Effect of metallothionein on tolerance of nitroglycerin in rats.
OBJECTIVE
To assess whether metallothionein (Met) could improve the nitroglycerin tolerance in vivo.


METHODS
Nitrate tolerance was induced by 2-d treatment of nitroglycerin (Nit) patch (0.05 mg.h-1). Endogenous Met production was induced by pretreatment of ZnCl2 and coadministration of intravenous Met (15 mg.kg-1.d-1) 2 d with Nit in tolerant rats. The induction of Met production was confirmed by the assay of liver and plasma Met levels.


RESULTS
ZnCl2 induced large amount of endogenous Met production in liver and plasma in Nit + ZnCl2 group than that in control group, (89 +/- 4) micrograms/g tissue vs (11.0 +/- 2.4) micrograms/g tissue in liver, P < 0.01, and in plasma (85 +/- 6) micrograms.L-1 vs (71 +/- 6) micrograms.L-1, P < 0.01. There was no significant difference in plasma Met levels in Nit and control groups [(75 +/- 6) micrograms.L-1 vs (71 +/- 6) micrograms.L-1, P > 0.05]. The endogenous Met production enhanced the hypotensive response in Nit + ZnCl2 group [(15.7 +/- 0.8) kPa vs (11.5 +/- 0.6) kPa, n = 6, P < 0.05]. The maximal vessel relaxation induced by sodium nitroprusside (SNP) was the same in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response to SNP) was found in tolerant group [(42 +/- 9) nmol.L-1, P < 0.01].


CONCLUSIONS
Exogenous Met or induction of endogenous Met production antagonize the development of Nit tolerance.
Shakya
U
U
Department of Pediatrics, First Hospital, Beijing Medical University, Beijing 100034, China.
Chen
Y H
YH
Wang
X H
XH
Tang
C S
CS
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002712:Chlorides; D004361:Drug Tolerance; D008099:Liver / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis / Q000494:pharmacology* / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D017967:Zinc Compounds
D002712:Chlorides; D014665:Vasodilator Agents; D017967:Zinc Compounds; C016837:zinc chloride; D008668:Metallothionein; D005996:Nitroglycerin