Inhibition of heparin synthesis by methotrexate in rats in vivo.
The content and synthesis of heparin and mast cell-dependent skin oedema (as an indirect evaluation of histamine and serotonin content) were investigated in the rat skin after chronic treatment with compound 48/80, a mast cell degranulating substance. The effect of methotrexate, a folic acid analogue that interrupts the synthesis of DNA and RNA, on heparin synthesis and amine storage also was evaluated in rat skin. The heparin content at 6 and 240 hr after treatment with compound 48/80 was reduced markedly (86 and 64%, respectively). At 6 hr, heparin synthesis increased 3.1-fold compared with control animals; maximal synthesis occurred at 24 hr post-treatment (12.8-fold increase), decaying at 240 hr (2.4-fold increase). The dermatan sulfate content and synthesis were not affected by treatment with compound 48/80. Autoradiographic analysis revealed that methotrexate (2.5mg/kg for 3 consecutive days) abolished heparin synthesis at 6, 24, and 72 hr after compound 48/80 treatment, without affecting dermatan sulfate synthesis. The oedema induced by intradermal injection of compound 48/80 (1 microg/site) into the rat skin was decreased significantly at 6 hr after chronic treatment with this compound, but was restored completely 72 hr post-treatment. This pattern of oedematogenic response was also observed in the methotrexate-treated rats. In conclusion, our results show that methotrexate suppresses heparin synthesis without affecting the synthesis of either dermatan sulfate or the co-stored amines histamine/serotonin (as evaluated by measuring the mast cell-dependent oedema), suggesting that the enzyme system involved in heparin synthesis is inducible.
Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, P.O. Box 6111, 13081-970 Campinas (SP), Brazil. s_marcondes@uol.com.br
Sisi
S
Marcondes
Elaine C
EC
Baú
Edson
E
Antunes
Carl P
CP
Dietrich
Helena B
HB
Nader
Gilberto
G
De Nucci
D000818:Animals; D003871:Dermatan Sulfate / Q000096:biosynthesis; D003879:Dermatologic Agents / Q000494:pharmacology*; D004487:Edema / Q000188:drug therapy; D006493:Heparin / Q000096:biosynthesis*; D006632:Histamine / Q000096:biosynthesis; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D016683:Supine Position; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
D003879:Dermatologic Agents; D003871:Dermatan Sulfate; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D006493:Heparin; D008727:Methotrexate