Garcia N H, Garvin J L
Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202.
J Clin Invest. 1994 Jun;93(6):2572-7. doi: 10.1172/JCI117268.
The effect of endothelin-1 (ET-1) on the proximal tubule remains unclear. This may be due to a biphasic effect on transport in this segment. We hypothesized that ET-1 has a biphasic effect on fluid absorption (Jv) in the proximal straight tubule and that its inhibitory effect is superimposed on its stimulatory effect. ET-1 (10(-13) M) stimulated Jv from 0.68 +/- 0.07 to 1.11 +/- 0.20 nl/mm/min, a 60% increase (P < 0.04). 10(-12) and 10(-10) M ET-1 had no significant effect. 10(-9) M ET-1 reduced Jv from 0.81 +/- 0.19 to 0.44 +/- 0.15 nl/mm/min (P < 0.009). Staurosporine (STP, 10(-8) M) prevented both 10(-9) and 10(-13) M ET-1 from altering Jv significantly indicating that protein kinase C (PKC) is involved. Indomethacin (10(-5) M) blocked the inhibition produced by 10(-9) M ET-1. ETI (10(-6) M), a lipoxygenase inhibitor, also blocked ET-1 inhibition of Jv. Interestingly ET-1 (10(-9) M) stimulated Jv in the presence of both indomethacin and ETI. When 10(-9) M ET-1 was added in the presence of 10(-5) M quinacrine, a phospholipase (PL) inhibitor, Jv also increased from 1.02 +/- 0.20 to 1.23 +/- 0.22 nl/mm/min (P < 0.03). STP blocked this increase. We conclude that (a) 10(-13) M ET-1 stimulates fluid absorption by activating PKC; (b) 10(-9) M ET-1 decreases Jv by PKC-, PL-, cyclooxygenase-, and lipoxygenase-dependent mechanisms; and (c) the inhibitory effect of ET-1 on Jv is superimposed on the stimulatory effect.
内皮素-1（ET-1）对近端小管的影响尚不清楚。这可能是由于其对该节段转运具有双相效应。我们推测ET-1对近端直小管的液体吸收（Jv）具有双相效应，且其抑制作用叠加于刺激作用之上。ET-1（10⁻¹³ M）使Jv从0.68±0.07增加至1.11±0.20 nl/mm/min，增加了60%（P<0.04）。10⁻¹² M和10⁻¹⁰ M的ET-1无显著影响。10⁻⁹ M的ET-1使Jv从0.81±0.19降至0.44±0.15 nl/mm/min（P<0.009）。星形孢菌素（STP，10⁻⁸ M）可防止10⁻⁹ M和10⁻¹³ M的ET-1显著改变Jv，表明蛋白激酶C（PKC）参与其中。吲哚美辛（10⁻⁵ M）可阻断10⁻⁹ M的ET-1产生的抑制作用。脂氧合酶抑制剂ETI（10⁻⁶ M）也可阻断ET-1对Jv的抑制作用。有趣的是，在同时存在吲哚美辛和ETI的情况下，ET-1（10⁻⁹ M）仍能刺激Jv。当在10⁻⁵ M喹吖因（一种磷脂酶（PL）抑制剂）存在的情况下加入10⁻⁹ M的ET-1时，Jv也从1.02±0.20增加至1.23±0.22 nl/mm/min（P<0.03）。STP可阻断这种增加。我们得出结论：（a）10⁻¹³ M的ET-1通过激活PKC刺激液体吸收；（b）10⁻⁹ M的ET-1通过PKC、PL、环氧化酶和脂氧合酶依赖性机制降低Jv；（c）ET-1对Jv的抑制作用叠加于刺激作用之上。
