Delayed endothelial protective effects of monophosphoryl lipid A after myocardial ischemia and reperfusion in rats.
Monophosphoryl lipid A (MLA) induces delayed (24 h) myocardial protection in various animal models of ischemia/reperfusion injury, and thus mimics the second window of preconditioning against cardiac injury. However, the potential endothelial protective effects of this drug have not been evaluated. The present study was designed to assess whether MLA exerts delayed protective effects against reperfusion-induced coronary endothelial dysfunction in rats, as well as the protective role of iNOS in this protection. Wistar rats received a single i.v. injection of MLA (450 microg/kg) or solvent. Twenty-four hours later, they were anesthetized and subjected to 20 min ischemia with 60 min reperfusion, in the absence or the presence of the iNOS inhibitor aminoguanidine (300 mg/kg i.p.). At the end of reperfusion, 1.5-2 mm coronary segments (average diameter 250 microm) were removed distal to the site of occlusion and mounted in wire myographs. Endothelium-dependent relaxations to acetylcholine were determined in arteries pre-contracted by serotonin. Ischemia/reperfusion induced a marked decrease in the coronary responses to acetylcholine (maximal relaxations: sham 64+/-8%, n=8; ischemia/reperfusion: 41+/-9%, n=8 P<0.05). This impaired response was partially restored by MLA (55+/-4%, n=10 P<0.05 vs ischemia/reperfusion). The effect of MLA was not affected by aminoguanidine (57+/-5%, n=6). Thus, in addition to protecting myocytes, MLA induces a delayed protection against coronary endothelial dysfunction. However, in contrast to its effects on myocytes, the endothelial protective effects do not appear to involve iNOS.
Richard
V
V
Department of Pharmacology (VACOMED, IFRMP 23), Rouen University Medical School and Rouen University Hospital, Rouen, France.
Danielou
E
E
Kaeffer
N
N
Thuillez
C
C
D000109:Acetylcholine / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D019610:Cytoprotection; D004730:Endothelium, Vascular / Q000187:drug effects*; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D016015:Logistic Models; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D008050:Lipid A; D014665:Vasodilator Agents; D012701:Serotonin; C002385:linsidomine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C048436:monophosphoryl lipid A; D000109:Acetylcholine