Effect of LP-805, a releaser of endothelium-derived nitric oxide, on systemic vasodilatation in vivo.
We have investigated relations between hypotensive responses to LP-805, a newly synthesized vasodilator, and the production of nitric oxide (NO), in anesthetized rats. LP-805 (0.1-0.5 mg/kg, i.v.) or acetylcholine (ACh) (0.3-3.0 micrograms/kg, i.v.) caused a dose-dependent transient decrease in diastolic blood pressure. The decrease induced by 0.3 mg/kg LP-805 (i.v.) was partially inhibited by pretreatment with NG-nitro-L-arginine (L-NNA), a specific inhibitor of endothelial NO synthase, but the responses to lower or higher doses of LP-805 (0.1 or 0.5 mg/kg, i.v.) were not affected. The dose-dependent decrease in diastolic blood pressure, caused by LP-805, was not affected by pretreatment with L- or D-arginine. The dose-dependent decrease in diastolic blood pressure caused by ACh was not affected by pretreatment with L-NNA or with L- or D-arginine. The hypotensive response to 20-min infusions of LP-805 (100 micrograms/kg per min) was significantly inhibited by pretreatment with L-NNA (10 mg/kg, i.v.). The half-recovery times (T 1/2) of LP-805 or ACh-induced depressor responses were shortened by pretreatment with L-NNA. They were prolonged by L-arginine, but not by D-arginine. This shortening, by L-NNA, of the half-recovery time after LP-805 or ACh was reversed by L-arginine, but not by D-arginine. The T 1/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin (1 mg/kg, i.v.). In the presence of L-NNA (10 mg/kg, i.v.), the T 1/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)
Inazu
M
M
Pharmaceutical Research Laboratories, POLA R & D Laboratories, POLA Corporation, Yokohama, Japan.
Tujitani
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D007022:Hypotension / Q000139:chemically induced; D007213:Indomethacin / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019335:Nitroarginine; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D011720:Pyrazoles; D011743:Pyrimidines; D014665:Vasodilator Agents; C073993:8-tert-butyl-6,7-dihydropyrrolo(3,2-e)-5-methylpyrazolo(1,5-a)pyrimidine-3-carbonitrile; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D007213:Indomethacin