Carney S L, Ray C, Gillies A H
Faculty of Medicine and Health Sciences, University of Newcastle, New South Wales, Australia.
Kidney Int. 1996 Aug;50(2):377-83. doi: 10.1038/ki.1996.326.
While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in the isolated rat papillary collecting duct have suggested that the defect may be due to a circulating factor that inhibits the action of arginine vasopressin (AVP). Since Li-treatment can produce a form of hyperparathyroidism and parathyroid hormone (PTH) can act as a partial agonist to AVP, in vivo and in vitro studies were performed on rats made polyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-treatment for three weeks produced an increase in PTH (194 +/- 20 compared with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an increase in the plasma calcium concentration (2.38 +/- 0.05 compared with 2.25 +/- 0.04 mmol/liter; P < 0.05). Clearance studies were performed on water loaded Li-treated and control rats, and the defect in urine concentration was only observed with a low physiological concentration of AVP (10 mU/kg body wt over 5 min). Maximal urine osmolality was 328 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. There was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papillary solute concentrations were unchanged. When Li-treated rats had been parathyroidectomized (PTX), a significant difference in urine concentration with the low AVP concentration could not be demonstrated when compared to non-PTX control rats. In the isolated papillary collecting duct preparation a medium was used that contained fresh plasma from Li-treated or control rats, both intact and PTX. Experiments using plasma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 microU/ml) compared to 52.6 +/- 9.0% in control rats (P < 0.01). However, when plasma from Li-treated PTX rats was used, the AVP induced increase in water permeability (54.7 +/- 11.2%) was not significantly different from that observed in PTX control rats. These studies show that the NDI-like defect in Li-treatment is small and easily overcome by higher concentrations of AVP and suggests that the concentration defect is at least in part due to increased circulating levels of PTH acting as a partial agonist to AVP and thereby inhibiting its hydroosmotic action.
虽然许多研究已证实长期锂（Li）治疗会导致肾性尿崩症综合征（NDI），但在离体大鼠乳头集合管中进行的实验表明，该缺陷可能归因于一种抑制精氨酸加压素（AVP）作用的循环因子。由于锂治疗可引发一种甲状旁腺功能亢进症，且甲状旁腺激素（PTH）可作为AVP的部分激动剂，因此对通过每日腹腔内（i.p.）注射锂（4 mmol/kg）治疗而出现多尿的大鼠进行了体内和体外研究。锂治疗三周导致PTH升高（与对照大鼠的118±18 pg/ml相比，为194±20；P<0.01），同时血浆钙浓度也升高（与2.25±0.04 mmol/升相比，为2.38±0.05；P<0.05）。对水负荷的锂治疗大鼠和对照大鼠进行了清除率研究，仅在低生理浓度的AVP（5分钟内10 mU/kg体重）下观察到尿液浓缩缺陷。最大尿渗透压为328±31，而对照大鼠为613±81 mOsm/kg（P<0.05）。在延长的最大生理AVP浓度（10 mU推注和每小时50 mU/kg体重）下未检测到差异，且乳头溶质浓度未改变。当对锂治疗的大鼠进行甲状旁腺切除（PTX）后，与未进行PTX的对照大鼠相比，在低AVP浓度下尿液浓缩方面未显示出显著差异。在离体乳头集合管制备中，使用了含有来自锂治疗或对照大鼠（完整和PTX）的新鲜血浆的培养基。与对照大鼠中添加AVP（200 μU/ml）后扩散水通透性增加52.6±9.0%相比，使用来自锂治疗的完整大鼠的血浆在添加AVP后仅使扩散水通透性增加25.4±5.1%（P<0.01）。然而，当使用来自锂治疗的PTX大鼠的血浆时，则AVP诱导的水通透性增加（54.7±11.2%）与PTX对照大鼠中观察到的情况无显著差异。这些研究表明，锂治疗中类似NDI的缺陷较小，且较高浓度的AVP可轻易克服该缺陷，并提示浓度缺陷至少部分归因于循环中PTH水平升高，其作为AVP的部分激动剂，从而抑制其水渗透作用。
