Phillips P A, Grant S L, Davidson A F, Risvanis J, Stephenson J, Gow C B
Department of Medicine, University of Melbourne, Austin Hospital, Heidelberg, Australia.
Kidney Int. 1994 Apr;45(4):1028-36. doi: 10.1038/ki.1994.139.
Since EGF causes diuresis through a renal action and may antagonize the hydroosmotic effect of AVP in vitro we investigated the antagonistic action of EGF with AVP in vivo and the mechanism of the antagonism in vitro. Conscious ewes received i.m. injections of a selective AVP V2-receptor agonist (1-desamino, D-Arg8 vasopressin acetate, DDAVP) every 12 hours for days 5 to 16. All ewes received an i.v. isotonic saline infusion (100 ml/day) for days 1 to 8 and days 13 to 16, and i.v. EGF in 100 ml saline/day at doses of 0 (N = 8) or 10 (N = 8) micrograms/hr for days 9 to 12. DDAVP reduced both urine volume and water intake, and increased urine osmolality. In contrast, simultaneous infusion of EGF reversed the DDAVP-induced responses, resulting in a transient negative fluid balance, kaliuresis and a transient natriuresis (all P < 0.05). When EGF treatment ceased, the effects of DDAVP treatment alone gradually became apparent. From the in vitro studies, the AVP-related peptides displaced specific AVP V1- and V2-receptor antagonist radioligands from rat renal inner medullary membranes, whereas EGF had no effect. However, EGF antagonized AVP V2-stimulated cAMP production in a dose-dependent way (IC50 = 2 x 10(-7) M). Therefore, the diuretic effect of EGF is not via direct antagonism of the antidiuretic AVP V2-receptor but seems mediated by inhibition of the antidiuretic AVP V2-receptor second messenger system.
由于表皮生长因子（EGF）通过肾脏作用引起利尿，且在体外可能拮抗精氨酸加压素（AVP）的水渗透效应，因此我们研究了EGF在体内对AVP的拮抗作用及其体外拮抗机制。清醒的母羊在第5至16天每12小时肌肉注射一次选择性AVP V2受体激动剂（1-去氨基，D-精氨酸8-血管加压素醋酸盐，DDAVP）。所有母羊在第1至8天和第13至16天接受静脉输注等渗盐水（100ml/天），在第9至12天接受静脉输注含EGF的100ml盐水/天，剂量为0（N = 8）或10（N = 8）微克/小时。DDAVP减少了尿量和水摄入量，并增加了尿渗透压。相比之下，同时输注EGF可逆转DDAVP诱导的反应，导致短暂的负水平衡、尿钾增多和短暂的尿钠增多（所有P < 0.05）。当EGF治疗停止时，单独DDAVP治疗的效果逐渐显现。从体外研究来看，AVP相关肽可使大鼠肾内髓质膜上的特异性AVP V1和V2受体拮抗剂放射性配体移位，而EGF无此作用。然而，EGF以剂量依赖的方式拮抗AVP V2刺激的环磷酸腺苷（cAMP）生成（半数抑制浓度[IC50] = 2×10⁻⁷ M）。因此，EGF的利尿作用并非通过直接拮抗抗利尿的AVP V2受体，而是似乎由抑制抗利尿的AVP V2受体第二信使系统介导。
