Bioactivation of nitroglycerin to nitric oxide (NO) and S-nitrosothiols in the rat liver and evaluation of the coexisting hypotensive effect.
The aim of the present study was to investigate nitroglycerin (NTG) bioactivation pathways in the liver after various periods of its administration. We also attempted to elucidate the relationship between nitric oxide (NO) and S-nitrosothiol (SNT) levels, and concentration of nonprotein thiols (NPSH) and intensity of peroxidative processes. Intravenous injections of NTG cause an increase in NO and SNT levels in the rat liver. The same intravenous NTG injections in the rats pretreated with 5-day i.p. NTG administrations lead to a drop in the levels of the biologically active NO, SNT and NPSH, with no concomitant changes in the rate of lipid peroxidation. This indicates that after such period of nitroglycerin pretreatment, levels of pharmacologically active NO and SNT decrease. However, during longer periods of NTG administration (for 10 and 17 days) NO, SNT and NPSH concentrations remain at the control level in spite of a considerably enhanced lipid peroxidation, which indicates that tolerance did not develop. Effects of NTG bioactivation in the liver, i.e. the levels of NO and SNT released from it, after different periods of drug administration correspond with hypotensive effects, which are known to be dependent on NTG biodegradation in vascular endothelial cells. The changes in NO and SNT levels observed in the rat liver after different periods of NTG administration parallel alterations in the hypotensive effect. In conclusion, NTG treatment for 10 and 17 days does not lead to tolerance, however, a transient loss of its pharmacological activity occurs after 5-day NTG pretreatment.
Sokołowska
Maria
M
Institute of Medical Biochemistry, Jagiellonian University, Collegium Medicum, Kopernika 7, 31-034 Krakow, Poland.
Bednarski
Marek
M
Kwiecień
Inga
I
Filipek
Barbara
B
Włodek
Lidia
L
D000818:Animals; D001711:Biotransformation; D005982:Glutathione Transferase / Q000378:metabolism; D007022:Hypotension / Q000139:chemically induced; D015227:Lipid Peroxidation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026403:S-Nitrosothiols / Q000378:metabolism*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D026403:S-Nitrosothiols; D014665:Vasodilator Agents; D009569:Nitric Oxide; D005982:Glutathione Transferase; D005996:Nitroglycerin