Kaushal R D, Wilson T W
Department of Pharmacology, University of Saskatchewan, Saskatoon, Canada.
Can J Physiol Pharmacol. 1990 Apr;68(4):500-4. doi: 10.1139/y90-071.
We had previously shown that selective thromboxane synthetase inhibition with furegrelate increases urinary excretion of 6-ketoPGF1 alpha, the hydrolysis product of prostacyclin after stimulation of renal prostaglandin synthesis with furosemide. The present study assessed the functional significance of this "redirection" of prostaglandin formation using a more physiologic stimulus, angiotensin II. Sprague-Dawley rats (n = 27) were fitted with a transabdominal bladder cannula. Five days later they were given angiotensin II (10 mg.kg-1.min-1) by intravenous infusion. After 30 min, an infusion of furegrelate, 2 mg/kg, then 2 mg.kg-1.h-1, (n = 9); indomethacin, 2 mg/kg, then 2 mg.kg-1.h-1 (n = 9); or vehicle, 250 microL, then 0.018 mL/min (n = 9) was begun for 60 min. Clearance of [14C]para-aminohippuric acid was taken as a measure of renal plasma flow. Angiotensin II raised the mean arterial pressure in all groups. Administration of furegrelate or indomethacin did not change mean arterial pressure or heart rate. Angiotensin II reduced [14C]p-aminohippuric acid clearance by about 32% (1.42 +/- 0.18 to 0.97 +/- 0.07 mL.min-1.100 g-1, p less than 0.05). Furegrelate attenuated this renal vasoconstriction (0.97 +/- 0.07 to 1.38 +/- 0.17 mL.min-1.100 g-1, p less than 0.05), while indomethacin increased it by a further 32% (1.78 +/- 0.12 to 1.20 +/- 0.12 mL.min-1.100 g-1, p less than 0.05). Vehicle alone had no effect. Furegrelate reduced serum thromboxane B2 by 90% (6.52 +/- 0.030 to 0.7 +/- 0.21 ng/100 microL, p less than 0.05), while indomethacin reduced it by 73% (5.9 +/- 0.99 to 1.4 +/- 0.20 ng/100 microL, p less than 0.05). We conclude that furegrelate attenuates the renal vasoconstriction of angiotensin II, presumably by enhancing the formation of vasodilator prostaglandins.
我们之前已经表明，使用呋格雷酯选择性抑制血栓素合成酶可增加6-酮前列环素F1α的尿排泄，6-酮前列环素F1α是在用速尿刺激肾前列腺素合成后前列环素的水解产物。本研究使用更具生理性的刺激物血管紧张素II评估了这种前列腺素生成“重定向”的功能意义。将27只Sprague-Dawley大鼠经腹插入膀胱插管。五天后，通过静脉输注给予它们血管紧张素II（10mg·kg-1·min-1）。30分钟后，开始输注2mg/kg的呋格雷酯，然后以2mg·kg-1·h-1的速度输注（n = 9）；2mg/kg的吲哚美辛，然后以2mg·kg-1·h-1的速度输注（n = 9）；或载体，250μL，然后以0.018mL/min的速度输注（n = 9），持续60分钟。以[14C]对氨基马尿酸的清除率作为肾血浆流量的指标。血管紧张素II使所有组的平均动脉压升高。给予呋格雷酯或吲哚美辛并未改变平均动脉压或心率。血管紧张素II使[14C]对氨基马尿酸清除率降低约32%（从1.42±0.18降至0.97±0.07mL·min-1·100g-1，p<0.05）。呋格雷酯减弱了这种肾血管收缩（从0.97±0.07升至1.38±0.17mL·min-1·100g-1，p<0.05），而吲哚美辛使其进一步增加32%（从1.78±0.12降至1.20±0.12mL·min-1·100g-1，p<0.05）。单独给予载体没有效果。呋格雷酯使血清血栓素B2降低90%（从6.52±0.030降至0.7±0.21ng/100μL，p<0.05），而吲哚美辛使其降低73%（从5.9±0.99降至1.4±0.20ng/100μL，p<0.05）。我们得出结论，呋格雷酯可能通过增强血管舒张性前列腺素的形成来减弱血管紧张素II引起的肾血管收缩。
