Acute pancreatitis induced by activated polyamine catabolism is associated with coagulopathy: effects of alpha-methylated polyamine analogs on hemostasis.
OBJECTIVE
Polyamines are ubiquitous organic cations essential for cellular proliferation and tissue integrity. We have previously shown that pancreatic polyamine depletion in rats overexpressing the catabolic enzyme, spermidine/spermine N(1)-acetyltransferase (SSAT), results in the development of severe acute pancreatitis, and that therapeutic administration of metabolically stable alpha-methylated polyamine analogs protects the animals from pancreatitis-associated mortality. Our aim was to elucidate the therapeutic mechanism(s) of alpha-methylspermidine (MeSpd).


METHODS
The effect of MeSpd on hemostasis and the extent of organ failure were studied in SSAT transgenic rats with either induced pancreatitis or lipopolysaccharide (LPS)-induced coagulopathy. The effect of polyamines on fibrinolysis and coagulation was also studied in vitro.


RESULTS
Pancreatitis caused a rapid development of intravascular coagulopathy, as assessed by prolonged coagulation times, decreased plasma fibrinogen level and antithrombin activity, enhanced fibrinolysis, reduced platelet count and presence of schistocytes. Therapeutic administration of MeSpd restored these parameters to almost control levels within 24 h. In vitro, polyamines dose-dependently inhibited fibrinolysis and intrinsic coagulation pathway. In LPS-induced coagulopathy, SSAT transgenic rats were more sensitive to the drug than their syngeneic littermates, and MeSpd-ameliorated LPS-induced coagulation disorders.


CONCLUSIONS
Pancreatitis-associated mortality in SSAT rats is due to coagulopathy that is alleviated by treatment with MeSpd.
Hyvönen
M T
MT
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland. mervi.hyvonen@uku.fi
Sinervirta
R
R
Keinänen
T A
TA
Fashe
T
T
Grigorenko
N
N
Khomutov
A R
AR
Vepsäläinen
J
J
Alhonen
L
L
D000123:Acetyltransferases / Q000235:genetics; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000378:metabolism; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011073:Polyamines / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D013095:Spermidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D011073:Polyamines; D013095:Spermidine; D000099228:Diamine N-Acetyltransferase; C073193:1-methylspermidine