Resorcylidene aminoguanidine induces antithrombotic action that is not dependent on its antiglycation activity.
There is good evidence supporting the notion that aminoguanidine(AG)-derived compounds prevent glycation/glycooxidation-dependent processes and therefore inhibit late diabetic complications. The aim of the present work was to analyse the antithrombotic action and antiglycation activity of beta-resorcylidene aminoguanidine (RAG) in comparison with another commonly used aminoguanidine (AG)-derived compound, pyridoxal aminoguanidine (PAG). In vitro RAG and PAG prevented exhaustive glycation and glycooxidation of BSA to a similar extent. However, merely RAG showed almost complete binding to sepharose-immobilized heparin, while PAG and other AG derivatives had much poorer affinities. In the model of in vivo thrombosis in Wistar rats with extracorporeal circulation RAG (i.v. 30 mg/kg), but not PAG, produced sustained (2 h) antithrombotic effect, which was abrogated by indomethacin (5 mg/kg) and rofecoxib (1 mg/kg). The 60-day treatment of streptozotocin-diabetic animals with RAG (p.o. 4 mg/kg) significantly decreased plasma concentration of a thromboxane B(2) and reduced whole blood platelet aggregability triggered by ADP or collagen. In conclusion, although RAG and PAG displayed similar antiglycation and antioxidation activities in vitro, only RAG showed antithrombotic activity in vivo that involved activation of COX-2/PGI(2) pathway. Our results indicate that designing novel RAG derivatives with optimal antithrombotic and antiglycation activities may prove useful to treat diabetic complications.
Watala
Cezary
C
Department of Haemostasis and Haemostatic Disorders, Chair of Laboratory Diagnostics, Medical University of Lodz, University Hospital no. 2, Lodz, Poland. cwatala@csk.umed.lodz.pl
Dobaczewski
Marcin
M
Kazmierczak
Piotr
P
Gebicki
Jerzy
J
Nocun
Marek
M
Zitnanova
Ingrid
I
Ulicna
Olga
O
Durackova
Zdena
Z
Waczulíková
Iveta
I
Carsky
Jozef
J
Chlopicki
Stefan
S
D000818:Animals; D002417:Cattle; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006031:Glycosylation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013927:Thrombosis / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology
D005343:Fibrinolytic Agents; D017127:Glycation End Products, Advanced; D006146:Guanidines; C115168:resorcylidene aminoguanidine; D012710:Serum Albumin, Bovine