Inhibitory effects of PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 on iNOS induction in rat mesenteric artery.
PGD2 and its metabolites PGJ2 and 15-deoxy-delta12,14-PGJ2 have been reported to inhibit iNOS induction in cultured vascular smooth muscle cells. The present study was undertaken to determine whether these prostanoids inhibit iNOS induction in the isolated rat mesenteric artery. The artery without endothelium was incubated with and without lipopolysaccharide (LPS) at 37 degrees C for 6 hrs, then washed and mounted in an organ bath to measure isometric changes in tension. L-arginine but not D-arginine (10(-6) - 10(-3) M) induced concentration-dependent relaxations only in the artery preincubated with LPS, the relaxations of which were attenuated by L-N(G)-nitroarginine methyl ester (LNAME, 10(-4) M), a non-selective iNOS inhibitor, and 1400W (10(-5) and 10(-4) M), a selective iNOS inhibitor. Co-treatment of cycloheximide (10(-5) M), a protein synthesis inhibitor, or actinomycin D (10(-7) M), an RNA synthesis inhibitor with LPS inhibited the development of relaxing ability in response to L-arginine, indicating iNOS induction by LPS. PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 but not PGE2, PGI2 or PGF2alpha also inhibited the development of relaxing ability in response to L-arginine when added during incubation with LPS. Incubation of the artery with LPS at 37 degrees C for 6 hrs markedly increased production of nitric oxide (NO), which was abolished by 15-deoxy-delta12,14-PGJ2 (10(-5) M). An imunohistochemical study using antibody against murine iNOS showed that 15-deoxy-delta12,14-PGJ2 (10(-5) M) inhibited the expression of iNOS protein in isolated rat mesenteric arteries. These results demonstrated that PGD2 and its metabolites inhibit iNOS induction by LPS in isolated rat mesenteric arteries, resulting in reduced relaxing ability in response to L-arginine.
Shirahase
H
H
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
Kanda
M
M
Nakamura
S
S
Tarumi
T
T
Uehara
Y
Y
Ichikawa
A
A
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D008070:Lipopolysaccharides; C037112:9-deoxy-delta-9-prostaglandin D2; D001120:Arginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015230:Prostaglandin D2