title: Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats.
abstract: 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.
authors.affiliation: Chair for Applied Pharmacology, Biozentrum/Pharmazentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nordheim
authors.forename: Janet R
authors.initials: JR
authors.lastname: Nicholson
authors.forename: Karol
authors.initials: K
authors.lastname: Dokladny
authors.forename: Patrick
authors.initials: P
authors.lastname: Dunant
authors.forename: Karl G
authors.initials: KG
authors.lastname: Hofbauer
mesh_terms: D000818:Animals; D001831:Body Temperature; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D003503:Cyclobutanes / Q000008:administration & dosage / Q000494:pharmacology*; D005247:Feeding Behavior / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000187:drug effects / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014851:Wakefulness / Q000502:physiology
chemical_list: D003503:Cyclobutanes; C467221: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; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4; D044005:Tetrahydroisoquinolines; D014230:Triazoles; C096756:HP 228; C058254:sibutramine