Administration of a matrix metalloproteinase inhibitor after hemorrhage improves cardiovascular and hepatocellular function.
Although matrix metalloproteinase inhibitors prevent the increase in soluble tumor necrosis factor-alpha during endotoxemia, it remains unknown whether a novel matrix metalloproteinase inhibitor, GM6001, improves cardiovascular and hepatocellular function after trauma and hemorrhage. To determine this, rats underwent laparotomy (i.e., trauma-induced), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal shed volume was returned in the form of Ringer's lactate. The animals were then resuscitated with 3 times the volume of maximal bleedout with Ringer's lactate over 45 min, followed by 2 times Ringer's lactate over 60 min. GM6001, at a dose of 100 mg/kg or an equal volume of normal saline, was administered subcutaneously 15 min before the completion of resuscitation. At 2 and 4 h after resuscitation, cardiac output was measured by indocyanine green (ICG) dilution. Hepatocellular function (i.e., maximum velocity and the efficiency of ICG clearance) was determined by in vivo ICG clearance. Microvascular blood flow in various organs was assessed by laser Doppler flowmetry. The results indicate that cardiac output, hepatocellular function, and tissue microvascular blood flow decreased significantly at 2 and 4 h after resuscitation. GM6001 treatment, however, significantly improved the depressed cardiovascular and hepatocellular function. Since GM6001 improves cardiovascular and hepatocellular function, this agent may be a useful adjunct to fluid resuscitation after trauma and hemorrhagic shock.
Wang
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P
Center for Surgical Research, Brown University School of Medicine, Providence, Rhode Island, USA.
Ba
Z F
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Galardy
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Chaudry
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IH
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006470:Hemorrhage / Q000188:drug therapy*; D008099:Liver / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008833:Microcirculation / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D012151:Resuscitation; D014947:Wounds and Injuries / Q000188:drug therapy
D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D008666:Metalloendopeptidases