Preservation of global cardiac function in the rabbit following protracted ischemia/reperfusion using monophosphoryl lipid A (MLA).
Monophosphoryl lipid A (MLA), a derivative of the minimal substructure of lipopolysaccharide (lipid A) possesses immunomodulatory activity of the parent lipid A yet enjoys reduced toxicity. It has previously been reported that pretreatment with MLA reduces myocardial infarct size and stunning in dogs following ischemia and reperfusion. The aim of this study was to evaluate the ability of monophosphoryl lipid A (MLA) to preserve global cardiac function and peripheral hemodynamics in a rabbit model of prolonged regional ischemia (90 min), and reperfusion (6 h). An evaluation of potential mechanisms by which MLA may preserve cardiac function was also undertaken. Single dose pretreatment with MLA (35 micrograms/kg i.v.) 24 h prior to ischemia resulted in significant improvement in left ventricular developed pressure, dP/dt, rate-pressure product and mean arterial pressure during reperfusion (P < 0.05 v control). Although in this model of prolonged ischemia MLA pretreatment did not reduce infarct size (54.5 +/- 11.4% in control v 63.3 +/- 8.3% in MLA, P = N.S.), evaluation of myocardial adenylate and adenosine catabolite pools at the end of ischemia indicated a preservation of ATP and ADP and a decreased production of downstream adenosine catabolites including inosine, xanthine and uric acid. Adenosine kinase, but not 5'-nucleotidase (5'-NTase) or adenosine deaminase activity determined following reperfusion was 76% and 60% higher (P < 0.05) in non-risk and post-ischemic myocardium of MLA pretreated rabbits compared with controls. Although there was a trend toward lower tissue myeloperoxidase activity in post-ischemic myocardium from treated rabbits, the results were not significantly different from control animals. These results suggest that a 24-h pretreatment with MLA, without further treatment during ischemia or reperfusion was associated with: (1) preservation of global myocardial function during reperfusion; (2) preservation of myocardial high energy adenylates and reduced formation of adenosine catabolites during ischemia; (3) elevated myocardial adenosine kinase activity. Increased recycling of adenosine to phosphorylated nucleotides may result from MLA's affect on adenosine kinase, which could explain the drugs effect on adenylate and adenosine metabolite pools.
Zhao
L
L
Department of Pharmaceutical Sciences, Ribi ImmunoChem Research Inc., Hamilton, Montana, USA.
Kirsch
C C
CC
Hagen
S R
SR
Elliott
G T
GT
D015720:5'-Nucleotidase / Q000378:metabolism; D000227:Adenine Nucleotides / Q000378:metabolism; D000243:Adenosine Deaminase / Q000378:metabolism; D000248:Adenosine Kinase / Q000378:metabolism; D000276:Adjuvants, Immunologic; D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure; D002240:Carbohydrate Sequence; D003331:Coronary Vessels; D004734:Energy Metabolism; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006339:Heart Rate; D006439:Hemodynamics / Q000187:drug effects; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D011817:Rabbits; D012016:Reference Values; D016277:Ventricular Function, Left
D000227:Adenine Nucleotides; D000276:Adjuvants, Immunologic; D008050:Lipid A; D011687:Purines; D009195:Peroxidase; D000248:Adenosine Kinase; D015720:5'-Nucleotidase; D000243:Adenosine Deaminase; C048436:monophosphoryl lipid A