Effects of glutathione S-transferase inhibitors on nitroglycerin action in pig isolated coronary arteries.

Abstract

1. The present study was designed to clarify the role of glutathione S-transferase (GST) in the vasorelaxation response and development of tolerance to nitroglycerin (GTN) using GST inhibitors. 2. In pig isolated coronary arteries, GST activity was significantly changed to 77 and 82, or 69% of the control level (100%) following treatment with bromosulphophthalein (BSP; 10-3 and 10-4 mol/L) or ethacrynic acid (ETA; 10-4 mol/L), both GST inhibitors, respectively, but not following treatment with 10-3 and 10-4 mol/L GTN (GST activity 97 and 98% of control, respectively). 3. In KCl-contracted coronary artery strips pre-incubated with 10-5 and 10-4 mol/L GTN, 10-4 and 10-3 mol/L BSP or 10-4 mol/L ETA, concentration-dependent relaxations produced by GTN were significantly decreased compared with control. 4. 8-Bromo cGMP (8-Br-cGMP), a membrane-permeable cGMP analogue, produced concentration-dependent relaxations in GTN-pretreated arterial strips that were identical to control responses. However, there was weak but significant decrease in concentration-dependent relaxations in response to 8-Br-cGMP in BSP- and ETA-pretreated arteries. 5. The cGMP content in coronary arteries was significantly increased with GTN, GTN + BSP or GTN + ETA to similar high levels compared with control. 6. The results of the present study show that BSP and ETA decrease GTN- and 8-Br-cGMP-induced vasorelaxation, but have no effect on the GTN-induced increase in cGMP content in coronary arteries, suggesting a possibility that the GST inhibitors may have depressant actions on GTN- and 8-Br-cGMP-induced vasorelaxation through direct inhibition of the vasorelaxation of vascular smooth muscle themselves, in addition to having inhibitory effects GST activity.