title: Ischemia/reperfusion-induced increase in the hepatic level of prostacyclin is mainly mediated by activation of capsaicin-sensitive sensory neurons in rats.
abstract: Capsaicin-sensitive sensory neurons are nociceptive neurons that release calcitonin gene-related peptide (CGRP) on activation by various noxious stimuli. CGRP has been shown to increase the endothelial production of prostacyclin, which reduces ischemia/reperfusion (I/R)-induced liver injury. Therefore, if the sensory neurons can be activated by the pathologic process of hepatic I/R, they might help ameliorate I/R-induced liver injury by promoting the endothelial production of prostacyclin, also known as prostaglandin I(2). In this study, we examined these possibilities using a rat model of I/R-induced liver injury. Male Wistar rats were subjected to 60-minute hepatic ischemia and subsequent reperfusion. Hepatic levels of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), a stable metabolite of prostacyclin, were significantly increased after hepatic I/R, peaking 1 hour after reperfusion. Administration of capsaicin and CGRP significantly enhanced I/R-induced increases in hepatic levels of 6-keto-PGF(1alpha), increased hepatic-tissue blood flow after reperfusion, and inhibited the I/R-induced increase in tissue levels of both tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase. Capsazepine, a vanilloid receptor antagonist; CGRP(8-37), a CGRP-receptor antagonist; l-nitro-arginine-methyl-ester (L-NAME), a nonselective inhibitor of nitric oxide (NO) synthase (NOS); and indomethacin, a nonselective inhibitor of cyclooxygenase, inhibited the I/R-induced increases in hepatic tissue levels of 6-keto-PGF(1alpha) and decreased hepatic-tissue blood flow after reperfusion. These compounds significantly enhanced the I/R-induced increases in hepatic tissue levels of both TNF-alpha and myeloperoxidase. Although I/R-induced liver injury was significantly reduced by capsaicin and CGRP, it was exacerbated by capsazepine, CGRP(8-37), L-NAME, and indomethacin. Administration of aminoguanidine, a selective inhibitor of the inducible form of NOS, and NS-398, a selective inhibitor of cyclooxygenase-2, demonstrated no effects on the liver injury or the hepatic levels of 6-keto-PGF(1alpha). These findings strongly suggest that the activation of the sensory neurons helps ameliorate I/R-induced liver injury both by increasing hepatic-tissue blood flow and by limiting inflammatory response through the enhancement of endothelial production of prostacyclin. In the sensory neuron-mediated enhancement of endothelial production of prostacyclin, CGRP-induced activation of both endothelial NOS and cyclooxygenase-1 may be critically involved.
authors.affiliation: Department of Laboratory Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, Kumamoto 068-0811, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Uchiba
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuragi
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D008565:Membrane Proteins; D008916:Miotics / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D013047:Specific Pathogen-Free Organisms; D013449:Sulfonamides / Q000494:pharmacology; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D006146:Guanidines; D007527:Isoenzymes; D008565:Membrane Proteins; D008916:Miotics; D009578:Nitrobenzenes; D010446:Peptide Fragments; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C058636:calcitonin gene-related peptide (8-37); C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D009195:Peroxidase; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D000637:Transaminases; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002211:Capsaicin; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin