Tolerance to nitroglycerin in rabbit aorta. Investigating the involvement of the mu isozyme of glutathione S-transferases.
We have proposed that glutathione S-transferases (GSTs), especially the mu isozyme, play a critical role in the metabolism of nitroglycerin (glyceryl trinitrate, GTN), leading to pharmacologic effects. Here we study this enzyme(s) during tolerance development in male New Zealand white rabbits. Each aorta was divided into two segments designated as GTN pretreated and buffer control. Tolerance was induced in rabbit aortic strips so assigned by incubation with GTN (0.22 mM). The activity of the mu isozyme and of total GSTs was determined in portions f each segment. In each rabbit aorta, the response to GTN (0.5 microM) was determined in GTN-pretreated and buffer-pretreated strips by measuring cyclic GMP levels (N = 7 pairs) and percent relaxation (N = 4 pairs). In GTN-pretreated strips, a significant decrease was observed in the activity of the mu isozyme of GST, while the total GST activity was unchanged as compared with control strips. The decrease in isozyme activity correlated very well with the decrease in response to GTN. Two rabbit aortae did not become tolerant, and the activity of the mu isozyme was also not affected. The levels of thiols were not affected by GTN pretreatment and aortae tolerant to GTN did not develop tolerance to S-nitroso acetylpenicillamine (SNAP), indicating that thiol depletion and guanylate cyclase desensitization probably play a minor role in tolerance development to GTN in our model. These studies suggest that tolerance to GTN in rabbit aorta in vitro is associated with a decrease in GST mu activity, which correlates well with the decrease in GTN response.
Kenkare
S R
SR
Department of Pharmacy, University of California, San Frnscisco, CA 94143-0446, USA.
Benet
L Z
LZ
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005982:Glutathione Transferase / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology*; D008297:Male; D005996:Nitroglycerin / Q000494:pharmacology*; D011817:Rabbits
D007527:Isoenzymes; D005982:Glutathione Transferase; D005996:Nitroglycerin; D006152:Cyclic GMP