ADMINISTRATION OF A MATRIX METALLOPROTEINASE INHIBITOR AFTER HEMORRHAGE IMPROVES CARDIOVASCULAR AND HEPATOCELLULAR FUNCTION

Although matrix metalloproteinase inhibitors prevent the increase in s oluble tumor necrosis factor-alpha during endotoxemia, it remains unkn own whether a novel matrix metalloproteinase inhibitor, GM6001, improv es cardiovascular and hepatocellular function after trauma and hemorrh age, To determine this, rats underwent laparotomy (i.e., trauma-induce d), 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 Ring er's lactate. The animals were then resuscitated with 3 times the volu me 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 o r an equal volume of normal saline, was administered subcutaneously 15 min before the completion of resuscitation. At 2 and 4 h after resusc itation, cardiac output was measured by indocyanine green (ICG) diluti on. Hepatocellular function (i.e., maximum velocity and the efficiency of ICG clearance) was determined by in vivo ICG clearance, Microvascu lar blood flow in various organs was assessed by laser Doppler flowmet ry. 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 impr oved the depressed cardiovascular and hepatocellular function, Since G M6001 improves cardiovascular and hepatocellular function, this agent may be a useful adjunct to fluid resuscitation after trauma and hemorr hagic shock.