Endothelin's biphasic effect on fluid absorption in the proximal straight tubule and its inhibitory cascade.
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.
Garcia
N H
NH
Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan 48202.
Garvin
J L
JL
D000042:Absorption; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001834:Body Water / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010740:Phospholipases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology
D016232:Endothelins; D011493:Protein Kinase C; D010740:Phospholipases; D000254:Sodium-Potassium-Exchanging ATPase; D007213:Indomethacin