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To gain direct insight into the role of melanocortin MC<jats:sub>4<\/jats:sub>receptors in haemorrhagic shock, we investigated the effects of two novel selective MC<jats:sub>4<\/jats:sub>receptor agonists.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach:<\/jats:title><jats:p>Severe haemorrhagic shock was produced in rats under general anaesthesia. Rats were then treated with either the non\u2010selective agonist [Nle<jats:sup>4<\/jats:sup>, D\u2010Phe<jats:sup>7<\/jats:sup>]\u03b1\u2010melanocyte\u2010stimulating hormone (NDP\u2010\u03b1\u2010MSH) or with the selective MC<jats:sub>4<\/jats:sub>agonists RO27\u20103225 and PG\u2010931. 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results:<\/jats:title><jats:p>All shocked rats treated with saline died within 30\u201035 min. Treatment with NDP\u2010\u03b1\u2010MSH, RO27\u20103225 and PG\u2010931 produced a dose\u2010dependent (13\u2010108 nmol kg<jats:sup>\u20101<\/jats:sup>i.v.) restoration of cardiovascular and respiratory functions, and improved survival. The three melanocortin agonists also markedly reduced circulating free radicals relative to saline\u2010treated shocked rats. All these effects were prevented by i.p. pretreatment with the selective MC<jats:sub>4<\/jats:sub>receptor antagonist HS024. Moreover, treatment with RO27\u20103225 prevented morphological and immunocytochemical changes in heart, lung, liver, and kidney, at both early (25 min) and late (24 h) intervals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications:<\/jats:title><jats:p>Stimulation of MC<jats:sub>4<\/jats:sub>receptors reversed haemorrhagic shock, reduced multiple organ damage and improved survival. Our findings suggest that selective MC<jats:sub>4<\/jats:sub>receptor agonists could have a protective role against multiple organ failure following circulatory shock.<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic>(2007)<jats:bold>150<\/jats:bold>, 595\u2013603. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0707115\">10.1038\/sj.bjp.0707115<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1038\/sj.bjp.0707115","type":"journal-article","created":{"date-parts":[[2007,1,23]],"date-time":"2007-01-23T16:23:53Z","timestamp":1169569433000},"page":"595-603","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Selective melanocortin MC<sub>4<\/sub>receptor agonists reverse haemorrhagic shock and prevent multiple organ 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