Comparing the role of glutathione-S-transferase and mitochondrial aldehyde dehydrogenase in nitroglycerin biotransformation and the correlation with calcitonin gene-related peptide.
Both glutathione-S-transferase (GST) and mitochondrial aldehyde dehydrogenase (ALDH-2) have been reported to participate in the biotransformation of nitroglycerin. In this study, we explored which is the major player in nitroglycerin biotransformation. In vivo, rats were treated with nitroglycerin, the blood pressure and plasma calcitonin gene-related peptide (CGRP) were measured. The inhibitor of GST (ethacrynic acid) or ALDH-2 (cyanamide) was given before nitroglycerin treatment; In vitro, the isolated aorta rings were incubated with nitroglycerin to obtain the concentration-response curve. Ethacrynic acid or cyanamide was pre-incubated with the rings before nitroglycerin treatment. The release of CGRP from the aorta rings was determined. Both ethacrynic acid and cyanamide were able to reverse the depressant action of nitroglycerin while the inhibitory effect of cyanamide was more profound. However, combined administration of both inhibitors did not produce an additive effect. The change of plasma CGRP level positively correlated with the change of nitroglycerin-induced hypotensive effects. In the isolated aorta rings, vasodilator responses to nitroglycerin were reduced in the presence of ethacrynic acid or cyanamide while the inhibitory effect of cyanamide was more profound. However, combined administration of both inhibitors did not produce an additive effect. The change of CGRP release from the rings positively correlated with the nitroglycerin-induced vasodilator responses. The present results suggest that both GST and ALDH-2 are involved in nitroglycerin action while ALDH-2 plays a major role, and the change of CGRP contents closely correlates with the biotransformation of nitroglycerin.
Zhang
Xiao-Jing
XJ
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, China.
Chang
Lan
L
Zhang
Yi-Ming
YM
Deng
Sheng
S
Li
Yuan-Jian
YJ
Peng
Jun
J
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D015740:Calcitonin Gene-Related Peptide / Q000097:blood / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D005996:Nitroglycerin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005996:Nitroglycerin; D015740:Calcitonin Gene-Related Peptide