Metabolism of nitroglycerin by smooth muscle cells. Involvement of glutathione and glutathione S-transferase.
Metabolism of nitroglycerin (GTN) in the vascular smooth muscle is required for the drug to be effective in the treatment of angina pectoris and congestive heart failure. The usefulness of GTN is limited by the development of tolerance to the drug. The metabolism of GTN was studied in its target tissue, vascular smooth muscle. Inorganic nitrite was produced by cultured smooth muscle cells when GTN was added to the culture dish. Nitrite production increased with increasing GTN concentration and with incubation time. The enzymatic nature of GTN metabolism to nitrite was assessed by enzyme inhibition studies. Indocyanine green, a non-substrate inhibitor of glutathione S-transferase, inhibited GTN metabolism by smooth muscle cells. Cellular glutathione is also involved in GTN metabolism by the smooth muscle cell. Pretreatment with phorone, a glutathione S-transferase substrate, depleted cellular glutathione and decreased nitrite production from GTN. Pretreatment with buthionine sulfoximine, inhibitor of gamma-glutamylcysteine synthetase, decreased intracellular glutathione and caused decreased GTN metabolism in smooth muscle cells. Removal of cysteine from the smooth muscle cell incubation medium in combination with buthionine sulfoximine pretreatment decreased GTN metabolism to a lower level than buthionine sulfoximine pretreatment alone. This study shows that glutathione S-transferase and glutathione are involved in GTN metabolism by cultured smooth muscle cells.
Hill
K E
KE
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
Hunt
R W
RW
Jones
R
R
Hoover
R L
RL
Burk
R F
RF
D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007208:Indocyanine Green / Q000494:pharmacology; D007659:Ketones / Q000494:pharmacology; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats
D007659:Ketones; D009573:Nitrites; C018637:phorone; D005982:Glutathione Transferase; D005996:Nitroglycerin; D005978:Glutathione; D007208:Indocyanine Green