Decreased Water Intake Research Articles

Interaction between supraoptic nucleus and septal area in the control of water, sodium intake and arterial blood pressure induced by injection of angiotensin II

We investigated the effects of injection into the supraoptic nucleus (SON) of losartanand PD 123319 (nonpeptide AT 1 and AT 2-angiotensin II [ANG II] receptor antagonists, respectively); d(CH 2) 5-Tyr(Me)-AVP (AVPA; an arginine–vasopressin [AVP] V 1 receptor antagonist), FK 409 (a nitric oxide [NO] donor), and N W-nitro- l-arginine methyl ester ( l-NAME; an NO synthase inhibitor) on water intake, sodium chloride 3% (NaCl) intake and arterial blood pressure induced by injection of ANG II into the lateral septal area (LSA). Male Holtzman rats (250–300 g) were implanted with cannulae into SON and LSA unilaterally. The drugs were injected in 0.5 μl over 30–60 s. Controls were injected with a similar volume of 0.15 M NaCl. ANG II was injected at a dose of 10 pmol. ANG II antagonists and AVPA were injected at doses of 80 nmol. FK 409 and l-NAME were injected at doses of 20 and 40 μg, respectively. Water and NaCl intake was measured over a 2-h period. Prior administration of losartan into the SON decreased water and NaCl intake induced by injection of ANG II. While there was a decrease in water intake, ANG II-induced NaCl intake was significantly increased following injection of AVPA. FK 409 injection decreased water intake and sodium intake induced by ANG II. l-NAME alone increased water and sodium intake and induced a pressor effect. l-NAME-potentiated water and sodium intake induced by ANG II. PD 123319 produced no changes in water or sodium intake induced by ANG II. The prior administration of losartan or AVPA decreased mean arterial pressure (MAP) induced by ANG II. PD 123319 decreased the pressor effect of ANG II to a lesser degree than losartan. FK 409 decreased the pressor effect of ANG II while l-NAME potentiated it. These results suggest that both ANG II AT 1 and AVP V 1 receptors and NO within the SON may be involved in water intake, NaCl intake and the pressor response were induced by activation of ANG II receptors within the LSA. These results do not support the involvement of LSA AT 2 receptors in the mediation of water and NaCl intake responses induced by ANG II, but influence the pressor response.

CROSSING INTERACTION OF ADRENERGIC, CHOLINERGIC, HISTAMINERGIC AND OPIOIDERGIC SYSTEMS ON WATER INTAKE IN ADULT MALE RATS

Several lines of evidence have indicated that many nuclei in the brain including preoptic nucleus, AV3V, subfornical organ, septal area and lateral hypothalamus are the targets of efferents from chemo-sensitive and pressure-sensitive systems. These areas may concern with regulation of fluid homeostasis. In the present study, intracerebroventricular injections were carried out in all experiments. After a 24 h deprivation of water, the volume of consumed water was measured for 1 h. Administration of pilocarpine (0.5-1 ?g/rat), prazocin (2 ?g/rat), histamine (40-80 ?g/rat) and naloxone (0.5-1 ?g/rat) increased, while scopolamine (5-10 ?g/rat), phenylepherine (30 ?g/rat), morphine (2.5 ?g/rat), pyrilamine (25-50 ?g/rat) and ranitidine (10-20 ?g/rat) decreased water intake in isolated rats. The activation of muscarinic cholinoceptors by pilocarpine attenuated the inhibitory effect induced by phenylepherine. Blockade of muscarinic cholinoceptors did not change the phenylepherine-induced response. Pretreatment of rats with prazocin decreased the pilocarpine-induced response. Pharmacological blockade of muscarinic cholinoceptors by scopolamine decreased the prazocin –induced effect on water intake. Blockade of histamine H1 and H2 receptors attenuated the histamine-induced response. Furthermore, pyrilamine, but not ranitidine, increased the inhibitory effect induced by morphine. Pharmacological blockade of H1 and H2 receptors decreased the naloxone-induced effect on water intake. It is concluded that the histaminergic system may have a close interaction with morphine and naloxone regarding drinking behavior. Also, muscarinic cholinoceptors and adrenoceptors may have an interactive effect in this respect.

Ingestive Pattern Changes in Blinded Rats

Eating and drinking patterns were examined in intact and blinded adult male Sprague-Dawley rats fed a choice among isocaloric casein, sucrose/dextrin, and vegetable shortening/soybean oil diets. Weekly mean intake of all nutrients was altered in blinded rats, with increased lipid intake and decreased water intake in rats blinded for 2 weeks, lower carbohydrate but higher protein and water intakes in rats blinded for 4 weeks, while 2 weeks later blinded rats maintained high intakes of protein and water. The amplitudes of the daily rhythms for each nutrient behaved similarly to the weekly intakes. Delayed daily time of peak intake for all nutrients over successive weeks after blindness were found, indicating that the timing of peak intake free-runs. 24 h profile indicated time of day variations of nutrient intake tending to be less marked over successive weeks of blindness. Free-running animals maintained the link between carbohydrate intake and hypothalamus serotonin.

Effect of morphine, naloxone and histamine system on water intake in adult male rats

The present study investigated the interaction between histamine and opioid systems on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments. Water intake was measured 1 h after drug injections. Administration of histamine (40–80 μg/rat) and naloxone (0.5–1 μg/rat) increased, while morphine (2.5 μg/rat), pyrilamine (25–50 μg/rat), the histamine H 1 receptor antagonist, and ranitidine (10–20 μg/rat), the histamine H 2 receptor antagonist, decreased water intake in isolated rats. Blockade of histamine H 1 and H 2 receptors attenuated the histamine-induced response. Pyrilamine, but not ranitidine, increased the inhibitory effect induced by morphine. Also, pharmacological blockade of histamine H 1 and H 2 receptors decreased the naloxone-induced effect on water intake. It is concluded that the histaminergic system may have a close interaction with morphine and naloxone on drinking behavior.

Effects of α 1-adrenoceptors and muscarinic cholinoceptors on water intake in rats

The present study investigated the effects of α 1-adrenoceptors and muscarinic cholinoceptors on water intake in adult male rats. Intracerebroventricular (i.c.v.) injections were carried out in all experiments after 24-h deprivation of water. After deprivation, the volume of consumed water was measured for 1 h. Administration of pilocarpine, a muscarinic cholinoceptor agonist (0.5–1 μg/rat), and prazosin, the α 1-adrenoceptors antagonist (2 μg/rat), increased, while scopolamine, a muscarinic cholinoceptor antagonist (5–10 μg/rat), and phenylephrine, an α 1-adrenoceptor agonist (30 μg/rat), decreased water intake in rats. The activation of muscarinic cholinoceptors by pilocarpine attenuated the inhibitory effect induced by phenylephrine. Blockade of muscarinic cholinoceptors did not change the phenylephrine-induced response. Pretreatment with prazosin decreased the pilocarpine-induced response. However, pharmacological blockade of muscarinic cholinoceptors by scopolamine decreased the prazosin-induced effect on water intake. It is concluded that muscarinic cholinoceptors and α 1-adrenoceptors may interact on water intake.

Prostaglandins.

Prostaglandins.

Estrogen influences stimulated water intake by ovariectomized female rats

To further elucidate the influence of estrogen on water consumption, we examined water intake by adult female rats stimulated by water deprivation, injection of hypertonic saline or injection of isoproterenol (ISOP), a β-adrenergic agonist that activates the renin–angiotensin system (RAS). Rats were ovariectomized (OVX) then injected with estradiol benzoate (EB; 10 μg/0.1 ml oil) or the oil vehicle (OIL; 0.1 ml) for 2 consecutive days. Twenty-four hours after the second injection, rats were deprived of food and water. On the following day, rats were given water and intake was measured after 2 h. EB significantly decreased water intake compared with that by OIL-treated rats following water deprivation. Two additional groups of adult female rats were OVX and treated with EB or OIL. Forty-eight hours after EB or OIL treatment, rats were injected with hypertonic saline (1 ml of 2 M NaCl) or ISOP (30 μg/kg in 0.15 M saline) and water intake was measured after 2 h. EB significantly attenuated water intake following ISOP but not after hypertonic saline. Finally, we examined plasma sodium concentration (pNa) after hypertonic saline and plasma renin activity (PRA) after ISOP in EB- and OIL-treated rats and found no differences in pNa or PRA. These results suggest that the stimuli for water intake after hypertonic saline and ISOP were comparable in EB- and OIL-treated rats. Taken together, these results raise the possibility that EB attenuation of stimulated water intake is specific to water intake elicited by activation of the RAS.

Involvement of activin and inhibin in the regulation of food and water intake in the rat.

The expression of activin and inhibin has been demonstrated in the hypothalamus, but their physiological roles in the brain remain to be elucidated. In the present study, involvement of activin and inhibin in the regulation of food and water intake was examined. Male rats were deprived of food or water for 12 and 60 hr, and mRNA levels of activin/inhibin alpha, betaA and betaB subunits in the hypothalamus were estimated by RT-PCR. Gene expression of alpha subunit transiently decreased at 12 hr of food deprivation, while it did not change during water deprivation. Food and water deprivation for 60 hr increased mRNA levels of betaA and betaB subunits, respectively. These results indicated that gene expression of each subunit was independently regulated. Injection of activin A (0.5 and 4.0 microg) into the third ventricle decreased food intake. Water intake was suppressed by 4.0 microg, but not 0.5 microg, of activin A. Intracerebroventricular injection of inhibin A (0.5 and 4.0 microg) decreased water intake in a dose dependent manner without affecting food intake, suggesting that inhibin could act independently of activin. Taken together, it is suggested that activin and inhibin take part in the central regulation of nutrient and fluid balance, though further study is needed to determine precise molecular species involved.

Effects of subcutaneous administration of the γ-aminobutyric acid A receptor agonist muscimol on water intake in water-deprived rats

The effects of the γ-aminobutyric acid A (GABA A) receptor agonist muscimol were investigated on water intake in rats that had been deprived of water for 16 h. Muscimol (0.5–2.0 mg/kg sc) produced a dose-related inhibition of water consumption in both male ( n=8) and female ( n=8) rats, with maximal suppression of drinking occurring during the first 30 min after administration. Doses of 1 and 2 mg/kg produced significant decreases in water intake ( P<.01), while a lower dose of 0.5 mg/kg was without effect. The hypodipsic effect of muscimol (1.0 mg/kg sc) was abolished by pretreatment of the animals with the GABA A receptor antagonist bicuculline (1 mg/kg sc). Furthermore, muscimol (2 mg/kg sc) did not produce aversion in a two-bottle conditioned taste aversion test, indicating that the suppressant effects of muscimol on water intake are not due to drug-induced malaise. The results suggest that systemic administration of muscimol produces a behaviourally specific suppression of primary drinking in rats by a GABA A receptor-mediated mechanism. Moreover, this action of muscimol appears to be independent of the gender of the animals.

Central 5-HT 3 receptors and water intake in rats

In the present paper, we studied in rats the effect of third ventricle administration of m-chlorophenylbiguanide hydrochloride (1-(3-chlorophenyl)biguanide ( m-CPBG), a selective 5-HT 3 agonist, on water intake induced by three different physiological stimuli: water deprivation, acute salt load and hypovolemia. Central acute m-CPBG injections in the doses of 80 and 160 nmol significantly reduced water intake elicited by an acute salt load. Third ventricle injections of m-CPBG in the dose of 160 nmol significantly inhibited water intake in hypovolemic animals, whereas third ventricle injections of m-CPBG in a higher dose (320 nmol) were necessary to decrease water intake in water-deprived rats. Pretreatment with 1-methyl- N-[8-methyl-8-azabicyclo(3.2.1)-oct-3-yl]-1 H-indazole-3-carboxamide (LY-278,584), a selective 5-HT 3 antagonist, abolished the inhibitory effect on water intake seen after central administration of m-CPBG in all groups studied. The central administration of m-CPBG was also able to inhibit water intake induced by pharmacological activation of central cholinergic and angiotensinergic pathways. Third ventricle injections of m-CPBG in the highest dose employed in this study (320 nmol) were unable to modify food intake in food-deprived rats. An aversion test has shown that acute third ventricle injections of m-CPBG do not induce illness-like effects that could explain the water intake inhibition here observed. Also, central administration of m-CPBG did not modify the intake of a “dessert” meal consisting of diluted condensed milk. It is concluded that central 5-HT 3 receptor activation exerts a specific inhibitory effect on water intake.

Neonatal Lead Exposure Potentiates Sickness Behavior Induced by Listeria monocytogenes Infection of Mice

The effects of lead (Pb) administration on infection-induced decreases in water intake, food intake, and body weight gain have been assessed as manifestations of sickness behavior using a BALB/c mouse model. Pb acetate (0.5 mM) was administered via drinking water to dams from Day 0 postpartum to weaning and to mouse pups after weaning until sacrifice. At 22 days after birth, young mice were infected with Listeria monocytogenes. Mice with blood Pb levels of less than 25 μg/dl exhibited enhanced and prolonged sickness behavior compared to mice not exposed to Pb. With this mouse model, after infection, serum levels of interleukin (IL)-1β and IL-6 were enhanced in Pb-exposed mice. Compared with control infected mice, significant reductions in the number of thymic CD4+CD8+, CD4+, CD8+, and CD4−CD8− T cells were observed in Pb-exposed mice. As a substitute for the infection, mice were injected with IL-1 and/or IL-6; Pb exacerbated sickness behavior only in mice injected peripherally with IL-1 and IL-6. Our data in young mice suggest that children with blood Pb levels during bacterial infection may exhibit enhanced and prolonged sickness behavior due to Pb/cytokine-dependent processes and that Pb appears to influence sickness behavior depending on the types and amounts of cytokines generated.

Central administration of mCPP, a serotonin 5-HT 2B/2C agonist, decreases water intake in rats

In the present study, we investigated in rats the effect of third ventricle injections of 1-(3-chlorophenyl)piperazine ( mCPP), a 5-HT 2 receptor agonist, on water intake induced by three different physiological stimuli: fluid deprivation, acute salt load and hypovolemia. Injections of mCPP in the doses of 80 and 160 nmol/rat were able to decrease water intake in all three conditions studied. Third ventricle injections of mCPP (160 nmol/rat) were no longer able to diminish water intake in the groups of rats pretreated with central injections of an equimolar amount of (+)-cis-4,5,7a,8,9,10,11,11a-octahydro-7 H-10-methylindolo[1,7-bc][2,6]-naphthyridine (SDZ SER 082), a selective 5-HT 2B/2C antagonist. The central administration of mCPP (160 nmol/rat) was not able to modify the intake of a 0.1% saccharin solution. It is suggested that the central activation of a 5-HT 2B/2C component is able to impair the drive for water intake induced by the physiological stimuli represented by fluid deprivation, acute salt load and hypovolemia. This effect seems not to be consequent on a general nonspecific central nervous system depression or on a locomotor deficit, because saccharin intake is not affected by third ventricle injections of mCPP.

Role of thromboxane receptors in the dipsogenic response to central angiotensin II.

Central angiotensin II (ANG II) regulates thirst. Because thromboxane A2-prostaglandin H2 (TP) receptors are expressed in the brain and mediate some of the effects of ANG II in the vasculature, we investigated the hypothesis that TP receptors mediate the drinking response to intracerebroventricular (icv) injections of ANG II. Pretreatment with the specific TP-receptor antagonist ifetroban (Ifet) decreased water intake with 50 ng/kg icv ANG II (ANG II + Veh, 7.2 +/- 0.7 ml vs. ANG II + Ifet, 2.8 +/- 0.8 ml; n = 5 rats; P < 0.001) but had no effect on water intake induced by hypertonic saline (NaCl + Veh, 8.4 +/- 1.1 ml vs. NaCl + Ifet, 8.9 +/- 1.8 ml; n = 5 rats; P = not significant). Administration of 0.6 microg/kg icv of the TP-receptor agonist U-46,619 did not induce drinking when given alone but did increase the dipsogenic response to a near-threshold dose of 15 ng/kg icv ANG II (ANG II + Veh, 1.1 +/- 0.7 vs. ANG II + U-46,619, 4.5 +/- 0.9 ml; n = 5 rats; P < 0.01). We conclude that central TP receptors contribute to the dipsogenic response to ANG II.

Fos-like immunoreactivity and thirst following hyperosmotic loading in rats with subdiaphragmatic vagotomy

If receptors in the gut relay information about increases in local osmolality to the brain via the vagus nerve, then vagotomy should diminish this signaling and reduce both thirst and brain Fos-like immunoreactivity (Fos-ir). Water intake in response to hypertonic saline (i.p. or i.g., 1 M NaCl, 1% BW; i.g., 0.6 M NaCl, 0.5% BW) was reduced during 120 min in rats with subdiaphragmatic vagotomy (VGX) compared to sham-VGX rats. Brain Fos-ir was examined in response to both i.g. loads. After the smaller load, VGX greatly reduced Fos-ir in the supraoptic nucleus (SON) and the magnocellular and parvocellular areas of the paraventricular nucleus (PVN). Fos-ir in the subfornical organ (SFO) and nucleus of the solitary tract (NTS) was not affected. After the larger load, VGX significantly reduced Fos-ir in the parvocellular PVN and in the NTS, but not in the other regions. Thus, decreased water intake by VGX rats was accompanied by decreased Fos-ir in the parvocellular PVN after the same treatments, indicating a role for the abdominal vagus in thirst in response to signaling from gut osmoreceptors. The decreased water intake in the VGX group was not reflected as a decrease in Fos-ir in the SFO. Absorption of the larger i.g. load may have activated Fos-ir through more rapidly increasing systemic osmolality, thereby obscuring a role for the vagus at this dose in the SON and magnocellular PVN.

Effect of the intracerebroventricular administration of GR 113808, a selective 5-HT4 antagonist, on water intake during hyperosmolarity and hypovolemia.

We demonstrate here that acute third ventricle injections of GR 113808, a highly selective 5-HT4 antagonist, decrease water intake induced by a previous salt load while potentiating drinking elicited by hypovolemia induced by previous subcutaneous administration of polyethylene glycol in male Wistar rats (200 +/- 20 g). At the dose of 160 nmol/rat, third ventricle injections of GR 113808 induced a significant reduction of water intake in salt-loaded animals after 120 min as compared to salt-loaded animals receiving third ventricle injections of saline (salt load + GR = 3.44 +/- 0.41 ml, N = 12; salt load + saline = 5.74 +/- 0.40 ml, N = 9). At the dose of 80 nmol/rat, GR 113808 significantly enhanced water intake in hypovolemic animals after 120 min as compared to hypovolemic animals receiving third ventricle injections of saline (hypovol + GR = 4.01 +/- 0.27 ml, N = 8; hypovol + saline = 2.41 +/- 0.23 ml, N = 12). We suggest that central 5-HT4 receptors may exert a positive drive on water intake due to hyperosmolarity and a negative input on drinking provoked by hypovolemia.

Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain.

Apelin, a peptide recently isolated from bovine stomach tissue extracts, has been identified as the endogenous ligand of the human orphan APJ receptor. We established a stable Chinese hamster ovary (CHO) cell line expressing a gene encoding the rat apelin receptor fused to the enhanced green fluorescent protein, to investigate internalization and the pharmacological profile of the apelin receptor. Stimulation of this receptor by the apelin fragments K17F (Lys1-Phe-Arg-Arg-Gln-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and pE13F (pGlu5-Arg-Pro-Arg-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) resulted in a dose-dependent inhibition of forskolin-induced cAMP production and promoted its internalization. In contrast, the apelin fragments R10F (Arg8-Leu-Ser-His-Lys-Gly-Pro-Met-Pro-Phe17) and G5F (Gly13-Pro-Met-Pro-Phe17) were inactive. The physiological role of apelin and its receptor was then investigated by showing for the first time in rodent brain: (i) detection of apelin neurons in the supraoptic and paraventricular nuclei by immunohistochemistry with a specific polyclonal anti-apelin K17F antibody; (ii) detection of apelin receptor mRNA in supraoptic vasopressinergic neurons by in situ hybridization and immunohistochemistry; and (iii) a decrease in vasopressin release following intracerebroventricular injection of K17F, or pE13F, but not R10F. Thus, apelin locally synthesized in the supraoptic nucleus could exert a direct inhibitory action on vasopressinergic neuron activity via the apelin receptors synthesized in these cells. Furthermore, central injection of pE13F significantly decreased water intake in dehydrated normotensive rats but did not affect blood pressure. Together, these results suggest that neuronal apelin plays an important role in the central control of body fluid homeostasis.

Antioxidant prevention of Heinz body formation and oxidative injury in cats.

To determine the effectiveness of 3 antioxidants in preventing Heinz body anemia in cats. Prospective study. 44 specific-pathogen-free healthy cats. Cats were housed individually, divided randomly into 4 groups, and given the following orally every 12 hours: empty gelcaps (control cats), N-acetylcysteine (NAC, 100 mg/kg of body weight), vitamin E (d,l-alpha-tocopherol; 400 IU), or ascorbate (250 mg). After 2 weeks, Heinz bodies were induced by dietary onion powder (OP; 1% or 3% of dry matter) or propylene glycol (PG, 8% wt/vol in drinking water) for an additional 3 weeks. Intake of treated water or food was recorded daily. Body weight, PCV, Heinz body and reticulocyte percentages, reduced glutathione concentration, and total antioxidant status were measured twice weekly in all cats. Heinz body percentage and degree of anemia did not differ significantly among cats receiving antioxidants and control cats except in cats that ingested water containing PG, in which antioxidant supplementation was associated with a decrease in water intake. Of cats that were fed a diet that contained OP, cats that received NAC had significantly higher reduced glutathione concentrations, compared with other cats in the experiment. Total antioxidant status did not consistently correlate with antioxidant supplementation or type of oxidant administered (ie, OP or PG). Although the effect of antioxidant supplementation on Heinz body anemia in cats was minimal, antioxidants may have subclinical biochemical effects such as GSH sparing that may be important against milder forms of oxidative stress.

Hypernatremia in a non insulin dependent (type 2) diabetic patient with central diabetes insipidus

We describe a patient with central diabetes insipidus who presented with hyperosmolar, non-ketotic hyperglycaemia. The role in this case of reduced thirst sensation with decreased water intake and abnormal AVP production illustrates the importance of these protective mechanisms in normal physiology regarding maintenance of normal plasma osmolality. Despite the complex pathophysiology in this patient, fluid resuscitation aimed at normalisation of the water deficit resulted in full recovery.

Neuropeptide-Y in the paraventricular nucleus increases ethanol self-administration

The paraventricular nucleus (PVN) of the hypothalamus is known to modulate feeding, obesity, and ethanol intake. Neuropeptide-Y (NPY), which is released endogenously by neurons projecting from the arcuate nucleus to the PVN, is one of the most potent stimulants of feeding behavior known. The role of NPY in the PVN on ethanol self-administration is unknown. To address this issue, rats were trained to self-administer ethanol via a sucrose fading procedure and injector guide cannulae aimed at the PVN were surgically implanted. Microinjections of NPY and NPY antagonists in the PVN were conducted prior to ethanol self-administration sessions. All doses of NPY significantly increased ethanol self-administration and preference, and decreased water intake. The NPY antagonist D-NPY partially reduced ethanol self-administration and completely blocked the effects of an intermediate dose of NPY (10 fmol) on ethanol intake, preference, and water intake. The competitive non-peptide Y1 receptor antagonist BIBP 3226 did not significantly alter ethanol self-administration or water intake when administered alone in the PVN but it completely blocked the effect of NPY (10 fmol) on ethanol intake. NPY infused in the PVN had no effect on ethanol self-administration when tested in rats that did not have a long history of ethanol self-administration. The doses of NPY tested produced no effect on food intake or body weight measured during the 24-h period after infusion in either ethanol-experienced or ethanol-inexperienced rats. These results indicate that elevation of NPY levels in the PVN potently increases ethanol self-administration and that this effect is mediated through NPY Y1 receptors.

Role of nitric oxide in hypodipsia of rats with obstructive cholestasis.

Cholestasis is associated with the overproduction of nitric oxide (NO), and NO acts as an inhibitory mechanism when thirst is stimulated by water deprivation or by angiotensin II. Due to the presence of hypodipsia in the cholestatic condition, we have compared the rate of water intake between bile duct-ligated (cholestatic) and sham-operated rats. We have evaluated the effect of NO synthesis inhibition by N(G)-nitro-L-arginine (L-NNA, 10 mg kg(-1)/day) on the rate of water intake in cholestatic rats. The results showed that plasma alkaline phosphatase activity (a marker of liver damage) increased after bile-duct ligation, and that its elevation was partially (but significantly) prevented by treatment with L-arginine. A two-week bile-duct obstruction induced a significant decrease in the rate of water intake compared with sham-operated animals (35.87 +/- 1.45 vs 42.37 +/- 1.99 mL/day, P < 0.05). This effect was corrected by the daily administration of L-NNA. Surprisingly, L-arginine (200 mg kg(-1)/day) showed similar activity as L-NNA in cholestatic rats and increased water intake, but not in control animals. Systemic NO synthesis inhibition corrected the decrease in water intake observed in cholestatic rats. This suggests an important role for NO in the pathophysiology of hypodipsia in cholestatic subjects. The effect of chronic L-arginine administration observed in cholestatic rats but not seen in the control rats could be explained theoretically by the amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats.