title: Melanocortin-4 receptor agonists alleviate intestinal dysfunction in secondary intra-abdominal hypertension rat model.
abstract: BACKGROUND
  Intra-abdominal hypertension (IAH) is a potentially life-threatening disease. Melanocortin-4 (MC4) receptor activation exhibits life-saving properties. The aim of the present study was to examine whether treatment with the MC4 receptor agonist RO27-3225 ameliorates intestinal injury in IAH rats.
  
  
  METHODS
  A total of 72 male Sprague-Dawley rats were randomized into six groups. Group 1 was the sham group. Group 2, the sham + RO group, received RO27-3225 (180 μg/kg, intraperitoneally). IAH was induced in group 3, the IAH group, by blood draw (mean arterial pressure = 30 mm Hg for 90 min) followed by shed blood and/or Ringer solution reinfusion. Intra-abdominal pressure was increased to 20 mm Hg by injecting air into the peritoneal cavity. Group 4, the RO group, was administered RO27-3225 at 5 min after blood draw. Groups 5 and 6 were the chlorisondamine (Chl) and HS024 groups, in which the rats were pretreated with the nicotinic acetylcholine receptor antagonist Chl or selective MC4 receptor antagonist (HS024), respectively, at 2 min before RO27-3225 was administered.
  
  
  RESULTS
  RO27-3225 restored mean arterial pressure, reduced tumor necrosis factor-α, and interleukin-1β messenger RNA expression increased by IAH, alleviated histologic damage, and improved superoxide dismutase activity in the intestine. Compared with the IAH group, the levels of intestinal fatty acid-binding protein, intestinal edema and intestinal permeability were lower in the RO group. Furthermore, the RO27-3225 treatment increased the expression of Rho-associated coiled-coil-containing protein kinase 1 and phosphorylated myosin light chain. Chl and HS024 abrogated the protective effects of RO27-3225.
  
  
  CONCLUSIONS
  These data indicate that the MC4 receptor agonist counteracts the intestinal inflammatory response, ameliorating intestinal injury in experimental secondary IAH by MC4 receptor-triggered activation of the cholinergic anti-inflammatory pathway. It may represent a promising strategy for the treatment of IAH in the future.
authors: Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Dong
authors: D
authors: Liu
authors: Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Hong-Guang
authors: HG
authors: Zhang
authors: Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Ming-Tao
authors: MT
authors: Chang
authors: Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors: Yang
authors: Y
authors: Li
authors: Trauma Center, State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China. Electronic address: dpzhangly@163.com.
authors: Lian-Yang
authors: LY
authors: Zhang
mesh_terms: D000818:Animals; D002714:Chlorisondamine; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D059325:Intra-Abdominal Hypertension / Q000188:drug therapy*; D008297:Male; D018994:Myosin Light Chains / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D010456:Peptides, Cyclic; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000037:antagonists & inhibitors; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D050556:Fatty Acid-Binding Proteins; C116098:HS 024; D053583:Interleukin-1beta; D018994:Myosin Light Chains; D010455:Peptides; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D014409:Tumor Necrosis Factor-alpha; C560214:butir-His-Phe-Arg-Trp-Sar-NH2; D013482:Superoxide Dismutase; C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases; D002714:Chlorisondamine
keywords: Intra-abdominal hypertension; Ischemia–reperfusion; Melanocortin receptors; Nicotinic acetylcholine receptors