Santos R A, Simões e Silva A C, Magaldi A J, Khosla M C, Cesar K R, Passaglio K T, Baracho N C
Laboratório de Hipertensao, Departmento de Fisiologia e Biofísica, Belo Horizonte, Brazil.
Hypertension. 1996 Apr;27(4):875-84. doi: 10.1161/01.hyp.27.4.875.
In this study we evaluated the possibility that angiotensin-(1-7) [Ang-(1-7)] acts as an endogenous osmoregulatory peptide by determining the effect of acute administration of its selective antagonist [D-Ala7]Ang-(1-7) (A-779) on renal function parameters in rats. In addition, we investigated the physiological mechanisms involved in the antidiuretic effect of Ang-(1-7). The antidiuretic effect of Ang-(1-7) (40 pmol/0.05 mL per 100 g BW) in water-loaded rats was completely blocked by A-779 (vehicle-treated, 3.34 +/- 0.43 mL/h; Ang-(1-7), 1.48 +/- 0.23; A-779, 2.72 +/- 0.35; Ang-(1-7) plus A-779, 3.26 +/- 0.49). In contrast, the antidiuretic effect of Ang-(1-7) was not significantly changed by a vasopressin V2 receptor antagonist in a dose that completely blocked the antidiuresis produced by an equipotent dose of vasopressin. In addition, Ang-(1-7) administration did not significantly change vasopressin plasma levels in water-loaded rats. The antidiuretic effect of Ang-(1-7) in water-loaded rats was associated with a reduction of creatinine clearance (0.68 +/- 0.04 versus 1.38 +/- 0.32 mL/min in vehicle-treated rats, P <.05) and an increase in urine osmolality (266.8 +/- 32.7 versus 182.8 +/- 14 mOsm/kg in vehicle-treated rats, P <.05). An effect of Ang-(1-7) in tubular water transport was demonstrated in vitro by a fourfold increase in the hydraulic conductivity of inner medullary collecting ducts in the presence of 1 nmol/L Ang-(1-7). Subcutaneous administration of A-779 (2.3 to 9.2 nmol/100 g) produced a significant increase in urine volume (4.6 nmol/100 g, 0.45 +/- 0.12 mL/h; vehicle-treated rats, 0.16 +/- 0.03 mL/h; P <.05) comparable to that of acute administration of a vasopressin V2 receptor antagonist. The diuretic effect of A-779 was associated with an increase in creatinine clearance and decrease in urine osmolality. In contrast, no significant effects on urine volume were observed after systemic administration of angiotensin subtype 1 or 2 receptor antagonists (DuP 753 and CGP 42112A, respectively). These findings suggest that endogenous Ang-(1-7), acting on specific receptors, participates in the control of hydroelectrolyte balance by influencing especially water excretion.
在本研究中，我们通过测定其选择性拮抗剂[D-Ala7]Ang-(1-7)（A-779）急性给药对大鼠肾功能参数的影响，评估血管紧张素-(1-7)[Ang-(1-7)]作为内源性渗透调节肽的可能性。此外，我们研究了Ang-(1-7)抗利尿作用涉及的生理机制。A-779完全阻断了水负荷大鼠中Ang-(1-7)（40 pmol/0.05 mL每100 g体重）的抗利尿作用（溶剂处理组，3.34±0.43 mL/h；Ang-(1-7)组，1.48±0.23；A-779组，2.72±0.35；Ang-(1-7)加A-779组，3.26±0.49）。相反，血管加压素V2受体拮抗剂在完全阻断等剂量血管加压素产生的抗利尿作用的剂量下，并未显著改变Ang-(1-7)的抗利尿作用。此外，给予Ang-(1-7)并未显著改变水负荷大鼠的血管加压素血浆水平。水负荷大鼠中Ang-(1-7)的抗利尿作用与肌酐清除率降低（溶剂处理组为1.38±0.32 mL/min，Ang-(1-7)组为0.68±0.04，P<0.05）和尿渗透压升高（溶剂处理组为182.8±14 mOsm/kg，Ang-(1-7)组为266.8±32.7，P<0.05）有关。体外实验表明，在1 nmol/L Ang-(1-7)存在下，内髓集合管的水力传导率增加了四倍，证明了Ang-(1-7)对肾小管水转运的作用。皮下注射A-779（2.3至9.2 nmol/100 g）使尿量显著增加（4.6 nmol/100 g，0.45±0.12 mL/h；溶剂处理组大鼠为0.16±0.03 mL/h；P<0.05），与急性注射血管加压素V2受体拮抗剂相当。A-779的利尿作用与肌酐清除率增加和尿渗透压降低有关。相反，全身给予血管紧张素1型或2型受体拮抗剂（分别为DuP 753和CGP 42112A）后，未观察到对尿量的显著影响。这些发现表明，内源性Ang-(1-7)通过作用于特定受体，特别是通过影响水排泄，参与水电解质平衡的控制。
