Thaliporphine increases survival rate and attenuates multiple organ injury in LPS-induced endotoxaemia.
This study addressed the question of whether thaliporphine, a phenolic aporphine alkaloid obtained from Chinese herbs and possessing antioxidant and alpha-1 adrenoceptor antagonistic activity, has protective effects in endotoxaemic rats and we attempted to elucidate the mechanisms contributing to such protective effects. Injection of rats with endotoxin (E. coli lipopolysaccharide, LPS) induced severe hypotension and tachycardia as well as vascular hyporeactivity to noradrenaline. Pretreatment of LPS-treated rats with thaliporphine attenuated the delayed hypotension significantly whilst only a higher dose (1 mg/kg) of thaliporphine decreased LPS-induced tachycardia. LPS significantly increased nitric oxide (NO.) and superoxide anion (O(2).(-)) levels, a response that was reduced by pretreatment with 1 mg/kg thaliporphine. Endotoxaemia for 240 min resulted in a bell-shaped time course for the change of serum tumour necrosis factor-alpha (TNF-alpha) level with a peak at 60 min. Pretreatment of LPS-treated rats with 1 mg/kg thaliporphine significantly reduced the serum TNF-alpha level at 60 min. In addition, LPS caused a biphasic change in blood glucose and thaliporphine attenuated the late-phase decrease in blood glucose. Endotoxaemia induced multiple organ injury in the liver, kidney and heart, as indicated by increases of aspartate aminotransferase (GOT), alanine aminotransferase (GPT), creatinine (CRE), lactate dehydrogenase (LDH) and creatine phosphate kinase muscle-brain (CKMB) levels in serum. These increases of biochemical markers and inflammatory cell infiltration into injured tissues were reduced significantly by treatment with thaliporphine. In addition, thaliporphine increased the survival rate of LPS-treated mice dose-dependently. In conclusion, our results suggest that thaliporphine could be a novel agent for attenuating endotoxin-induced circulatory failure and multiple organ injury and may increase the survival rate. These beneficial effects of thaliporphine may be attributed to the suppression of TNF-alpha, NO. and O(2).(-) production.
Chiao
Chin-Wei
CW
Institute of Pharmacology, College of Medicine, National Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei, 100, Taiwan.
Lee
Shoei-Sheng
SS
Wu
Chin-Chen
CC
Su
Ming-Jai
MJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001060:Aporphines / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D016753:Interleukin-10 / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D009102:Multiple Organ Failure / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009566:Nitrates / Q000097:blood; D009638:Norepinephrine / Q000097:blood; D016877:Oxidants / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D012769:Shock / Q000503:physiopathology / Q000517:prevention & control; D013481:Superoxides / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000627:therapeutic use*
D001060:Aporphines; D001786:Blood Glucose; D008070:Lipopolysaccharides; D009566:Nitrates; D016877:Oxidants; D018340:Receptors, Adrenergic, alpha-1; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D013481:Superoxides; D016753:Interleukin-10; C080702:thaliporphine; D009638:Norepinephrine