The Effects of Higenamine on LPS-Induced
Experimental Disseminated Intravascular Coagulation (DIC) in Rats

Abstract

The effect of higenamine, a benzyl-tetrahydroisoquinoline alkaloid of the roots of Aconitum spp. (Ranunculaceae), on disseminated intravascular coagulation (DIC), was investigated using an experimental DIC rat model. The oral administration of higenamine (10 mg/kg or 50 mg/kg), significantly ameliorated the decrease of fibrinogen level in plasma, the increase of fibrinogen/fibrin degradation product (FDP) level, and the prolongation of prothrombin time (PT) induced by the i. v. infusion of lipopolysaccharide (LPS). The prolongation of activated partial thrombin time (aPTT) and the decrease of platelet count were suppressed. The increase in serum aspartate aminotransferase (AST) and blood urea nitrogen (BUN) were also significantly prevented with higenamine. The above results are suggestive that higenamine has therapeutic potential for DIC and/or accompanying multiple organ failure (MOF).

Key words

Higenamine - benzyl-tetrahydroisoquinoline - Aconitum spp. - Ranunculaceae - disseminated intravascular coagulation (DIC) - multiple organ failure (MOF)

References

• 1 Muller-Berghaus G. Pathophysiologic and biochemical events in disseminated intravascular coagulation: Dysregulation of procoagulant and anticoagulant pathway.  Seminars in Thrombosis Hemostasis. 1989;  15 58-86
• 2 Hugo T C. Phathophysiology of disseminated intravascular coagulation in sepsis.  Critical Care Medicine 2000. (Supplement);  28 S9-11
• 3 Kosuge T, Yokota M. Studies on cardiac principle of Aconite root.  Chemical and Pharmaceutical Bulletin. 1976;  24 176-8
• 4 Kosuge T, Yokota M, Nagasawa M. Studies on cardiac principle in Aconite roots. I. Isolation and structure determination of higenamine.  Yakugaku Zasshi. 1978;  98 1370-5
• 5 Kosuge T, Yokota M, Nukaya H, Gotoh Y, Nagasawa M. Studies on antitussive principles of Asiasari radix.  Chemical and Pharmaceutical Bulletin. 1978;  26 2284-5
• 6 Bensky D, Gamble A. (compiled and translated). Chinese Herbal Medicine Materia Medica. Eastland Press Seattle; 1986: 428-31
• 7 Chang K C, Lim J K, Park C W. Synthesis of higenamine and its cardiovascular effects in rabbit: Evidence for β-adrenoceptor agonist.  Korean Journal of Pharmacology. 1986;  22 96-104
• 8 Chang K C, Chong W S, Lee I J. Different pharmacological characteristics of structurally similar benzylisoquinoline analogs. Papaverine, higenamine, and GS 389, on isolated rat aorta and heart.  Canadian Journal of Physiology & Pharmacology. 1994;  72 327-34
• 9 Chong W S, Lee Y S, Kang Y J, Lee D H, Ryu J C, Yun-choi H S, Chang K C. Comparison of inodilator effect of higenamine, YS-49, YS-51, tetrahydroisoquinoline analogs, and dobutamine in the rat.  Korean Journal of Physiology & Pharmacology. 1998;  2 323-30
• 10 Yun-Choi H S, Pyo M K, Park K M, Chang K C, Lee D H. Anti-thrombotic effect of higenamine.  Planta Medica. 2001;  67 619-22
• 11 Kang Y J, Lee G w, Ku E B, Lee H Y, Chang K C. Inhibition of higenamine of LPS-induced iNOS mRNA expression and NO production in rat aorta.  Korean Journal of Physiology & Pharmacology. 1997;  1 297-302
• 12 Lee H Y, Lee J S, Kim E J, Han J W, Lee H W, Kang Y J, Chang K C. Inhibition of lipopolysaccharide-induced inducible nitric oxide (iNOS) mRNA expression and nitric oxide production by higenamine in murine peritoneal macrophages.  Archives of Pharmacal Research. 1999;  22 55-9
• 13 Yun-Choi HS and Kim M H. Higenamine reduced mortalities in the mouse models of thrombosis and endotoxic shock.  Yakhak Hoeji. 1994;  38 191-6
• 14 Chang K C, Yun-Choi H S, Lim J K, Park C W. Synthesis of higenamine, A cardiotonic principle of Aconite root.  Archives of Pharmacal Research. 1984;  7 133-6
• 15 Kim Y S, Pyo M K, Park K M, Hahn B S, Yang KY and Yun-Choi H S. Dose dependency of earthworm powder on antithrombotic and fibrinolytic effects.  Archives of Pharmacal Research.. 1998;  4 374-7
• 16 Kawamura M, Terashita Z, Kmura Y, Shino A, Nishikawa K. Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in rats: Possible role of PAF in tissue factor generation.  Thrombosis Research. 1993;  70 281-93
• 17 Mark E A, Eric C R. Septic shock.  Lancet. 1998;  351 1501-5
• 18 Thiagarajih S, Wheby M S, Jain , May H V, Bourgeois J, Kitchin J D. Disseminated intavascular coagulation in pregnancy; The role of heparin therapy.  Journal of Reproductive Medicine. 1981;  26 17-20
• 19 Petitti D B, Strom B L, Melmon K L. Prothrombin time ratio and other factors associated with bleeding in patients treated with wafferin.  Journal of Clinical Epidemiology. 1989;  42 759-64
• 20 Onaya J, Kyogashima M, Sunose A, Miyauchi S, Mizuno S, Horie K. Effects of dermatan sulfate, a heparin cofactor II mediated thrombin inhibitor, on the endotoxin-induced disseminated intravascular coagulation model in the rat: comparison with low-molecular weight heparin, nafamostat mesilate and argathroban.  Japanese Journal of Pharmacology. 1998;  76 397-404