Oxytocin polyuria and polydipsia is blocked by NaCl administration in food-deprived male rats.

We examined the effects of NaCl injections on the polydipsia and polyuria induced by subcutaneous oxytocin (OT) administration in food-deprived male rats. During the first 12 h of the treatment day, both food deprivation and OT administration increased urine excretion but reduced water intake, water balance (fluid intake minus urine volume) and body weight. OT treatment enhanced urine excretion and the reduction in water balance and body weight without reducing the water intake of food-deprived animals. Analysis of the physiological effects of OT administration showed increases in urinary sodium concentration, sodium excretion and a reduced plasma sodium concentration. During the second 12 h, OT increased both urine excretion and water intake in food-deprived but not in ad lib.-fed rats. However, hypertonic NaCl administration at the start of this second 12-h period blocked the polyuric and polydipsic responses observed in the OT/deprived group but increased the water intake of the ad lib. groups. After the whole 24-h period, animals treated with OT showed a water balance and body weight change matching those observed in Control animals. Although the recording time period is a critical factor to demonstrate the effect of peripheral OT administration on water intake, the results obtained suggest that the polyuric and polydipsic responses observed in food-deprived animals depend on the negative sodium and water balance induced by the natriuretic effect of OT and the unavailability of sodium. These OT-induced deficits can be counteracted by the administration of hypertonic NaCl solutions or simply by the intake of standard food.

The natriuretic effect of oxytocin blocks medial tuberomammillary polydipsia and polyuria in male rats.

Lesions of the tuberomammillary complex, a neuroanatomical system closely related to the hypothalamic supraoptic and paraventricular nuclei, induce strong polydipsia in male rats. It was recently demonstrated that this increase in water intake is immediate, persistent, follows circadian rhythms and appears to be related to sodium regulation. The present study found that urine osmolality was significantly lower in tuberomammillary-lesioned animals vs. their respective controls at 8:00 h after surgery. Therefore, the aim of the present study was to examine the natriuretic effect of intraperitoneal oxytocin (OT) administration on medial ventral tuberomammillary nucleus (E3) polydipsia and polyuria of lesioned and control male rats. At 24:00 h post-lesion, OT blocked the hyperdipsic and polyuric responses of E3-lesioned animals but not those of non-lesioned controls, which did however significantly increase their water intake. Moreover, urinary osmolality and sodium excretion increased in E3 -lesioned animals that received OT but not in lesioned controls receiving physiological saline (992 +/- 187.19 vs. 215.83 +/- 23.39 mOsm/kg; 1.68 +/- 0.13 vs. 0.47 +/- 0.1 mEq/L). At 48:00 h post-lesion, OT administration also induced a higher intake of water and of simultaneously offered hypertonic NaCl (1.5%) in E3-lesioned animals. These results are interpreted in terms of the hypothalamic systems involved in sodium and water homeostasis.

Role of the renin-angiotensin system in the development of thyroxine-induced hypertension.

OBJECTIVE: We evaluated the influence of chronic blockade of the renin-angiotensin system on hypertension induced by long-term thyroxin (T4) administration. To this end, we determined the effects of chronic treatment with captopril on blood pressure, cardiac hypertrophy and other renal and metabolic variables of hypertensive hyperthyroid rats. METHODS: T4 was administered s.c. at 0.38 mumol/kg per day and captopril was given in the drinking water (1.38 mmol/l). Both treatments were maintained for 6 weeks. Control rats received tap water. After the treatment period, the rats were placed in metabolic cages. Later, blood pressure was measured in conscious rats by intra-arterial determination. RESULTS: T4-treated rats showed an increased mean arterial pressure (MAP) whereas, in rats treated with T4 plus captopril, MAP was similar to that of the control group. Captopril did not affect the increased heart rate or ventricular weight/body weight ratio of hyperthyroid rats, but it improved the reduced creatinine clearance of these animals. CONCLUSIONS: The elevation in blood pressure produced by long-term T4 administration was prevented by chronic blockade of the renin-angiotensin system. Captopril improved the renal function of hyperthyroid rats, but did not affect the relative cardiac hypertrophy of these animals.

Endothelium-dependent and endothelium-independent vasodilation in hyperthyroid and hypothyroid rats.

The effects of hyper- and hypothyroidism on the vasorelaxing responses to acetylcholine (ACh), sodium nitroprusside (NP), and CaCl2 were investigated in aortic strips and isolated perfused kidneys. The renal vascular reactivity to ACh and NP was increased in hyperthyroid rats, whereas the concentration-response curve to ACh in hypothyroid rats was flattened. In the renal vasculature from hypothyroid rats, NP produced a dual response: vasoconstriction at low doses and vasodilation at medium to high doses. Aortic strips from hyperthyroid rats showed an increased response to ACh without significant differences between hypothyroid and control groups. Aortic strips from all three experimental groups showed a similar relaxing response to CaCl2. These results indicate that: (1) the raised arterial pressure of hyperthyroid rats is not associated with a reduced endothelium-dependent and calcium-induced vasodilation, and (2) the changes in responsiveness to vasodilators in resistance vessels from hyper- and hypothyroid rats may play a role in the increased and decreased peripheral vascular resistances, respectively, previously reported in such animals.

Vascular reactivity to vasoconstrictors in aorta and renal vasculature of hyperthyroid and hypothyroid rats.

Vascular reactivity to vasoconstrictors in relation to altered thyroid function was studied in two preparations: aortic strips and the isolated perfused kidney. To assess whether the possible alterations in vascular reactivity were restricted to a specific agonist or whether they involved the contractile system, receptor-mediated and nonspecific smooth muscle stimulants were used. Male Wistar rats were divided into three groups: control, hyperthyroid and hypothyroid rats. Aortic strips from hypothyroid rats were less sensitive to phenylephrine and KCl when the data were expressed in absolute values or as percentages of the maximum responses. Sensitivity and reactivity in strips from hyperthyroid rats were similar to those observed in control strips. Renal vasculature obtained from hypothyroid rats also showed a markedly reduced sensitivity to phenylephrine, with normal maximal responses. The response to vasopressin at 3-10(-11) mol/l was also decreased, as was the reactivity to barium chloride. In contrast, renal vasculature of hyperthyroid rats showed markedly enhanced reactivity to all agonists: the concentration-response curves were characterized by a similar threshold and a greater maximal response. These results demonstrate that hypothyroidism is accompanied by a marked decrease in sensitivity to vasoconstrictors in large arteries as well as in resistance vessels. This decrease may be secondary to a generalized alteration in the contractile system of vascular smooth muscle cells and may play a role in the decreased blood pressure in these animals. In contrast, isolated perfused kidneys of hyperthyroid rats showed increased vascular reactivity to vasoconstrictors, which may play a role in the maintenance of elevated blood pressure in these animals.

Effects of Nw-nitro L-arginine methyl ester on the response to NaCl load in hyper- and hypothyroid rats.

We assessed the effects of the inhibition of endogenous nitric oxide (NO) synthesis with Nw-nitro-L-arginine methyl ester (L-NAME) on water and sodium handling after NaCl load containing the inhibitor at 0, 0.5, 5 and 50 mg/kg in conscious control, hyper- and hypothyroid rats. L-NAME at 0.5 mg/kg caused a similar decrease in diuresis and natriuresis in control and hypothyroid rats, whereas no changes were seen in the hyperthyroid group. The saline load with 5 mg/kg of L-NAME produced no significant changes with respect to the 0 dose in any variable in control and hypothyroid rats, but increased natriuresis in the hyperthyroid group. The highest dose of L-NAME (50 mg/kg) increased the diuretic and natriuretic response in control and hyperthyroid groups, whereas in the hypothyroid group no urinary variable was significantly modified with respect to the 0 dose. These results indicate that the antidiuretic and antinatriuretic effects of L-NAME at low doses are suppressed in hyperthyroid rats, whereas the diuretic and natriuretic effects at high doses are absent in hypothyroid rats. Our findings suggest that the modulatory role of NO on sodium and water excretion is affected in both thyroid disorders. In addition, the highest dose of L-NAME killed hyperthyroid rats, indicating that NO plays an essential role for life in hyperthyroidism.

Chronic insulin treatment in rats: evidence against a role for insulin as a pressor agent.

1. The present study was undertaken to test whether insulin acts as a pressor agent and causes hypertension in rats. 2. Insulin at doses of 10 or 100 units day-1 kg-1 was administered daily by subcutaneous injection to normal rats for 6 weeks. As it has been suggested that sodium retention plays a major role in the putative hypertensive activity of this hormone, insulin was also administered to saline- (1% NaCl) drinking rats according to the same protocol. Water- and saline-drinking rats served as controls. 3. After 6 weeks of insulin treatment, the mean arterial blood pressure did not increase in any of the insulin-treated or the insulin-salt-treated groups. However, in both insulin-salt-treated groups, absolute and relative ventricular and renal hypertrophy with increased ventricular water content as well as increased urine output with reduced osmolality were observed. 4. All insulin-treated groups showed increased plasma levels of glucose, insulin and antidiuretic hormone when compared with their respective controls. 5. These results demonstrate that chronic insulin treatment did not increase blood pressure in rats, even when drinking water was supplemented with NaCl, and suggest that a polyuria-polydipsia syndrome was present in both insulin-salt-treated groups. Moreover, increased plasma levels of antidiuretic hormone were observed in all insulin-treated groups.

Effects on renal function and digoxin-like immunoreactivity produced by methimazole in low-renal mass hypertension.

This study evaluates the effects of methimazole, an antithyroid drug, on blood pressure, digoxin-like immunoreactive factor (DLIF) production and other variables related to salt and water metabolism in low-renal mass (LRM) hypertension. Drinking administration of methimazole (0.025%) from replacement of water by the 1% NaCl solution maintained the blood pressure of low-renal mass rats at normal levels during four weeks after hypertension induction. Serum and urinary excretion of DLIF were significantly increased in LRM rats with respect to controls; in all tests, the highest values of DLIF were found in LRM-methimazole treated (LRM-M) rats. Urinary excretion of DLIF showed positive correlations with diuresis and natriuresis in all three groups (control, LRM and LRM-M rats). However, the correlation between DLIF and sodium disappeared when both factors were expressed as a function of their concentrations. These results indicate that methimazole prevents LRM hypertension and suggest that DLIF might not represent the putative natriuretic hormone. Other findings were that methimazole-treatment reduced renal compensatory hypertrophy subsequent to subtotal nephrectomy, and did not modify the characteristic polyuria-polydypsia in this type of hypertension.

[Developement and quality control of a radioimmunoassay for measurement of endogenous digoxin]. / Desarrollo y control de calidad de un radioinmunoensayo para la medida de digoxina endógena.

It has been suggested that sodium renal excretion is regulated, at least partially, by a factor with natriuretic properties called digoxin-like factor (DLF). As this substance crossreacts with digoxin antibodies, it was measured with a radioimmunoassay used to determine exogenous digoxin. Methodological conditions and quality control to determine DLF in plasma and urine have been established. Good correlation coefficients in specificity as well as dilution studies were obtained. Within--and between--assay coefficients of variations indicate good reproducibility. Moreover, changes in plasma DLF levels were detected in patients with cirrhosis or with renal failure, diseases which thrive on alterations in salt and water metabolism. In conclusion, this radioimmunoassay method for measuring DLF may be useful to investigate the role of this factor in several physiological and pathological conditions.

Urinary excretion of digoxin-like factor (DLF) and ADH during DOCA-salt and Goldblatt 2 kidney-1 clip hypertension development.

Urinary digoxin-like factor, ADH, sodium and potassium excretion and urine osmolality were studied during the development of two pathogenically different models of hypertension, DOCA-salt (low-renin) and Gold-blatt 2 kidney-1 clip (renin-dependent). Urinary digoxin-like factor was increased in rats that were given saline (NaCl 1%) to drink, uninephrectomized-salt and DOCA-salt rats, with no significant differences between the two groups urinary ADH was elevated in DOCA-salt rats during the study, compared with uninephrectomized-salt rats. Urinary digoxin-like factor and urinary ADH were not significantly modified in Goldblatt 2 kidney-1 clip and sham-operated rats. In addition, positive correlations between digoxin-like factor urinary excretion and urinary ADH and also with sodium urinary excretion were found. These data suggest that: a) digoxin-like factor and ADH could play a role in the pathogenesis of DOCA-salt but not in Goldblatt 2 kidney-1 clip hypertension. b) A common mechanism may stimulate ADH and digoxin-like factor simultaneously. c) Digoxin-like factor plays a role in the control of urinary sodium excretion.

[Plasma concentration of atrial natriuretic peptide, vasopressin and aldosterone in the umbilical cord blood: its relation to perinatal asphyxia]. / Concentraciones plasmáticas de péptido natriurético atrial, vasopresina y aldosterona en sangre de cordón umbilical: sus relaciones con la asfixia perinatal.

Aldosterone, vasopressin (AVP) and atrial natriuretic factor (ANF) plasmatic concentrations were determined in cord arterial blood from 42 newborns to term: 29 healthful and 13 with perinatal asphyxia. Control group showed plasmatic levels (pg/dl) AVP, aldosterone and ANF significantly lower than perinatal asphyxia newborns group (AVP: 2.27 +/- 1.43 vs 4.26 +/- 2.86; aldosterone: 1.113 +/- 384.79 vs 1,540.38 +/- 595.96; ANF: 2.27 +/- 1.43 vs 4.26 +/- 2.86, respectively (p less than 0.05). We found an inverse correlation between umbilical arterial pH vs AVP, aldosterone and AFN, and a direct correlation between ANF vs aldosterone. Perinatal asphyxia induces secretion of the three studied hormonal factors, likely as a physiologic mechanism of fetal adaptation to hydroelectrolytic and hemodynamic changes which occur during the asphyxia.

Effects of K+-canrenoate on the development of DOCA-salt hypertension.

The effects of K+-canrenoate, a digoxin antagonist, on the role of digoxin-like factor in the development of DOCA-salt hypertension has been examined. DOCA-salt rats treated with 66 mg kg-1 day-1 of K+-canrenoate (s.c.) presented a lower increase in blood pressure (P less than 0.01), less cardiac hypertrophy (P less than 0.05) and hypokalaemia (P less than 0.05) than non-treated DOCA-salt rats. K+-canrenoate treatment did not lead to significant changes in urinary volume, Na+ and K+ urinary excretion or suppression of plasma renin activity in DOCA-salt rats. None of the parameters were significantly different between uninephrectomized-salt rats treated or non-treated with K+-canrenoate. These data suggest a role for digoxin-like factor in DOCA-salt hypertension. However, the non-normalization of blood pressure observed in K+-canrenoate DOCA-salt treated rats indicates that other factors contribute to the initiating mechanisms in this type of hypertension. Moreover, these data suggest that digoxin-like factor plays no role in the suppression of plasma renin activity induced by DOCA and salt treatment.

beta-adrenergic reactivity in conscious DOCA-salt hypertensive rats.

The endocrine (plasma renin activity, insulin and ADH) and hemodynamic responses (heart rate and mean arterial pressure) to isoprenaline infusion were examined in conscious deoxycorticosterone-salt hypertensive rats (DS) and compared with uninephrectomized-salt control rats (US). A dose-related rise in plasma renin activity and plasma insulin values was found in US rats, while no change in either parameter was observed in DS rats after 30 min of isoprenaline infusion. ADH was not increased in US rats at any dose of isoprenaline infusion. However, in DS rats the largest dose (450 ng/kg/min) produced a significant rise. Isoprenaline infusion increased the heart rate in both groups, but the increases in the DS group were significantly lower than in the US group for the 200-ng/kg/min dose (p less than 0.01). The drop in mean arterial pressure was found to be more pronounced in DS rats than in US rats at 50, 100 and 200-ng/kg/min isoprenaline doses. Recovery of the mean arterial pressure to basal levels was also found in US rats with the various doses of isoprenaline administered. However, in DS rats the different doses of isoprenaline produced a progressive drop in mean arterial pressure with no recovery at the end of 30 min of isoprenaline infusion. The present results provide no evidence of subsensitivity to isoprenaline in the resistance vessels of conscious DS rats and suggest that the greater hypotensive response observed in these rats may be due to the inability of the renin-angiotensin system to adequately compensate the vasodilation produced by isoprenaline.

The handling of NaCl load in rats during DOCA-salt and Goldblatt 2 kidney-1 clip hypertension development.

The handling of an intraperitoneal NaCl load (2% body weight, 0.9% NaCl) administered twice a week during DOCA-salt and Goldblatt 2K-1C hypertension development has been evaluated. An exaggerated natriuresis was observed in DS-hypertensive rats since blood pressure became higher with respect to normal (C), Doca (D) and uninephrectomized-salt (NS) rats that served as controls. However, this phenomenon was not observed in Goldblatt 2K-1C hypertensive rats (2K-1C) when compared to the response obtained in sham-operated (SO) rats. These results suggest that: 1) An increased blood pressure, per se, is not a determinating factor for exaggerated natriuresis. 2) Rise in blood pressure and exaggerated natriuresis may be related through a common mechanism in Doca-salt hypertension.

Studies on thyroid activity in deoxycorticosterone-salt and Goldblatt two-kidney, one-clip hypertensive rats.

In this paper we studied the role of thyroid gland function in two experimental hypertension models with different pathophysiological mechanisms: deoxycorticosterone-salt (DOCA-salt, volume dependent) and Goldblatt 2-kidney, 1-clip (2K1C, renin dependent). DOCA-salt hypertensive rats showed lower T3 and T4 serum levels by the third week of induced hypertension. Goldblatt 2K1C hypertensive rats, however, exhibited normal values for both hormones. Treatment with thyroxine accelerated the evolution of hypertension and did not affect the PRA of DOCA-salt rats. Radiothyroidectomy inhibited DOCA-salt and Goldblatt 2K1C hypertension, and prevented the suppression of PRA in DOCA-salt rats, without altering PRA or serum aldosterone in Goldblatt 2K1C rats. These results suggest that: a) a thyroid depressing factor is not activated in Goldblatt 2K1C rats; b) thyroidectomy interferes with the suppressor effect of mineralocorticoid on renin secretion; and c) normal thyroid activity is required for the hypertensive effect of the renin-angiotensin-aldosterone system in Goldblatt 2K1C rats.

Effect of captopril at two different dosage regimens in hypertensive non-insulin dependent patients.

Thirty patients (21 F, 9 M) of mean age 55.3 years with non-insulin dependent diabetes mellitus of mean duration 10.8 years and hypertension (blood pressure 160/95 mm Hg) of 0.3 to 4.0 years were randomly allocated to either a twice daily regimen of captopril (50 mg twice daily, Group A) or a once daily captopril schedule (50 mg once daily, Group B). Good glycaemic control (HbA1c, mean 7.63%) had been achieved with sulphonylureas in 22 patients and insulin in 8 patients. There were no statistical differences in baseline values between the two groups. For the 15 patients in Group A, blood pressure fell significantly from a baseline of 177 +/- 13.2/106 +/- 7.8 mm Hg to 161 +/- 14.3/91 +/- 6.9 after one month (P less than 0.05) and continued to decrease at 3 and 6 months. In Group B the blood pressure changed from 179 +/- 19.0/110 +/- 15.6 to 169 +/- 21.0/98 +/- 7.2 at 1 month (P less than 0.05) with further reductions again seen at 3 and 6 months. Nine patients had poorer response than the other 21 but there were no demographic differences between these subgroups nor were there any differences in plasma renin activity or aldosterone responses. There were no statistically significant changes in haematological or biochemical values in either group during treatment. In particular, HbA1c and fasting glucose were unaffected by captopril treatment. No side effects were encountered during the 6 months of follow-up. In conclusion, captopril is an effective antihypertensive in non-insulin dependent diabetes mellitus with mild to moderate hypertension and a once daily regimen could improve compliance.

[Water intake induced by isoprenaline in 2 models of experimental hypertension in rats]. / Ingesta de agua inducida por isoprenalina en dos modelos de hipertensión experimental en rata.

The drinking response to systemic injection of isoprenaline has been used to study the decreased beta-adrenergic reactivity in hypothyroid rats. Using the same test, the beta-adrenergic responsiveness has been investigated in two models of experimental hypertension (DOCA-salt and Goldblatt two kidney one clip rats). Three weeks after induction of hypertension, control and hypertensive rats were injected subcutaneously isoprenaline (0.1 mg/kg) and the accumulative water intake at 1st, 2nd and 3rd hours was recorded. Isoprenaline induced a smaller drinking response in DOCA-salt hypertensive (DS) and DOCA-normotensive (D) rats than in normotensive (age control, normal uninefrectomized-salt and sham operated) or hypertensive Goldblatt two kidney one clip rats. Isoprenaline induced a 50% mortality in the mineral-corticoid treated D and DS rats. The present study suggests that the reduced beta-adrenergic response (water intake) and the rate of mortality observed in DOCA treated rats may be due to the absence of renin release after isoprenaline injection, as previously reported by us.

Haemodynamic and endocrine effects of digitoxin in healthy volunteers.

A study was conducted to evaluate the effects of a single oral dose of digitoxin on the circulatory function and the renin-angiotensin-aldosterone system. Seven doses of digitoxin and 6 of a placebo were given at random to 13 healthy volunteers, all of whom remained at rest, without smoking, throughout the study. Blood samples were taken initially after 1 h at rest, and at 1, 2 and 24 h after receiving the dose. Concentrations of serum digitoxin, aldosterone, angiotensin II (A II) as well as plasma renin activity (PRA) were determined by radioimmunoassay (RIA). In all subjects the blood pressure did not change throughout the study. Digitoxin decreased the heart rate significantly during the first and second hours, while in the placebo group the heart rate remained unchanged during the same period. The placebo had no detectable effect on PRA, A II and aldosterone. Digitoxin decreased PRA and A II levels, reaching its maximum effect 2 h after the administration. There was no correlation between the serum digitoxin concentration and PRA, A II or the aldosterone values. Digitoxin reached its maximum effect upon these parameters faster than what is generally accepted.

Adipsia-polydipsia induced by simultaneous lesion of the medioventral septum and anteroventral third ventricle area in the rat.

The medioventral septal area (MVS) and also the tissue surrounding the periventricular preoptic-hypothalamic region (AV3V) of male rats, were destroyed by mean of electrolytic lesions. Before and after the lesions, daily water and food intakes, diuresis, body weight, urine osmolarity, and sodium and potassium excretion were determined. Rats with simultaneous AV3V-MVS lesions showed a biphasic pattern of drinking behavior characterized by a first period of adipsia followed by another period of polydipsia. During the first period of adipsia and except for the first two days, postlesion rats were able to reduce total urine volume but failed to produce an appropriate concentrated urine. During the polydipsia period, on the contrary, rats increased urine output and decreased urine osmolarity in a parallel fashion. Immediately after the lesion, food intake was decreased but recovered to pre-lesion levels gradually. By contrast, body weight was decreased during the entire period of the experiment. Sodium but not potassium excretion showed a significant increase from the 9th to the 20th day postlesion. The results suggest that the AV3V and MVS are part of a circuitry subserving the control of water intake and electrolyte balance.

Effects of changes in circulating volume and in arterial pressure on plasma renin activity in the intact rat.

The effects of changes in arterial pressure and in circulating volume on Plasma Renin Activity (PRA) in the intact rat were compared by two experimental procedures. Gradual volume depletion was induced by intraperitoneal injection of a hyperoncotic polyethyleneglycol solution (PEG) in absence of acute changes in Systolic Arterial Pressure (SAP). SAP was measured in the conscious state by the tail cuff technique. Plasma Protein Concentration (PPC) and Hematocrit (Hct) increases after PEG injection were compared as the index for measuring the Plasma Volume Reduction (PVR). PRA showed a significant (p less than 0.001) linear relationship with PPC, suggesting a direct dependence of renin secretion on volume depletion. Acute changes in the circulating volume were induced by controlled hemorrhages of 5.0, 10.0, 15.0 and 20.0 ml of blood/kg body weight. The increase in PRA showed a significant relationship with the changes in circulating volume, but it did not show any dependence on the changes in Mean Arterial Pressure (MAP). Our results suggest that, in the intact and conscious rat, renin secretion responds to the information from the cardiopulmonary volume receptors rather than to that from the high pressure receptors.