Histamine protects against the acute phase of experimentally-induced hepatic ischemia/re-perfusion.
Histamine, involved in many inflammatory reactions and immune responses, is reported to suppress--via H4R stimulation--injury concomitant with the late phase of warm hepatic ischemia/re-perfusion (I/R). The current study investigated the possible effects of histamine on the acute phase of hepatic I/R injury, and the possible underlying mechanisms like oxidative stress and release of inflammatory cytokines (e.g., tumor necrosis factor (TNF)-α nd interleukin [IL]-12). Rats were divided into naïve, sham-operated, and I/R groups. The I/R group was divided into sub-groups and pre-treated with histaminergic ligands before induction of ischemia. Anesthetized rats were subjected to warm ischemia for 30 min by occlusion of the portal vein and hepatic artery, then re-perfused for 90 min. Rats in the control I/R group showed significant increases in hepatic malondialdehyde (MDA), TNFα, and IL-12 contents, and in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, along with significant decreases in hepatic reduced glutathione (GSH) content and marked diffuse histopathologic damage. Pre-treatment with histamine resulted in significant mitigation of each of these end-points. The protective effect of histamine was not antagonized by pre-treatment with mepyramine (H1R antagonist) or ranitidine (H2R antagonist) and completely reversed by pre-treatment with thioperamide (H3R and H4R antagonist). In addition, the histamine protective effect was mimicked by pre-treatment of rats with clozapine (H4R agonist). These observations strongly suggested that histamine has a protective effect against hepatic I/R-mediated tissue injury during the acute phase, and this effect was mediated through an H4R stimulation that led to a decrease in IL-12 and TNFα production--outcomes that consequently decreased localized oxidative stress and afforded hepatic protection in general.
Department of Pharmacology and Toxicology, Tanta University, Tanta, Egypt.
Nageh A
NA
El-Mahdy
Alaa E
AE
El-Sisi
Bedair I
BI
Dewidar
Karima I
KI
El-Desouky
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D006632:Histamine / Q000276:immunology*; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015427:Reperfusion Injury / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D006633:Histamine Antagonists; D018836:Inflammation Mediators; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D008315:Malondialdehyde; D006632:Histamine; D011899:Ranitidine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011738:Pyrilamine; C052075:thioperamide