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Evidence for bradykinin as a stimulator of thirst.

Angiotensin-converting enzyme inhibition (ACEI) with captopril has been shown to increase water intake and urine output in rats, but the mechanism is unknown. ACEI impairs the conversion of ANG I to ANG II, a dipsogenic hormone, and impairs the degradation of bradykinin. The goal of this study was to examine the role of bradykinin in the polydipsia and polyuria associated with ACEI. Male Sprague-Dawley rats received captopril (CPT; 20 mg.kg(-1).day(-1)) in ground chow for 48 h. Water intake, food intake, and urine output were monitored and compared with control rats (CTL), rats receiving captopril treatment with limited water intake (CPT-LIM), and rats receiving captopril treatment with ad libitum water intake plus 24-h treatment with the bradykinin antagonist B-9430 (CPT-BK1). CPT rats consumed significantly more water and produced more urine vs. CTL. Urine osmolality was significantly decreased in CPT rats vs. CTL. Inner medullary aquaporin-2 (AQP2) protein abundance was also markedly decreased in CPT rats vs. CTL. These findings were reversed in CPT-LIM rats, suggesting captopril-induced primary polydipsia. CPT-BKI rats demonstrated parameters no different from CTL despite ad libitum water intake. Mean arterial pressure and 24-h creatinine clearance did not differ among groups. We conclude that ACEI with captopril induces primary polydipsia despite impaired production of the dipsogen ANG II and that this primary increase in water intake is likely the cause of the decreased protein abundance of inner medullary AQP2. Furthermore, this dipsogenic effect was reversed by antagonism of bradykinin, thus implicating this hormone in thirst regulation in the rat.

Angiotensin-Converting Enzyme Inhibitors↗

Galphaq-dependent signaling cascades stimulate water-seeking behavior.

We used the mouse nephrin promoter to express a constitutively active Galphaq [Galphaq(Q>L)] transgene in mice. As previously reported, the transgene was expressed in kidney, pancreas, and brain, and the kidney phenotype was characterized by albuminuria and reduced nephron mass. Additional studies revealed a second phenotype characterized by polyuria and polydipsia. The polyuric phenotype was not caused by abnormal glucose metabolism or hypercalcemia but was accompanied by reduced urinary concentrating ability. Additional studies found that 1) water restriction was associated with an appropriate increase in serum vasopressin levels in transgenic (TG) mice; 2) the urinary concentrating defect was not corrected by administration of desamino-d-arginine vasopressin (DDAVP); and 3) papillary length was similar in TG and non-TG mice. To examine the renal response to DDAVP at the molecular level, we monitored aquaporin 2 (AQP2) and vasopressin V2 receptor (V2R) mRNA levels in mouse kidney. Consistent with the known effects of vasopressin, administration of DDAVP caused a decrease in V2R mRNA levels and an increase in AQP2 mRNA levels in both TG and non-TG animals, suggesting an appropriate renal response to DDAVP in the TG mice. To determine whether the urine concentrating abnormality was the result of primary polydipsia, water intake by TG mice was restricted to the amount ingested by non-TG animals. After 5 days, urinary concentrating ability was similar in TG mice and non-TG littermate controls. These data are consistent with the notion that expression of the Galphaq(Q>L) transgene in the brain induced primary polydipsia in the TG mice.

Animal Feed↗

Water metabolism after cisplatin in the rat.

A polyuric state is often observed after cis-dichlorodiammine platinum (cisplatin). To study the mechanism of this polyuria we gave 5-6 mg/kg cisplatin to conscious rats and observed polydipsia and a polyuric form of mild acute renal failure. A defect in renal concentrating ability was observed 1 and 8 days after cisplatin. Animals demonstrated diminished postdehydration plasma vasopressin at 1 but not at 8 days after cisplatin, and exogenous vasopressin corrected the renal concentration defect at 1 but not at 8 days after cisplatin. To assess the role of polydipsia in the concentration defect, water intake in cisplatin-treated animals was matched to pair-fed controls. Prevention of polydipsia improved the polyuria but not the concentration defect seen 8 days after cisplatin. To assess intrarenal factors in the renal concentration defect, postdehydration interstitial solute was measured and was significantly lower in cisplatin-treated than in control animals. To determine whether the diminished interstitial solute was due to vascular mechanisms, inner medullary plasma flow was measured and was identical in cisplatin-treated and control rats. Treatment with cisplatin also resulted in decreased excretion of a water load. We conclude that either impaired synthesis or release of vasopressin is the cause of the impaired renal concentration seen 1 day after cisplatin. Eight days after cisplatin, the renal concentration defect is due in part to decreased interstitial tonicity.

Animals↗

Administration of lithium to rats by different routes.

Rats were given identical doses of lithium chloride, 4 mmol/kg body weight/day for 8 days, by different routes. Intraperitoneal administration led to a high serum lithium peak and the development of pronounced polyuria-polydipsia. Subcutaneous administration led to a lower serum peak and the development of less pronounced polyuria-polydipsia. Administration by gastric tube led to a nearly constant serum lithium concentration without any peak and the development of moderate polyuria-polydipsia. Our study shows that the route by which lithium is administered affects the lithium concentration pattern and may influence lithium effects.

Administration, Oral↗

[Effects of Byakko-ka-ninjin-to, Bofu-tsusho-san and Gorei-san on blood glucose level, water intake and urine volume in KKAy mice].

KKAy mouse, a genetic animal model of diabetes mellitus, is characterized by not only hyperglycemia, but also polydipsia and polyuria like human diabetes mellitus. In this study, we investigated the effects of Byakko-ka-ninjin-to (BKN), Bofu-tsusho-san (BOF) and Gorei-san (GRE) on blood glucose level, water intake and urine volume in KKAy mice. All these Kampo medicines were administered to the mice as the food admixture containing 1.5% or 4.5% of weight of food for 4 weeks. BKN at 1.5% and 4.5% decreased water intake without affecting blood glucose level. BOF at 1.5% showed the same effects as BKN did, but it decreased both water intake and blood glucose level at 4.5%. Furthermore, BOF at 4.5% obviously, but BKN at 4.5% slightly, decreased urine volume. However, GRE at 4.5% did not show any effects on blood glucose level, water intake and urine volume. From these results, BKN is confirmed to be effective against the polydipsia accompanied by diabetes mellitus, while BOF is suggested to be effective against not only polydipsia, but also polyuria and hyperglycemia in diabetes mellitus.

Animals↗

Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs.

The objective of this study was to evaluate the safety and efficacy of a purified porcine insulin zinc suspension for treating dogs with uncomplicated diabetes mellitus. Fifty-three dogs were treated for 60 days after an initial dose determination period. The means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs were determined before beginning insulin therapy (time 0), at the end of the dose determination period (time 1), 30 days after time 1 (time 2), and 60 days after time 1 (time 3). Presence of polyuria, polydipsia, and ketonuria was determined at each time point. Adequacy of control of hyperglycemia was based on 12-hour blood glucose curves and improvement in clinical variables (results of physical examinations, historic information, polyuria, polydipsia, and ketonuria). Safety was evaluated by questionnaire, performance of physical examination, CBC, serum chemistry profile, and urinalysis. The means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs at times 1, 2, and 3 were significantly lower compared with time 0 (P < .0001). There was a reduction in the proportion of dogs with polyuria, polydipsia, and ketonuria of 82, 86, and 80%, respectively. All of the dogs had adequate glycemic control at time 1, 66% at time 2, and 75% at time 3. At time 3, 66% of dogs required insulin injections q12h. Other than hypoglycemia, there were no important adverse effects of insulin administration. The insulin, was safe and efficacious for reducing blood glucose and clinical signs in dogs with diabetes mellitus.

Animals↗

[Psychogenic water intoxication].

Six new cases of psychogenic water intoxication are discussed in the light of 150 observations published in the literature since 1935. 87% of all patients were schizophrenic, and 13% had other psychoses and a variety of functional and organic psychopathies. Psychogenic polydipsia is a prerequisite of psychogenic water intoxication. Water intake either overrides an intact osmoregulation (46% of all cases) or, allied to an inadequate urinary dilutional capacity (54%), leads to a transitory, sometimes repeated, and (in 8% of all cases) lethal water intoxication and hypoosmolality. - The consequence of hypoosmolality is metabolic encephalopathy, with agitation, convulsions and coma as its most common symptoms. Profuse diuresis, enuresis and urinary retention, gastric dilatation, watery vomiting and watery diarrhea are diagnostically helpful symptoms of polydipsia typically denied by the patients. Hypoosmolality/hyponatremia are the hallmarks of water intoxication. However, fewer than 50% of all patients present with the expected maximal urinary dilution. Inadequate ADH activity and increased sensitivity of the renal tubule to antidiuretic hormone are the pathogenetic factors in this inappropriate urinary dilution, while psychosis, psychotropic drugs, diuretics, nicotine and alcohol withdrawal are possible causes and cofactors of polydipsia and inadequate urinary dilution. New aspects of treatment are discussed.

Aged↗

Partial deficiency of antidiuretic hormone in a cat.

Marked polydipsia and polyuria developed subsequent to trauma in a 1 1/2-year-old male Abyssinian cat. Diabetes insipidus was suspected, inasmuch as intramuscualr vasopressin administration resulted in amelioration of polydipsia and polyuria. However, hypertonic (3%) saline solution given intravneously resulted in anuria, an indication of antidiuretic hormone activity. Polyuria and polydipsia were abolished by oral chlorpropamide therapy, which was indirect evidence for partial deficiency of antidiuretic hormone.

Animals↗

Symptoms and complications of adult diabetic patients in a family practice.

OBJECTIVES: To determine the frequency of common symptoms and complications amoung adult patients with either non-insulin-dependent or insulin-dependent diabetes mellitus and to examine associations of these problems with vascular disease risk factors. DESIGN: Cross-sectional determination of the prevalence of symptoms, complications, and risk factors among adult patients with diabetes, and a case-control design of a subsample of those case patients with non-insulin-dependent diabetes mellitus who were age-, race-, and sex- matched 2:1 to adult control patients with hypertension. SETTING: A large family practice ambulatory care unit in which the patients were demographically representative of the Piedmont region of North Carolina. PATIENTS: Three hundred thirty-six adults participated; of these participants, 223 case patients had non-insulin-dependent diabetes mellitus and 23 case patients had insulin-dependent diabetes mellitus. An additional 90 control patients were selected who had hypertension but did not have diabetes. MAIN OUTCOME MEASURES: Frequencies and odds ratios of symptoms and complications that were categorized by diabetic type, another chronic disease (eg hypertension), or vascular risk factors (eg, the duration of diabetes, levels of glycosylated hemoglobin, fasting blood glucose, total cholesterol, and high-density lipoprotein cholesterol, or mean arterial blood pressures). METHODS: Standardized medical histories, physical examinations and anthropometric and serum chemistry studies were done. Microalbuminuria was measured by unrinary albumin excretion ratios. RESULTS: Results: Symptoms of polydipsia, fatigability or cold intolerance, palpitations, dyspnea, orthostasis, indigestion, frequent urination, male impotence, blurred vision, paresthesias, forgetfulness occurred in more that one third of the adult diabetic patients as did complications of hypertension, microalbuminuria, peripheral neuropathy, and hypercholesterolemia. Those patients with non-insulin-dependent diabetes mellitus were more likely than those with insulin-dependent diabetes mellitus to have recent symptoms of polydipsia, chest pains, shortness of breath, orthostasis, light-headedness, and vaginal discharge. They were also more likely to have hypertension and hypercholesterolemia, but less likely to have dipstick proteinuria. Patients with non-insulin-dependent diabetes mellitus were more likely than those with hypertension alone to have a variety of general, cardiovascular, and neurologic symptoms and more likely to have peripheral vascular disease, neuropathy, retinopathy, and proteinuria. Regardless of the diabetic type, nearly half of the patients had microalbuminuria. The presence of symptoms was often associated with the duration of diabetes and poor glycemic control as were complications, but complications were often also associated with dyslipidemias and an elevated mean arterial pressure. CONCLUSIONS: Previous studies have documented such a wide variety of symptoms and complications, but these studies have been based on those patients who attended specialized referral settings. Our findings show that these problems are surprisingly common among adult diabetic patients who are cared for in a primary care setting. The fact that nearly half of the patients had microalbuminuria suggests that the onset of significant vascular complications had already begun in most of these patients. The occurrence of symptoms of depression, anxiety, panic, and forgetfulness were unexpectedly common and may have adversely affected the ability of diabetic patients to comply with the intended therapy.

Adult↗

Compulsive water drinking in pregnancy.

A case report of a pregnant woman with primary polydipsia is presented. The workup, including an investigation of the disturbance and the implications for fetal outcome, is described. The terms primary and secondary polydipsia are defined, and the differential diagnosis is discussed. Compulsive water drinking was finally diagnosed following psychiatric evaluation. A brief review of the literature concerning compulsive water drinking is presented.

Adult↗

Acute water intoxication after intranasal desmopressin in a patient with primary polydispsia.

Only a few cases of severe acute water intoxication (AWI) due to intranasal desmopressin have been reported, none of which occurred in patients with primary polydipsia. We describe a case of AWI with semicoma and convulsions, due to intranasal desmopressin, in a 32-year-old patient with dipsogenic diabetes insipidus. Previous reported cases of AWI due to desmopressin are discussed. The importance of ruling out primary polydipsia when this drug is used, not only for central diabetes insipidus but also for other current indications such as classic hemophilia, is stressed.

Administration, Intranasal↗

Clozapine enhances breakpoint in common marmosets responding on a progressive ratio schedule.

RATIONALE: Motivational effects of psychotropic drugs may contribute to their therapeutic profile and progressive ratio (PR) schedules provide a method of measuring these effects in animals. OBJECTIVE: Determine effects of selected antipsychotic, psychotomimetic, anxiolytic and antidepressant drugs on PR performance in common marmosets. METHOD: Marmosets were trained to lever press for banana milkshake reinforcement using a PR schedule, in which the number of lever presses to achieve successive reinforcements increased by one until responding ceased (breakpoint). RESULTS: Clozapine administered intramuscularly (0.01-2 mg/kg IM; 30 min pretreatment time (ptt) or by oral gavage (0.1-4 mg/kg PO; 60 min ptt) significantly increased the breakpoint. Independent tests of fluid consumption failed to show enhanced fluid intake after clozapine pretreatment, suggesting this effect was not due to drug induced polydipsia. Neither haloperidol (0.005-0.1 mg/kg PO; 60 min ptt) nor risperidone (0.0025-0.05 mg/kg PO; 60 min ptt) altered breakpoint. Olanzapine (0.01-1 mg/kg PO; 60 min ptt) significantly enhanced the breakpoint at 0.05 mg/kg PO, but the effect was not robust. Amphetamine (0.2-2 mg/kg SC; 30 min ptt) significantly reduced the breakpoint at 2 mg/kg and fluoxetine (0.1-1 mg/kg PO; 60 min ptt) was without effect. Diazepam significantly increased the breakpoint at 0.5 mg/kg PO. Drug-induced polydipsia might play a role in this response as independent tests showed increased fluid consumption following diazepam. CONCLUSIONS: These results demonstrate that, unlike other antipsychotics, clozapine over a wide dose range increased the motivational state of marmosets to respond for banana milkshake. This motivational aspect of clozapine's actions may contribute to its unique clinical profile and the PR procedure may provide a method for detecting novel antipsychotics with a clozapine-like profile.

Amphetamine↗

Clinical, hormonal and imaging findings in 27 children with central diabetes insipidus.

UNLABELLED: Clinical, auxological, biological and neuroradiological characteristics of 27 children with central diabetes insipidus (CDI) were retrospectively analysed. Median age at diagnosis was 8.6 years (range: 0.3-16.1 years). Final aetiologies were postsurgical infundibulo-hypophyseal impairment (n=7), cerebral tumour (n=8), Langerhans cell histiocytosis (n=3), septo-optic dysplasia (n=1), ectrodactyly ectodermal dysplasia clefting syndrome (n=1), and idiopathic (n=7). In the non-postsurgical CDI patients, major cumulative and often subtle presenting manifestations were: polyuria (n=20), polydipsia (n=19), fatigue (n=11), nycturia (n=10), growth retardation (n=9), and headache (n=9). An associated antehypophyseal insufficiency, mainly somatotropic, was documented in 11 children. All patients except one who initially had a cerebral tomography, underwent magnetic resonance imaging revealing the lack of the physiological posterior pituitary hyperintense signal. One third of the idiopathic patients initially had a thickened pituitary stalk. All patients with idiopathic CDI were intensively followed up with 3-monthly physical examination, antehypophyseal evaluation, search for tumour markers, and cerebral MRI every 6 months. In one of them the pituitary stalk had normalized after 4.3 years. In one patient Langerhans cell histiocytosis was diagnosed after 7 months of follow-up, and in another patient a malignant teratoma was found after 2.4 years of follow-up. CONCLUSION: CDI may be the early sign of an evolving cerebral process. The association of polyuria-polydipsia should incite a complete endocrine evaluation and a meticulous MRI evaluation of the hypothalamo-hypophyseal region. A rigorous clinical and neuroradiologic follow-up is mandatory to rule out an evolving cerebral process and to detect associated antehypophyseal insufficiencies.

Adolescent↗

Familial central diabetes insipidus detected by nocturnal enuresis.

A 10-year-old male referred to our clinic with the chief complaint of nocturnal enuresis also complained of daytime polyuria, frequency, and polydipsia. The clinical diagnosis was central diabetes insipidus. Since the patient's father had complained of similar symptoms, the arginine vasopressin-neurophysin II gene was examined. This revealed a single base substitution in one of two alleles in the patient, his father, and his grandfather (a C to T transition at nucleotide position 280 at codon 19 in the first exon). In conclusion, a history of polyuria or polydipsia should be carefully noted and the urinary volume and urine gravity or osmolarity examined in cases of nocturnal enuresis.

Arginine Vasopressin↗

Kappa-opioid antagonist strongly attenuates drinking of genetically polydipsic mice.

Effects of opioid antagonists on the genetic polydipsia of the STR/N strain of mice were investigated. Naltrexone (0.5-5.0 mg/kg) injected subcutaneously before dark period attenuated spontaneous drinking for the first 3 h after injection only in the inbred polydipsic mice (STR/N), whose water intake was 5 times that of controls (non-polydipsic mutant, STR/1N, and Swiss/Webster mice). The highest dose (5 mg/kg) of naltrexone administration reduced drinking also during the next 3-6 h period and overnight feeding. Cerebroventricular (i.c.v.) injection of naltrexone, 1.0 and 2.5 micrograms (per mouse), suppressed drinking only in the polydipsic mice, while the higher dose (5.0 micrograms) attenuated drinking and feeding of both the polydipsic mice and their controls. However, i.c.v. injection of specific kappa-receptor antagonist, nor-binaltorphimine (nor-BNI, 0.5-2.5 micrograms), suppressed drinking only in the polydipsic strain of mice at one-half dose of that needed for naltrexone. Furthermore, even a higher dose of nor-BNI administration was without effect on food intake in all strains. These findings suggest that the central opioid system plays an important role in causing the polydipsia in the STR/N mice, probably through the kappa-opioid receptor.

Animals↗

Effects of the opiates on the paraventricular nucleus in genetically polydipsic mice.

The inbred mice, STR/N, are known to possess extreme polydipsia with no known abnormality in vasopressin system and the kidney function. Our previous studies indicate that the opiate antagonists given intracerebroventricularly strongly attenuated spontaneous drinking. To determine the site(s) of action, the present study was undertaken. Microinjections of naltrexone methobromide and a selective kappa-receptor antagonist, nor-binaltorphimine (nor-BNI), into the paraventricular nucleus of the hypothalamus (PVN) greatly attenuated drinking of the STR/N for 0.5 to 16 h after injections, while in the two control groups, non-polydipsic STR/1N and Swiss/Webster strains, drinking was not affected by the injections. Food intake was not much altered in all groups. Studies of PVN neurons in vitro (n = > 160 for each group) showed that basal firing rates and patterns were similar in the STR/N and the control groups. Morphine added to the medium inhibited some but excited none in all strains tested. The threshold for the inhibitory action was higher in the polydipsic STR/N mice (10(-8) M), compared to that in the control, S/W mice (10(-9) M). Further, a proportion of neurons inhibited by morphine in the PVN was significantly smaller (P < 0.01) in the STR/N (41.7%), compared to that in the control (64.9%). Dynorphin had very similar effect to that of morphine, but the proportion of cells inhibited was 25.4% in the STR/N, and 70.4% in the S/W. Prior applications of naloxone to the medium prevented the action of both morphine and dynorphin. Under the synaptic blockade (in a low Ca2+ and high Mg2+ medium) the inhibitory effect of the opiates persisted. We concluded that the PVN is at least one of the possible sites where the opiates are acting to cause the polydipsia in the STR/N mice.

Animals↗

Water deprivation induces regional expression of c-fos protein in the brain of inbred polydipsic mice.

We studied the effects of water deprivation on the expression of c-fos protein (Fos) in the brain of inbred polydipsic mice, STR/N strain, that show extreme polydipsia without a lack of vasopressin in the body. Non-polydipsic mice, ICR strain, were used as controls. All male animals were deprived of water for 24 and 48 h. Fos-like immunoreactivity (Fos-LI) in the brain was studied by immunohistochemical techniques. In both groups of mice water deprivation induced a remarkable increase in Fos-LI in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, the median preoptic nucleus (MnPO), the organum vasculosum laminae terminalis (OVLT) and the subfornical organ (SFO). A far more increase, however, was seen in the MnPO, the SFO and the area postrema (AP) of the polydipsic mice compared to those of the non-polydipsic control mice. In the nucleus of the tractus solitarius (NTS) and in the anteroventral part of the PVN (avPVN), water deprivation caused a clear increase in Fos-LI in the polydipsic mice, while in the non-polydipsic mice the same treatment induced no Fos-LI in the NTS and no change in the avPVN. These results indicate that neurons in the circumventricular organs and the NTS are strongly activated by water deprivation in the polydipsic mice, suggesting that these brain structures play an important role in the polydipsia.

Animals↗

Cholinergic and catecholaminergic interaction and fluid intake in the rat.

The effect of simultaneous topical application of adrenergic agonists was investigated on the polydipsia caused by direct carbachol (CCh) stimulation of the rat brain. In addition, fluid selection (4-choice arrangement) was studied. Noradrenaline and isoprenaline fully antagonized the CCh effect after either intracerebroventricular, intraseptal or intrapreoptic application. Phenylephrine inhibited CCh polydipsia after intracerebroventricular or intrahypothalamic but not after intraseptal injection. Previous experiments had shown that adrenergic agonists also exerted a marked modulatory influence on an affective behavioural reaction pattern (rage reaction) of the cat. The results of the present experiments corroborate the assumption that, also in non-striatal brain structures, adrenergic modulation of cholinergic behavioural patterns is perhaps a more general and important phenomenon than had been assumed so far.

Adrenergic Agonists↗