MECHANISM OF LITHIUM-INDUCED POLYURIA IN THE RAT

While many studies have demonstrated a nephrogenic diabetes insipidus syndrome (NDI) with prolonged lithium (Li) treatment, experiments in t he isolated rat papillary collecting duct have suggested that the defe ct may be due to a circulating factor that inhibits the action of argi nine vasopressin (AVP). Since Li-treatment can produce a form of hyper parathyroidism and parathyroid hormone (PTH) can act as a partial agon ist to AVP, in vivo and in vitro studies were performed on rats made p olyuric by daily intraperitoneal (i.p.) Li (4 mmol/kg) treatment. Li-t reatment for three weeks produced an increase in PTH (194 +/- 20 compa red with 118 +/- 18 pg/ml in control rats; P < 0.01) as well as an inc rease 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 32 8 +/- 31 compared with 613 +/- 81 mOsm/kg (P < 0.05) in controls. Ther e was no detectable difference with a prolonged maximal physiological AVP concentration (10 mU bolus and 50 mU/kg body wt per hr) and papill ary solute concentrations were unchanged. When Li-treated rats had bee n parathyroidectomized (PTX), a significant difference in urine concen tration 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 L i-treated or control rats, both intact and PTX. Experiments using plas ma from Li-treated intact rats produced only a 25.4 +/- 5.1% increase in diffusional water permeability with the addition of AVP (200 mu U/m l) 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 f rom that observed in PTX control rats. These studies show that the NDI -like defect in Li-treatment is small and easily overcome by higher co ncentrations of AVP and suggests that the concentration defect is at l east in part due to increased circulating levels of PTH acting as a pa rtial agonist to AVP and thereby inhibiting its hydroosmotic action.