Suppression of ischemia/reperfusion liver injury by histamine H4 receptor stimulation in rats.
Inflammatory reactions play an important role in ischemia/reperfusion injury in various organs. Since histamine is closely related to inflammatory reactions and immune responses, effects of postischemic administration of histaminergic ligands on ischemia-induced liver injury were examined in rats. Animals were subjected to warm ischemia for 30 min by occlusion of the left portal vein and hepatic artery under halothane anesthesia, and liver damage was evaluated by assessing plasma concentrations of transaminases after 24 h. Warm ischemia for 30 min provoked severe liver damage after 24 h, and the plasma concentrations of alanine transaminase (ALT) and aspartate transaminase (AST) were 8600 I.U./l and 13100 I.U./l, respectively. Subcutaneous injections of histamine twice, immediately and 6 h after reperfusion (20 mg/kg, each), alleviated liver damage. The plasma concentrations of ALT and AST in the histamine group were 35% and 24% of those in the control group, respectively. Neither mepyramine (3 mg/kg x 2), an H1 antagonist, nor cimetidine (15 mg/kg x 2), an H2 antagonist, affected the outcome in histamine-treated rats. However, thioperamide (5 mg/kg x 2), an H3/H4 antagonist, completely abolished the alleviation caused by histamine. Administration of dimaprit (1-10 mg/kg x 2), an H2/H4 agonist, mimicked the protective effect of histamine, and the effect of dimaprit is reversed by thioperamide, whereas neither H1 nor H2 antagonists altered the outcome caused by dimaprit. Clozapine (15 mg/kg x 2), an H4 agonist, also mimicked the protective effect of histamine. These findings indicate that stimulation of histamine H4 receptors after ischemic events prevents development of reperfusion injury in the liver.
Adachi
Naoto
N
Department of Anesthesiology and Resuscitology, Ehime University Graduate School of Medicine, Shitsukawa, Touon-shi, Ehime 791-0295, Japan. nadachi@m.ehime-u.ac.jp
Liu
Keyue
K
Motoki
Atsuko
A
Nishibori
Masahiro
M
Arai
Tatsuru
T
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D017259:Dimaprit / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism; D007511:Ischemia / Q000473:pathology; D008099:Liver / Q000293:injuries / Q000473:pathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D015427:Reperfusion Injury / Q000188:drug therapy*; D013997:Time Factors
C498828:Hrh4 protein, rat; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D006632:Histamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003024:Clozapine; D017259:Dimaprit