The effect of vasopressin analogs on water metabolism

The effects of naturally occurring lysine and arginine vasopressins (LVP and AVP) were compared with those of 1-deamino-8-D-arginine-vasopressin (dDAVP) and 1-deamino-4-valine-D-arginine-vasopressin (dVDAVP). The changes of minute diuresis, urinary osmolarity and the duration of action were followed. dDAVP and dVDAVP in a single intravenous and intranasal dose decreased the diuresis more markedly (3.5-fold) and for a longer duration (3.3-fold) than did LVP in patients with central diabetes insipidus. The administration of dDAVP and dVDAVP in the form of sublingual tablets also proved to be effective, where dVDAVP acted more markedly and longer (16 hrs) than dDAVP (12 hrs) in a single dose of 30 micrograms. During one week of sublingual dDAVP administration, the accumulation of the drug was indicated by the gradual decrease of diuresis and the increase of urine osmolarity. The misuse of such highly active drugs may even result in iatrogenic inappropriate ADH syndrome (Schwartz-Bartter). The danger of this syndrome will be demonstrated in a case history. Some more recently synthesized vasopressin analogues with antagonistic action on the diuresis may have an important role in the therapy of Schwartz-Bartter syndrome. The authors present their results with one of these antagonists [1-(beta-mercapto-beta, beta-cyclopentamethylene-propionic acid), 2-O-ethyltyrosine, 4-valine] arginine vasopressin (d/CH2/5Tyr/Et/VAVP) both in Brattleboro and in R-Amsterdam rats. This analogue blocks the antidiuretic effect of both exogenous and endogenous vasopressin.     

The role of vasopressin in the impaired water excretion of myxedema

The plasma vasopressin response to acute water ingestion was evaluated in 20 patients with myxedema prior to definitive treatment and in eight of these same patients following therapy of their hypothyroidism. Vasopressin levels were elevated and failed to completely suppress following water ingestion in 15 subjects (75 per cent). Two hypothyroid patients with elevated plasma vasopressin levels (10 per cent) had a normal renal response to the water challenge suggesting partial end organ hormonal unresponsiveness. In three (15 per cent) of the five patients with suppressible vasopressin, water excretion was impaired indicating a nonvasopressin-mediated renal defect. In eight patients restudied after achievement of a euthyroid state, vasopressin inhibltion and urinary excretion were normal following the oral water load. Although intrinsic renal changes in the hypothyroid state may contribute to the observed defect in water diuresis, the present study suggests a role of endogenous vasopressin in this disorder.     

Water-losing and water-retaining states: role of water channels and vasopressin receptor antagonists

Alterations in water metabolism are present in conditions such as diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, cardiac failure, cirrhosis, and pregnancy. Recent advances in molecular biology have enhanced our understanding of disordered water metabolism in these conditions. This review examines the roles of central vasopressin synthesis and release and collecting duct vasopressin V2 receptor and aquaporin-2 water channel regulation in water-losing and water-retaining states.     

The role of vasopressin and prolactin in abnormal salt and water metabolism of obese patients before and after fasting and during refeeding.

Arginine vasopressin (AVP) and prolactin (PRL) concentrations were measured in the plasma of grossly obese subjects to determine if abnormalities in salt and water homeostasis could be related to these hormones. Acute oral water loads and hypertonic saline infusions were administered during baseline obesity, after prolonged fasting, and after hypocaloric refeeding. Only 64.7%, 46.1%, and 70.1% of a water load was excreted during the respective three stages. Pre-water load plasma AVP levels were normal, but after the water load the obese failed to suppress AVP secretion in a normal fashion; this defect was corrected after fasting and with refeeding. Salt loading resulted in appropriate osmolality and AVP responses. Serum prolactin levels, normal at baseline during all phases, rose slightly after water loading during fasting. Hypertonic.saline produced no changes in prolactin levels in the obese or in the normal controls. In the disordered salt and water metabolism of the obese, persistently high AVP values during water loading appeared to be a factor in the delay of water excretion. In the observed water retentionduring dietary restriction and refeeding, secretion of AVP and PRL did not appear to have a major regulatory function.     

Altered bile acid metabolism in vegetarians

Bile acid kinetics were studied in a group of healthy vegetarians and a matched group of healthy control subjects. The daily fractional turnover rate of cholic acid was significantly smaller in the vegetarians than in the controls and deoxycholic acid pool size was significantly smaller in the vegetarians than in the controls. The data suggest that enterohepatic conservation of cholic acid is more efficient in vegetarians than in control subjects resulting in decreased deoxycholic acid input in vegetarian subjects. The possible significance of these data to intestinal oncogenesis is discussed.     

Altered methionine metabolism in streptozotocin-diabetic rats

Summary We examined the origin of hypermethioninaemia in streptozotocin-diabetic rats. In rats administered streptozotocin over a range from 55 to 75 mg/kg, the dose of drug injected correlated directly with the plasma methionine concentration and inversely with the plasma insulin level. Although insulin administration prevented hypermethioninaemia in streptozotocin-diabetic rats, discontinuing insulin treatment resulted in a time-dependent increase in the plasma methionine level. Plasma methionine concentration was, however, normal in insulin-deprived BB Wistar rats despite severe hyperglycaemia. Thus, although insulin deficiency may be a contributing factor, it does not cause hypermethioninaemia independent of other drug-related effects. Administering a loading dose of methionine (100 mg/kg) indicated that streptozotocin-diabetic rats have a reduced metabolic capacity. Since dietary intake is the primary source of methionine, it is likely that hyperphagia combined with limited disposal produces hypermethioninaemia. Methionine is the most toxic amino-acid; therefore, metabolic studies using the streptozotocin model of insulin deficiency must be interpreted with caution.     

Calcium metabolism in tuberculosis

To investigate the role of Ca metabolism in granulomatous lung diseases, 187 patients with pulmonary tuberculosis 42 patients with sarcoidosis, and 47 patients with pneumonia were examined. The mean value of serum Ca on admission in tuberculosis patients was significantly lower than in patients with sarcoidosis. Of 183 patients with tuberculosis, 69 patients (38%) showed Ca level lower than normal range. The longitudinal observation of serum Ca level in 33 drug-responsive patients with tuberculosis disclosed that mean Ca level rose significantly at the third month of treatment, and maintained the similar level up to the sixth month. These findings suggest that the dynamics of Ca metabolism seen in tuberculosis were similar to that in pneumonia and differed from that in sarcoidosis, although both tuberculosis and sarcoidosis are characterized histologically by granuloma formation induced by cell-mediated immunity. To explain changes in Ca level, the chronological analysis of serum Vitamin D level was done, and it showed no correlation with serum Ca level. The lower serum Ca level on admission and their normalization according to the improvement of clinical course in tuberculosis have not been reported yet. It seems that there are responsible factors other than Vit D for Ca level fluctuation, and further studies are needed.     

Altered hepatic drug metabolism in senescent mice

Age-related alterations were examined in the system of hepatic drug metabolism in male mice. Although cytochrome P₄₅₀ content and composition did not change, several mixed-function oxidase activities decreased with age. However, both benzo(a)pyrene hydroxylase and 7-ethoxycoumarin de-ethylase showed a significant increase in the senescent mouse, in contrast to the situation previously described in aging rats. Old mice were able to respond to treatment with polychlorinated biphenyls, potent inducers of hepatic drug metabolism. The basis for senescent changes in hepatic drug metabolism still requires elucidation.     

Altered triiodothyronine metabolism in Zucker fatty rats

Genetically obese Zucker fatty rats require two autosomal recessive genes (fa/fa) to express the obese phenotype. The obese Zucker rat (fa/fa) has decreased total and free serum T3 concentrations, but normal serum T4 concentrations, compared to those in their lean littermates. To elucidate the mechanism of these differences, we measured the MCR and production rate (PR) of T4 and T3 in the three genotypes of 4-month-old male Zucker rats (Fa/Fa, Fa/fa, and fa/fa). In addition, 5'-deiodinase activity in liver, kidney, and brown adipose tissue homogenates was determined. T4 MCRs were equivalent in all three genotypes, but a decreased T3 MCR was seen in Fa/fa and fa/fa rats. An additive effect of the fa gene was noted with respect to the decrease in T3 MCR (Fa/Fa, 42.0 +/- 1.5; Fa/fa, 38.7 +/- 2.4; fa/fa, 34.7 +/- 3.4 ml/h; P less than 0.05). Whole body T4 PRs were equal in all three genotypes, but the T3 PR was decreased in the fa/fa rat by 25% compared to that in the homozygous lean rats (15.7 +/- 2.1 vs. 21.2 +/- 2.4 ng/h; P less than 0.005). Liver and kidney 5'-deiodinase activities were decreased in the fa/fa rat by 34% (P less than 0.005) and 20% (P less than 0.01), respectively. Brown adipose tissue and pituitary 5'-deiodinase activity were similar in all three genotypes. These results show a reduction in T3, but not T4, MCR in obese Zucker rats. Whole body T3 production and type I 5'-deiodinase activity were decreased in the obese (fa/fa) rats. These results suggest that decreased T4 to T3 conversion is responsible for the decreased T3 production rate in the fatty rat and may contribute to its obesity.     

Risk factors of tuberculosis in Mizoram: First report of the possible role of water source

BackgroundVarious risk factors of tuberculosis have been studied across the globe, but these may be altered over time and can be specific to geographical regions and there is not much information available from Northeastern region of India. This study aims to investigate the various risk factors of tuberculosis and analyze the presence of any less-established risk factors.MethodsA total of 400 TB cases and 840 healthy controls were interviewed from December 2017 - June 2020. Logistic regression model was used to analyze associated risk factors. Patients were categorized into pulmonary and extrapulmonary TB.ResultsClinical presentation such as fever, cough, weight loss, chest pain and night sweats were more prominent among pulmonary TB patients. The most common mode of diagnosis among pulmonary and extrapulmonary TB were GeneXpert and X-ray, respectively. Tuberculosis was found to be strongly prevalent among patients from lower socio-economic status, less educated, unemployed and improper housing condition. Other risk factors associated were alcohol consumption, neighbours with TB, travel history, no BCG vaccine, mass gathering, and non-ideal weight. An interesting less-established risk factor that demands attention is the source of water supply (p-0.017, OR-2.313, CI: 1.160–4.613), which was significant in this study.ConclusionOur data suggests that apart from all the well-established risk factors for TB, water supply might play a crucial role towards the transmission of TB, since proper hospital waste water treatment is yet to be adopted in Mizoram, Northeast India. From a public health standpoint, this highlights the need for further research in this area.     

Depressor effects of captopril in DOCA-salt hypertensive rats: role of vasopressin

Oral administration of the angiotensin I-converting enzyme inhibitor captopril produced a substantial reduction of blood pressure in DOCA-salt hypertensive rats. After oral administration of captopril (30 mg/kg), mean blood pressure decreased from 172 +/- 11 to 148 +/- 9 mmHg (P less than 0.01) in one hour and its antihypertensive effects lasted for the next seven hours. Plasma vasopressin levels showed a marked elevation in DOCA-salt hypertensive rats compared with control values (22 +/- 5 versus 5 +/- 3 pg/ml). This increase in vasopressin was significantly reduced by captopril from 25 +/- 5 to 8 +/- 6 pg/ml. In addition, whole body vascular reactivity to norepinephrine was examined. Responsiveness was at first attenuated but returned to control value in spite of reduction of both plasma vasopressin and blood pressure. Thus, captopril reduces blood pressure in DOCA-salt hypertensive rats and the fall in blood pressure is accompanied by reduction of plasma vasopressin and attenuation of vascular reactivity.     

Altered muscle metabolism in rats after thermal injury

Burn injury is associated with an elevation in total body oxygen consumption, increased hepatic alanine uptake and conversion to glucose, and a negative nitrogen balance. The primary source of the alanine used for gluconeogenesis by the liver and of the nitrogen lost as urea is believed to be from skeletal muscle. Selected muscle regulatory enzymes and pyruvate and oleate oxidation rates were assayed for maximal activity during the postburn period. Male Sprague-Dawley rats that received 50% total body surface scald burns on the dorsum and abdomen were examined for citrate synthase (CS), phosphofructokinase (PFK), and glutamate-pyruvate transaminase (GPT) activity in uninjured muscle at 3, 7, 13, and 20 days postburn, and the ability of muscle to oxidize pyruvate and oleate was measured at 3 and 13 days after injury. CS, PFK, and GPT activities increased significantly (p < 0.05) by 13–20 days after injury in the soleus and diaphragm. The epitrochlearis showed no change in CS, but PFK and GPT were elevated within this time frame. The gastrocnemius muscle showed an elevated oleate oxidation rate at 13 days after injury, but no change at 3 days postburn. Pyruvate oxidation rates were unaltered.The results of this study indicate that during the postburn period several metabolic alterations occur in muscle. These adaptations include: (1) elevated CS activity which may be associated with increased oxidative capactiy, (2) increased PFK activity which implies that more substrate is being shuttled through the glycolytic pathway, (3) increased GPT activity which may reflect increased pyruvate conversion to alanine, and (4) increased oleate oxidation rates which demonstrate that muscle is utilizing more fatty acid substrates during the postburn period.     

Altered bile acid metabolism in primary biliary cirrhosis

Selected aspects of bile acid metabolism were assessed in six women with primary biliary cirrhosis and varying degrees of cholestasis. Urinary bile acid excretion was markedly increased and correlated highly with serum levels. In three patients in whom urinary bile acids were separated by chromatography, the majority of urinary bile acids were monosulfated (34%, 42%, 32%) or polysulfated and/or glucuronidated (30%, 20%, 38%). The monosulfates of chenodeoxycholic acid were conjugated at either the 3 position (67%, 68%, 73%) or the 7 position (33%, 32%, 27%); similarly, the monosulfates of cholic acid were conjugated at the 3 position (65%, 58%, 68%) or the 7 position (35%, 42%, 32%). The position of sulfation was not markedly influenced by the mode of amidation with glycine or taurine. Chenodeoxycholic exchangeable pool size, turnover rate, and synthesis were measured by isotope dilution and found to be well within normal limits, despite the cholestasis. The fraction of chenodeoxycholic acid synthesis excreted in urine ranged from 9 to 48%; 4–38% of chenodeoxycholic acid synthesis was sulfated. These data indicate that the major abnormalities in bile acid metabolism in patients with cholestasis secondary to primary biliary cirrhosis are formation of sulfated bile acids in greatly increased amounts, elevation of blood levels of primary bile acids, and a shift to renal excretion as a major mechanism for bile acid elimination. Chenodeoxycholic acid synthesis continues at its usual rate despite cholestasis. Whether these changes, including the formation of 7-monosulfated bile acids, occur in other forms of cholestasis and whether either the persistance of unchanged chenodeoxycholic acid synthesis or the formation of such novel conjugates has any pathophysiological significance remain to be investigated.Supported by NIH grant AM 21506 to the University of California and grant RR 00585 and NIH grants AM 19448 and AM 16770 to the Mayo Clinic and Mayo Foundation. In addition, research at the University of California was supported by grants-in-aid from the Rorer Company, the Eli Lilly Company, and the Canada Packers Limited Company.     

Altered norepinephrine turnover and metabolism in diabetic cardiomyopathy

Cardiac norepinephrine turnover and metabolism were examined in rats 8 weeks after the induction of chronic diabetes by an intravenous injection of streptozotocin (65 mg/kg). Cardiac norepinephrine concentration, norepinephrine turnover, and norepinephrine uptake were markedly increased in chronic diabetes in comparison with control values; these changes were reversible by 28-day insulin therapy. When the animals were exposed to cold for 6 hours, norepinephrine turnover rate constant increased in control and decreased in diabetic animals; cold exposure also increased norepinephrine concentration in diabetic hearts. Both cardiac norepinephrine concentration and turnover rate in diabetic rats were restored toward control values by ganglionic blockade with pentolinium. The conversion of [3H]tyrosine to [3H]catecholamine was enhanced and tyrosine hydroxylase as well as dopa decarboxylase activities were increased in diabetic hearts. The higher concentrations of [3H]normetanephrine and deaminated catechols indicated a faster metabolic rate of norepinephrine metabolism in hearts from diabetic rats; both monoamine oxidase and catechol-O-methyltransferase activities were also increased. The increased activities of the enzymes for the synthesis and metabolism of norepinephrine were not evident on treating the diabetic animals with insulin. These data not only support the view that chronic diabetes in rats is associated with increased sympathetic activity but also indicate that the cardiac norepinephrine concentration in diabetic rats may be maintained at a higher than normal level by an increased synthesis and uptake of norepinephrine in the adrenergic nerve terminals.