects,  metabolism*
Tetrahydroisoquinolines / pharmacology
Triazoles / pharmacology
Wakefulness / physiology
Reg. No./Substance:
0/Cyclobutanes; 0/N-(1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl)-1-(4-chlorobenzyl)-2-(4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl)-2-oxoethylamine; 0/Oligopeptides; 0/Receptor, Melanocortin, Type 4; 0/Tetrahydroisoquinolines; 0/Triazoles; 106650-56-0/sibutramine; 109022-88-0/HP 228

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