title: Involvement of alpha-calcitonin gene-related peptide in monophosphoryl lipid A-induced delayed preconditioning in rat hearts.
abstract: Recent study has shown that monophosphoryl lipid A-induced delayed preconditioning enhanced preservation with cardioplegia and that the protective effects of monophosphoryl lipid A were related to stimulation of calcitonin gene-related peptide (CGRP) release. The purpose of the present study was to explore whether the elevated release of CGRP induced by monophosphoryl lipid A is secondary to stimulation of CGRP synthesis via the nitric oxide (NO) pathway and to characterize the isoform of CGRP. Sprague-Dawley rats were pretreated with monophosphoryl lipid A 24 h before the experiment, and then the left main coronary artery of rat hearts was subjected to 1 h occlusion followed by 3 h reperfusion. Infarct size, plasma creatine kinase activity, the plasma level of CGRP, and the expression of CGRP isoforms (alpha- and beta-CGRP) mRNA in lumbar dorsal root ganglia were measured. Pretreatment with monophosphoryl lipid A (500 microg/kg, i.p.) significantly reduced infarct size and creatine kinase release. Monophosphoryl lipid A caused a significant increase in the expression of alpha-CGRP mRNA, but not of beta-CGRP mRNA, concomitantly with an increase in plasma concentrations of CGRP, and the increased level of CGRP expression happened before stimulation of CGRP release. The effect of monophosphoryl lipid A was completely abolished by pretreatment with L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of NO synthase or capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. The results suggest that the delayed cardioprotection afforded by monophosphoryl lipid A involves the synthesis and release of CGRP via the NO pathway, and that the protection is mainly mediated by the alpha-CGRP isoform.
authors.affiliation: Department of Pharmacology, Xiang-Ya Medical College, Central South University, Hunan 410078, Changsha, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
authors.forename: Rong
authors.initials: R
authors.lastname: Lu
authors.forename: Han Wu
authors.initials: HW
authors.lastname: Deng
authors.forename: Yuan Jian
authors.initials: YJ
authors.lastname: Li
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003402:Creatine Kinase / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D008050:Lipid A; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D003402:Creatine Kinase; D015740:Calcitonin Gene-Related Peptide; C048436:monophosphoryl lipid A; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester