Relationship between biotransformation of glyceryl trinitrate and cyclic GMP accumulation in various cultured cell lines.
We assessed glyceryl trinitrate (GTN) biotransformation and cyclic GMP accumulation in cultured rat lung fibroblasts (RLF), porcine kidney epithelial (PK1), bovine aortic endothelial (BAE) and bovine aortic smooth muscle (BASM) cells. Biotransformation of 0.1 microM GTN was linear over 30 min and the percentage of glyceryl dinitrate (GDN)/10(6) cells for BAE, BASM, RLF and PK1 at 30 min was 3.1, 2.3, 5.8 and 21.7%, respectively. At low GTN concentration (0.01-0.1 microM) there was a highly selective formation of 1,2-GDN, whereas at higher GTN concentration (greater than 1 microM) this selectivity was lost. Cyclic GMP accumulation did not occur in BAE or BASM at any GTN concentration, whereas for RLF and PK1 it was highly correlated to the rate of GDN formation. Upon re-exposure to GTN after treatment of RLF or PK1 cells for 3 hr with 0.1 mM GTN, there was an almost complete loss of the cyclic GMP response, GTN biotransformation was attenuated markedly and the selective formation of 1,2-GDN at low GTN concentration was absent. However, when GTN-treated cells were incubated for 18 hr in GTN-free media, there was a recovery of the cyclic GMP response, GTN biotransformation and selective 1,2-GDN formation toward control values.(ABSTRACT TRUNCATED AT 250 WORDS)
Bennett
B M
BM
Department of Medicine, Stanford University, Palo Alto, California.
Leitman
D C
DC
Schröder
H
H
Kawamoto
J H
JH
Nakatsu
K
K
Murad
F
F
D000818:Animals; D001711:Biotransformation; D002460:Cell Line; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism*; D014316:Tritium
D014316:Tritium; D005996:Nitroglycerin; D006152:Cyclic GMP