A B S T R A C T To determine vasopressin (VP)-potentiating effect of chlorpropamide (CPMD), we studied the effect of CPMD in vivo and in vitro in kidneys and in specific tubule segments of rats with hypothalamic diabetes insipidus, homozygotes of the Brattleboro strain (DI rats). Rats on ad lib. water intake were treated with CPMD (20 mg/100 g body wt s.c. daily) for 7 d. While on ad lib. water intake, the urine flow, urine osmolality, urinary excretion of Na+, K+, creatinine, or total solute excretion did not change. However, corticopapillary gradient of solutes was significantly increased in CPMD-treated rats. Higher tissue osmolality was due to significantly increased concentration of Na+, and to a lesser degree urea, in the medulla and papilla of CPMD-treated rats. Consequently, the osmotic gradient between urine and papillary tissue of CPMD-treated rats (A = 385±47 mosM) was significantly (P < 0.001) higher compared with controls (A = 150±26 mosM). Minimum urine osmolality after water loading was higher in CPMD-treated DI rats than in controls. Oxidation of ['4C] Based on the findings recounted above, we propose a hypothesis that CPMD administration enhances the antidiuretic effect of VP, primarily by increasing medullary and papillary tonicity due to increased NaCl reabsorption in MAL. There is no evidence that CPMD sensitizes collecting tubules to the action of VP, at least at the cAMP-generation step. Therefore, increased antidiuretic response to VP in the kidneys of CPMDtreated DI rats is due to enhanced osmotic driving force for water reabsorption (lumen-to-interstitium osmotic gradient) in collecting tubules, rather than due to increased VP-dependent water permeability of tubular epithelium.
A B S T R A C T Among other defects in water metabolism, adrenal insufficiency is associated with an inability to concentrate urine maximally in both man and experimental animals. Recent studies in the rabbit cortical collecting tubule have suggested indirectly that this defect may result from impaired cyclic AMP (cAMP) formation in response to antidiuretic hormone stimulation. In the present study, we examined key elements of arginine vasopressin (AVP)-dependent cAMP metabolism in the papillary collecting duct (PCD), microdissected from 8-d adrenalectomized (ADX) and sham-operated control rats.AVP-sensitive adenylate cyclase (ADC) activity in PCD did not differ between control and ADX rats. cAMP-phosphodiesterase activity (cAMP-PDIE), measured at 10'6 M cAMP substrate concentration, was significantly higher (A + 31.6%) in PCD of ADX rats compared with controls. Incubation of intact PCD from ADX rats with AVP resulted in an accumulation of cAMP (A -48.5%) significantly lower than observed in control PCD. Chronic administration of dexamethasone reduced cAMP-PDIE activity in PCD of ADX rats to levels close to or below those observed in controlThe results of this work were presented in part at the
In mice with hereditary nephrogenic diabetes insipidus (NDI), the high activity of cAMP-phosphodiesterase (cAMP-PDIE) in medullary collecting tubules (MCT) prevents the increase in cAMP content in response to vasopressin [Arg8]vasopressin (AVP). Even when the cAMP response to AVP is partly corrected by cAMP-PDIE inhibitor 1-methyl-3-isobutylxanthine (MIX), under all tested conditions the cAMP levels in MCT of NDI mice remained much lower than in controls (B. A. Jackson, R. M. Edwards, H. Valtin, and T. P. Dousa, J. Clin. Invest. 66: 110-122, 1980). In the present study, we explored which factors may account for this defect. We determined contents of ATP, nicotinamide adenine dinucleotide (NAD), and the levels of cAMP in MCT and in medullary thick ascending limb of Henle's loop (MAL) microdissected from control and NDI mice. In the presence of 1 microM AVP and 0.05 mM MIX, the cAMP levels accumulated in MCT of NDI mice were four times lower compared with controls, but the levels of ATP and NAD were not different. ATP levels in MAL of NDI mice were slightly (delta -23%) lower than in MAL from controls, and in distal convoluted tubules (DCT) of NDI mice the ATP levels were also decreased (delta -49%). Although AVP alone had little effect on cAMP levels in mouse MAL in the presence of 0.1 mM forskolin, the AVP elicited a 20-fold increase of cAMP of both the control and NDI mice. Addition of 0.1 mM forskolin further increased the cAMP accumulation in MCT incubated with AVP.(ABSTRACT TRUNCATED AT 250 WORDS)
Responsiveness of proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) microdissected from mouse kidney to PTH, in terms of cAMP accumulation and stimulation of adenylate cyclase, was examined. In both PCT and DCT, the cell-free adenylate cyclase was stimulated at least 10-fold by the same dose (10 U/ml) of PTH, and activity of cAMP phosphodiesterase was about 80% higher in DCT than in PCT. In intact tubules, while the incubation with PTH increased cAMP content in DCT more than 10-fold, it failed to increase the cAMP levels in PCT. To explain discrepancies between cell-free and intact cell incubations, ATP content in microdissected tubules was determined with use of a microbioluminescence assay. ATP content in PCT (4.0 +/- 1.3 fmol/mm, n = 30) was dramatically lower than ATP content of DCT (376.8 +/- 54.3 fmol/mm, n = 25). Incubation with 1 microM rotenone reduced markedly (delta -98%) the ATP content in DCT. In DCT, with ATP depleted by 1 microM rotenone, PTH failed to increase the cAMP, although 1 microM rotenone did not inhibit the adenylate cyclase activity. When 0.1 mM of 1-methyl-3-isobutylxanthine (MIX) was added to the incubation medium, PTH caused a marked elevation in tubular cAMP in PCT and to even a greater degree in DCT. Present results show that various segments of microdissected tubules differ greatly in their ability to maintain adequate ATP levels for cAMP generation in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
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