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, iv.) or acetylcholine (ACh) (0.3-3.0 mug/kg, iv.) caused a dose-dependent transient decrease in diastolic blood pressure. The decrease induced by 0.3 mg/kg LP-805 (iv.) was partially inhibited by pretreatment with N(G)-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, iv.) 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 mug/kg per min) was significantly inhibited by pretreatment with L-NNA (10 mg/kg, iv.). The half-recovery times (T1/2) 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 T1/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin (I mg/kg, iv.). In the presence of L-NNA (10 mg/kg, iv.), the T1/2 of the LP-805-induced hypotensive response was not affected by pretreatment with indomethacin. The results suggest that the LP-805-induced hypotensive response may be related to direct or indirect activation of NO synthase in vascular endothelial cells, and to release of endothelium-derived NO.