Selective melanocortin MC4 receptor agonists reverse haemorrhagic shock and prevent multiple organ damage.
OBJECTIVE
In circulatory shock, melanocortins have life-saving effects likely to be mediated by MC4 receptors. To gain direct insight into the role of melanocortin MC4 receptors in haemorrhagic shock, we investigated the effects of two novel selective MC4 receptor agonists.


METHODS
Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non-selective agonist [Nle4, D-Phe7]-melanocyte-stimulating hormone (NDP--MSH) or with the selective MC4 agonists RO27-3225 and PG-931. Cardiovascular and respiratory functions were continuously monitored for 2 h; survival rate was recorded up to 24 h. Free radicals in blood were measured using electron spin resonance spectrometry; tissue damage was evaluated histologically 25 min or 24 h after treatment.


RESULTS
All shocked rats treated with saline died within 30-35 min. Treatment with NDP--MSH, RO27-3225 and PG-931 produced a dose-dependent (13-108 nmol kg-1 i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline-treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC4 receptor antagonist HS024. Moreover, treatment with RO27-3225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals.


CONCLUSIONS
Stimulation of MC4 receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC4 receptor agonists could have a protective role against multiple organ failure following circulatory shock.
Giuliani
D
D
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
Mioni
C
C
Bazzani
C
C
Zaffe
D
D
Botticelli
A R
AR
Capolongo
S
S
Sabba
A
A
Galantucci
M
M
Iannone
A
A
Grieco
P
P
Novellino
E
E
Colombo
G
G
Tomasi
A
A
Catania
A
A
Guarini
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000097:blood; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D009102:Multiple Organ Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D015656:Respiratory Mechanics; D012720:Severity of Illness Index; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
C486899:Ac-Nle-c(Asp-Pro-D-Phe-Arg-Trp-Lys)-Pro-Val-NH2; D005609:Free Radicals; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-