Monophosphoryl lipid A-induced delayed preconditioning is mediated by calcitonin gene-related peptide.
The delayed preconditioning of the heart by monophosphoryl lipid A is mediated by endogenous nitric oxide (NO), and the cardioprotection afforded by nitroglycerin is related to stimulation of calcitonin gene-related peptide (CGRP) release. The objective of this study was to explore whether improvement of preservation with cardioplegia by monophosphoryl lipid A is mediated by CGRP. In addition, we examined the effect of monophosphoryl lipid A on the tumor necrosis factor-alpha (TNF-alpha) content of myocardial tissues. The isolated rat heart was perfused in the Langendorff mode. Heart rate, coronary flow, left-ventricular pressure, and its first derivatives (+/-dp/dt(max)) were recorded, and plasma levels of NO and CGRP, the release of creatine kinase in coronary effluent and the content of TNF-alpha in myocardial tissues were measured. Hypothermic ischemia for 4 h caused a decline in cardiac function, and an increase in the release of creatine kinase and in the content of TNF-alpha. Pretreatment with monophosphoryl lipid A (500 microg/kg, i.p.) for 24 h improved the recovery of cardiac function and reduced the release of creatine kinase concomitantly with a decrease in the content of cardiac TNF-alpha. Monophosphoryl lipid A markedly increased plasma concentrations of CGRP and NO. After pretreatment with L-nitroarginine methyl ester (L-NAME), the cardioprotection and the increased release of NO and CGRP induced by monophosphoryl lipid A were abolished. Capsaicin also abolished the cardioprotection and the increased release of CGRP induced by monophosphoryl lipid A, but did not affect the content of NO. The results suggest that monophosphoryl lipid A-induced preconditioning enhances preservation with cardioplegia and that the protective effects of monophosphoryl lipid A are related to stimulation of CGRP release.
He
S Y
SY
Department of Pharmacology, Hunan Medical University, Hunan 410078, Changsha, People's Republic of China.
Deng
H W
HW
Li
Y J
YJ
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000187:drug effects* / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D008050:Lipid A / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
D008050:Lipid A; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003402:Creatine Kinase; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester