Inhibition of NO synthase induction by an anticancer drug 4'-epi-doxorubicin in rats.
1. Nitric oxide (NO) plays various physiological roles in tumour tissues. Herein, we examined the effects of an anticancer drug 4'-epi-doxorubicin on NO synthase and the related responses in rat thoracic aorta, rat cerebellum and lung homogenates. 2. Treatment with an anticancer drug 4'-epi-doxorubicin in vitro or in vivo had little effect on the relaxation response to acetylcholine or nitroprusside in rat thoracic aorta. 3. Treatment with 4'-epi-doxorubicin in vitro or in vivo did not alter the constitutive NO synthase activity of rat cerebellum ([3H]-citrulline production from [3H]-arginine). 4. After inducible NO synthase had been induced by lipopolysaccharide, 4'-epi-doxorubicin also neither affected the relaxation response to L-arginine in rat thoracic aorta nor the enzyme activity of rat lung. 5. Coincubation with lipopolysaccharide and 4'-epi-doxorubicin in vitro prevented the development of relaxation response to L-arginine in rat thoracic aorta. Pretreatment with 4'-epi-doxorubicin in vivo also prevented the induction of inducible NO synthase by lipopolysaccharide in rat thoracic aorta and lung. 6. These results suggest that 4'-epi-doxorubicin selectively inhibits the induction of NO synthase without affecting constitutive and inducible NO synthase activities. This effect was discussed in relation to the anticancer and side effects of the drug.
Sakai
T
T
Department of Radiology, Fukui Medical School, Japan.
Muramatsu
I
I
Hayashi
N
N
Ishii
Y
Y
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000201:enzymology; D001120:Arginine / Q000494:pharmacology; D002531:Cerebellum / Q000201:enzymology; D002956:Citrulline / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004790:Enzyme Induction / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D008070:Lipopolysaccharides; D009599:Nitroprusside; D002956:Citrulline; D015251:Epirubicin; D001120:Arginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine