Specific changes in the sodium chloride intake and activity of the taste receptor apparatus of rats administered the peptide litorin and its albumin conjugate

The role of bombesin-like peptide litorin in control of salt consumption was studied in rats. The influence of exogenous injection and binding of the endogenous litorin in the organism on the consumption of sodium chloride and sucrose solutions was analyzed in deprived rats in the process of 15-min. testing. It was found that intraperitoneal injection of 10(-6) - 10(-5) M of litorin led to an increase, and rats immunization by peptide conjugate with ox serum albumin--to a decrease of the consumption of salt solution, without changing the consumption of sucrose solution. Titres of antibodies to litorin in the plasma of rats immunized with the conjugate were higher than in the control. Intraperitoneal, subcutaneous or intranasal injections of 10(-5) M of litorin led to selective increase of gustatory responses (recorded from the chorda tympani) to tongue stimulation by salt and acid solutions not influencing the responses to quinine and sucrose in anesthetized rats. The study shows, that the peptide litorin selectively participates in the control of sodium chloride consumption. In the process of such control the increase of taste apparatus sensitivity to the sodium chloride is probably involved.     

Hypertension in Brattleboro rats and the injurious influence of salt in youth

The effect of long-term intake of 0.6% NaCl solution on survival of Brattleboro rats, both homozygous for diabetes insipidus (DI) and heterozygous (non-DI), was investigated. Studies included whether the survival of animals could be influenced a) by the age at which the high salt intake started (either from prepuberty, i.e. from the 4th week, or after sexual maturation, i.e. from the 12th week of age); b) by uninephrectomy (UNX) which elicited hypertension in DI rats drinking saline from youth. All non-DI and those DI rats that drank saline only from adulthood, survived for the whole duration of the experimental, i.e. 14 weeks. Only 43% of animals survived in the group of DI rats drinking saline from youth. This high mortality was reduced by UNX carried out either simultaneously or 8 weeks after the onset of saline drinking. DI rats consumed several times more saline than non-DI rats. Nevertheless, the consumption was greater in the low-mortality than in the high-mortality group. Salt intake was moderately lowered by UNX. Plasma Na+ concentration was higher in rats of the high-mortality group and it was not affected by UNX. In DI rats plasma volume was greater than in non-DI rats and its values in the low-mortality group exceeded those ones of the high-mortality group. It was decreased by UNX in the low-mortality group but this was not true for the high-mortality group. It is concluded that high mortality in DI rats consuming saline from prepuberty is abolished by the intervention producing hypertension. The role of hypertension in a protection against the toxic effects of salt is discussed.     

Effect of taste deafferentation on the preference for solutions of saccharose, saccharin and salt in rats

The preference of sucrose, saccharin and salt solutions to water was analyzed during 5 days in rats with bilateral section of the lingual nerve comprising the taste nerve--chorda tympani. In the process of the analysis of daily consumption and choice of solutions, different types of behavioural reactions were found: stable preference and change of preference. The number of rats preferring NaCl was greater among the animals with sectioned lingual nerve than among sham-operated control rats and rats with ligated ducts of submaxillary and sublingual salivary glands. The number of rats with the lingual nerve section preferring sucrose or saccharin solutions to water was equal to that among the sham-operated rats. At the same time the mean volume of sucrose solution taken in daily by rats with sectioned lingual nerve was twice as great as the volume of saccharin, drunk by the same animals. The role of taste in the process of choice and preference of NaCl to sweet solutions is discussed.     

Adult offspring long-term effects of high salt and water intake during pregnancy

Offspring from dams subjected to hypereninemia, hyperdipsia, and natriophilia by partial aortic ligation (PAL) showed a long-term modification of their ingestive behavior. These rats, upon reaching adulthood, showed an increased appetite for low-concentration saline solutions (0.1 M) when compared to control rats. They also presented a high intake of a medium concentration NaCl solution (0.45 M) after having been offered a very aversive highly concentrated NaCl solution (1.0 M) along with water for 2 days. An increase was also observed in their salt/water intake ratio following two different thirst challenges, 24-h fluid deprivation or sodium depletion by furosemide treatment. The demonstration of the long-term effect of pregnancy history on salt preference in adult offspring draws attention to the possible physiopathological aspects that may be of relevance, considering the well-established relationship between salt intake and hypertension, a disease most commonly occurring in the adult and aged population.     

Investigations on the physiological controls of water and saline intake in C57BL/6 mice

To examine the behavioral and neural control of body fluid homeostasis, water and saline intake of C57BL/6 mice was monitored under ad libitum conditions, after treatments that induce water or salt intake, and after ablation of the periventricular tissue of the anteroventral third ventricle (AV3V). Mice have nocturnal drinking that is most prevalent after the offset and before the onset of lights. When given ad libitum choice, C57BL/6 mice show no preference for saline over water at concentrations up to 0.9% NaCl and a progressive aversion to saline above that concentration. Systemic hypertonic saline, isoproterenol, and polyethylene glycol treatments are dipsogenic; however, systemic ANG II is not. Intracerebroventricular injections of both hypertonic saline and ANG II are dipsogenic, and diuretic treatment followed by a short period of sodium deprivation induces salt intake. After ablation of the AV3V, mice can be nursed to recovery from initial adipsia and, similar to rats, show chronic deficits to dipsogenic treatments. Taken together, the data indicate that mechanisms controlling thirst in response to cellular dehydration in C57BL/6 mice are similar to rats, but there are differences in the efficacy of extracellular dehydration-related mechanisms, especially for systemic ANG II, controlling thirst and salt appetite.     

Sodium transport and salt appetite; the effect of DPH on sodium preference and electrolyte balance in rats

The sodium transport hypothesis of salt appetite asserts thatdrugs affect this appetite according to their effect on sodiumtransport. Sodium appetite was therefore studied in rats treatedwith DPH in order to stimulate sodium transport. During 8 daysof administration by gastric tube rats increased their sodiumintake and preference significantly above control levels involvingintubation with vehicle alone. This response was observed in22 rats offered hypotonic saline (0.5%) and 8 rats offered hypertonicsaline (2%), i.e. solutions to which the rats were normallyneutral or averse. In rats receiving sodium solely in theirfood DPH depressed urinary sodium excretion. The results thussupport the prediction of the hypothesis, namely, that DPH enhancessodium appetite despite its underlying tendency to cause renalsodium retention.     

Effects of forebrain circumventricular organ ablation on drinking or salt appetite after sodium depletion or hypernatremia

In many previous studies, one or the other forebrain circumventricular organ, the subfornical organ (SFO) or organum vasculosum laminae terminalis (OVLT), was lesioned to test whether it was critical for the behavioral or physiological responses to sodium depletion and hypernatremia. These studies conflict in their conclusions. The present study was designed to create discrete lesions of both the SFO and OVLT in the same animals and to compare these with rats having a lesion of only the SFO or OVLT. Both the OVLT-lesioned group and the combined SFO + OVLT-lesioned group drank significantly more water and saline on a daily basis than Controls or SFO-lesioned rats. In both sodium depletion and hypertonic saline testing, rats with SFO lesions displayed transient deficits in salt appetite or thirst responses, whereas the rats with single OVLT lesions did not. In the sodium depletion test, but not in the hypernatremia test, rats with lesions of both the SFO and OVLT exhibited the largest deficit. The data support the hypothesis that a combined lesion eliminates redundancy and is more effective than a single lesion in sodium depletion tests. The interpretation of the OVLT lesion-only data may have been complicated by a tendency to drink more fluid on a daily basis, because some of those animals drank copious water in addition to saline even very early during the salt appetite test.     

Genetic influence on saline consumption and salt hypertension as exhibited by the response of various rat strains and sub-strains.

Female rats of 2 Sprague-Dawley sub-strains and of the Wistar and Fischer 344 strains were sensitized to the hypertensogenic effect of excess salt by removal of 1 kidney and by being given 1% NaCl solution as their sole drinking fluid. One of the Sprague-Dawley sub-strains (SPD) and the Wistar (CFEP) rats developed progressive saline polydipsia of equivalent degree, blood pressure rose, and about half of the members became hypertensive during treatment. Rats of the other Sprague-Dawley strain (CFNP) also showed a progressive saline intake; but although they drank substantially less saline, the incidence of hypertension among them was increased by 50%. Animals of the Fischer 344 strain displayed neither saline polydipsia--the intake remaining relatively constant at a very low level throughout the experiment--nor hypertension. Salt hypertension appears to be affected by genetic factors in at least 2 ways, one of which regulates the quantity of salt ingested (salt appetite), while the other controls the susceptibility to salt excess or perhaps to hypertension per se. Fischer 344 rats have the ability to restrict the volume consumption of saline; their resistance to enforced high salt intake has yet to be established.     

Effects of ethanol on locomotor and anxiety-like behaviors and the acquisition of ethanol intake in Lewis and spontaneously hypertensive rats

The purpose of the present study was to investigate whether Lewis (LEW) and spontaneously hypertensive rats (SHR), characterized in numerous behavioral tests as strains with high-anxiety and low-anxiety, respectively, could differ in their sensitivity to the effects of ethanol in the elevated plus maze (EPM) and the open field (OF), two classical models of anxiety/emotionality, as well as in the acquisition of ethanol drinking behavior. It was also of interest to examine the relationship between sweet and bitter fluids preference and ethanol intake. SHR and LEW rats were given saline or ethanol injections (0.6 or 1.2 g/kg, ip.) and tested in the EPM and OF. Subsequently the same animals were given continuous free choice between water and ethanol solution (2-8%). Additional groups of animals were exposed to a free-choice regimen between saccharin (0.002-0.09%) or quinine (0.0001-0.0015%) and water. The low dose of ethanol (0.6 g/kg) induced anxiolytic-like effects and intensive locomotor activation mainly in SHR rats tested in the OF arena. Overall, LEW counterparts were unaffected in OF test. In oral self-administration paradigm, SHR rats consumed significantly more ethanol than LEW rats. Concerning other solutions, SHR rats consumed large amounts of saccharin compared with LEW rats. These data indicate that the SHR preference for ethanol intake may be positively related to their differential sensitivity to the anxiolytic/stimulant effects of ethanol and to the sensitivity of this strain for saccharin reinforcement. In addition, these findings provide evidence that the SHR strain may represent a useful genetic and pharmacological tool to investigate ethanol drinking traits.     

Time course of synergistic interaction between DOCA and salt on blood pressure: roles of vasopressin and hepatic osmoreceptors

In DOCA-salt rats, the time course of the synergistic interaction between osmolality and DOCA to produce hypertension is unknown. Therefore, in rats 2 wk after implantation of subcutaneous silicone pellets containing DOCA (65 mg) or no drug (sham), we determined blood pressure (BP) and heart rate (HR) responses, using telemetric pressure transducers, during 2 wk of excess salt ingestion (1% NaCl in drinking water). BP was unaltered in sham rats after increased salt, but in DOCA rats BP increased within 4 h. The initial hypertension of 30-35 mmHg stabilized within 2 days, followed approximately 5 days later by a further increment of approximately 30 mmHg. HR first decreased during the dark phase; the second phase was linked to an abrupt increase in HR and BP variability and decreased HR variability. Pressor responses to acute intravenous hypertonic saline infusion were doubled in DOCA-treated rats via vasopressin and nonvasopressin mechanisms. Only in DOCA-treated rats, portal vein hypertonic saline infusion increased BP, which was prevented by V(1) vasopressin blockade. After 2 wk of DOCA-salt, oral ingestion of water rapidly decreased BP. Intraportal infusion of water did not lower BP in DOCA-salt rats, suggesting that hepatic osmoreceptors were not involved. In summary, the hypertension of DOCA-treated rats consuming excess salt exhibits multiple phases and can be rapidly reversed. Hypertonicity-induced vasopressin and nonvasopressin pressor mechanisms that are augmented by DOCA, and hepatic osmoreceptors may contribute to the initial developmental phase. With time, combined DOCA-salt induces marked changes in the regulation of the autonomic nervous system, which may favor hypertension development.     

Changes in the activity of the taste receptor apparatus and the preference for a sodium chloride solution in newborn rats receiving capsaicin]

Taste receptor organ activity and preference of sodium chloride solution in rats with deficit of substance P (SP) were studied. Total impulse activity of chorda tympani nerve of 7-8 week old rats was recorded under nembutal anesthesia. The taste responses to four solutions (sucrose, quinine sulfate, sodium chloride and citric acid) were decreased in rats injected with capsaicin in comparison with rats injected with vehicle. The rats injected with capsaicin preferred water to sodium chloride (two-bottle technique). On the contrary the rats injected with capsaicin preferred the salt solution. These data together with previous studies show the important role of peptide SP in taste receptor activity and "salt appetite".     

Changes of hypothalamic and plasma vasopressin in rats with deoxycorticosterone-acetate induced salt appetite.

Mineralocorticoids play a predominant role in development of salt appetite and hypertension. Since vasoactive peptides could mediate the central effects of mineralocorticoids, we evaluated changes of immunoreactive (IR) arginine vasopressin (AVP) in the paraventricular (PVN) and supraoptic (SON) hypothalamic nucleus during DOCA-induced salt appetite. In one model, rats having free access to water and 3% NaCl during 9 (prehypertensive stage) or 21 days (hypertensive stage) received DOCA (s.c., 10 mg/rat/in alternate days). A decrease in the IR cell area, number of IR cells and staining intensity was obtained in magnocellular PVN of rats treated during 9 days. After 21 days IR cell area and number of cells in the PVN also decreased, but staining intensity of remaining cells was normal. The same parameters were unchanged in the SON. In another model, animals treated with DOCA during 9 days had only access to 3% NaCl or water. The IR cell area in PVN and SON significantly increased in mineralocorticoid-treated and control animals, both drinking 3% NaCl. Staining intensity (PVN and SON) and number of IR cells (PVN) also augmented in DOCA-treated animals drinking salt respect of a group drinking water. Plasma AVP in rats treated with DOCA and offered salt and water, exhibited a 2-2.5 fold increase at the time of salt appetite induction. Plasma AVP was substantially higher in rats drinking salt only, while the highest levels were present in salt-drinking DOCA-treated rats. Thus, peptide depletion in the PVN may be due to increased release, because reduced levels of hypothalamic and posterior pituitary AVP were measured in this model. In rats drinking salt only the substantial increase of IR AVP in the PVN and SON, may be due to dehydration and hyperosmosis. Because DOCA-salt treated rats showed higher AVP levels in the PVN compared to untreated rats drinking salt only, it is possible that DOCA sensitized PVN cells to increase AVP production. The results suggest the vasopressinergic system could mediate some central functions of mineralocorticoids.     

Low dose domoic acid in neonatal rats abolishes nicotine induced conditioned place preference during late adolescence

In this study, neonatal rats were chronically exposed to low, non-convulsive doses of the kainate receptor agonist domoic acid (DOM), or saline. Later, as adolescents, all animals were tested in a nicotine-induced conditioned place preference (CPP) paradigm. As expected, a nicotine-induced CPP was evident in the adolescent control rats, but surprisingly, not in the DOM animals. This study demonstrates the importance of KA receptors in the development of normal adolescent behaviors manifested in response to the rewarding properties of nicotine.     

Response of the hypothalamo-neurohypophyseal axis (AVP system) and the kidney to salt load in young propylthiouracil-treated rats

The development of the ability of the kidney to concentrate urine was studied in normal and propylthiouracil-treated rats by measuring urinary sodium concentration and osmolarity at different ages. It was shown that the normal animals, but not the PTU-treated ones were able to concentrate urine at 35 days of age. The response of the hypothalamo-neurohypophyseal axis (AVP system) and that of the kidney were investigated in the two categories of animals at 35 days of age by measuring concomitantly the AVP content of the hypothalamus and neurohypophysis, the AVP plasma concentration and the natremia and plasma osmolarity at various intervals after intraperitoneal injection of a 5% NaCl solution. In normal, as well as in PTU-treated rats, salt load did not lead to significant modifications of the hypothalamic AVP content. In comparison with normal rats, the neurohypophysis of the PTU-treated ones released AVP more slowly, but with a similar amplitude. In normal rats, the plasma AVP concentration was already maximal 30 min after salt load and then decreased and returned to the normal value at 2 hrs; at the same time, the natremia and plasma osmolarity also recovered their normal value. In contrast, the plasma AVP concentration as well as the natremia remained high 1 h 30 after salt load in PTU-treated rats. It is concluded that PTU-treated young rat is unable to compensate the salt load in normal delays. Beside the slowing in AVP release by neurohypophysis and decreased AVP plasma level, the responsiveness of the kidney seems to be altered.     

Kin discrimination in prepubescent and adult Long-Evans rats

The present study investigated the preference of prepubescent and adult rats for an unrelated conspecific over a closely related conspecific (e.g., father, mother). Preference was measured by the amount of time spent in the vicinity of the stimulus animals as well as who was visited first. To prevent mating behavior, stimulus animals were housed behind wire-mesh. Experiment 1 determined if adult female offspring prefer an unrelated, unfamiliar adult male or their father. The preference of adult female rats was independent of kinship. Experiment 2 evaluated the preference of prepubescent female and male offspring for an unrelated, unfamiliar adult male or their father. The preference of prepubescent female and male rats was also independent of kinship. Experiment 3 evaluated the preference of adult male offspring for an unrelated, unfamiliar adult female or their mother. The preference of adult male rats was independent of kinship. In summary, prepubescent and adult rats do not demonstrate preference for kin vs. non-kin (as measured by time spent near stimulus animals or who was visited first). Although kin recognition provides a mechanism for inbreeding avoidance (Wilson, 1987), in the present study adult rats show no evidence of inbreeding avoidance.     

Salt Appetite Is Reduced by a Single Experience of Drinking Hypertonic Saline in the Adult Rat

Salt appetite, the primordial instinct to favorably ingest salty substances, represents a vital evolutionary important drive to successfully maintain body fluid and electrolyte homeostasis. This innate instinct was shown here in Sprague-Dawley rats by increased ingestion of isotonic saline (IS) over water in fluid intake tests. However, this appetitive stimulus was fundamentally transformed into a powerfully aversive one by increasing the salt content of drinking fluid from IS to hypertonic saline (2% w/v NaCl, HS) in intake tests. Rats ingested HS similar to IS when given no choice in one-bottle tests and previous studies have indicated that this may modify salt appetite. We thus investigated if a single 24 h experience of ingesting IS or HS, dehydration (DH) or 4% high salt food (HSD) altered salt preference. Here we show that 24 h of ingesting IS and HS solutions, but not DH or HSD, robustly transformed salt appetite in rats when tested 7 days and 35 days later. Using two-bottle tests rats previously exposed to IS preferred neither IS or water, whereas rats exposed to HS showed aversion to IS. Responses to sweet solutions (1% sucrose) were not different in two-bottle tests with water, suggesting that salt was the primary aversive taste pathway recruited in this model. Inducing thirst by subcutaneous administration of angiotensin II did not overcome this salt aversion. We hypothesised that this behavior results from altered gene expression in brain structures important in thirst and salt appetite. Thus we also report here lasting changes in mRNAs for markers of neuronal activity, peptide hormones and neuronal plasticity in supraoptic and paraventricular nuclei of the hypothalamus following rehydration after both DH and HS. These results indicate that a single experience of drinking HS is a memorable one, with long-term changes in gene expression accompanying this aversion to salty solutions.     

Acquisition and extinction of conditioned suppression of a graft-vs-host response in the rat

Injection of rats with cyclophosphamide (CY) after their consumption of a novel saccharin-flavored drinking solution results in a conditioned aversion to saccharin and a conditioned suppression of immune responses. In this study, female Lewis X Brown Norwegian F1 rats were conditioned by pairing saccharin with 50 mg/kg CY. Seven weeks later (day 0), a graft-vs-host response (GvHR) was induced in these animals by injecting splenic leukocytes from Lewis donors into a rear footpad. At this time, some conditioned animals were reexposed to saccharin, the conditioned stimulus. During the 7-wk interval between conditioning and immunization, subgroups of conditioned rats were given 0, 4, 9, or 18 extinction trials (saccharin followed by saline injections). Animals receiving 4, 9, or 18 extinction trials showed a greater preference for saccharin on day 0 than did animals receiving no extinction trials, but these groups did not differ among themselves; all conditioned groups showed a lower preference for saccharin than placebo-treated animals. There was a clear effect of number of extinction trials on the GvHR. Animals receiving 9 or 18 extinction trials did not differ from controls, whereas animals receiving 0 or 4 trials had a milder GvHR than did conditioned rats that were not reexposed to saccharin at the time of immunization. These results confirm a previous report of conditioned suppression of a GvHR, demonstrate that conditioned immunopharmacologic responses are subject to experimental extinction, and indicate that conditioned immunosuppression can be dissociated from conditioned taste aversion.     

Prenatal and early postnatal dietary sodium restriction sensitizes the adult rat to amphetamines

Acute sodium deficiency sensitizes adult rats to psychomotor effects of amphetamine. This study determined whether prenatal and early life manipulation of dietary sodium sensitized adult offspring to psychomotor effects of amphetamine (1 or 3 mg/kg ip) in two strains of rats. Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) dams were fed chow containing low NaCl (0.12%; LN), normal NaCl (1%; NN), or high NaCl (4%; HN) throughout breeding, gestation, and lactation. Male offspring were maintained on the test diet for an additional 3 wk postweaning and then fed standard chow thereafter until testing began. Overall, blood pressure (BP), total fluid intake, salt preference, and adrenal gland weight were greater in SHR than in WKY. WKY LN offspring had greater water intake and adrenal gland weight than did WKY NN and HN offspring, whereas WKY HN offspring had increased BP, salt intake, and salt preference compared with other WKY offspring. SHR HN offspring also had increased BP compared with other SHR offspring; all other measures were similar for SHR offspring. The low-dose amphetamine increased locomotor and stereotypical behavior compared with baseline and saline injection in both WKY and SHR offspring. Dietary sodium history affected the rats' psychomotor response to the higher dose of amphetamine. Injections of 3 mg/kg amphetamine in both strains produced significantly more behavioral activity in the LN offspring than in NN and HN offspring. These results show that early life experience with low-sodium diets produce long-term changes in adult rats' behavioral responses to amphetamine.     

Angiotensin II generation in mesenteric arteries in rats: effects of nephrectomy, deoxycorticosterone and dexamethasone

Angiotensin II (ANG II) generation in the mesenteric arteries was studied in four groups of rats: deoxycorticosterone (DOCA)/salt treated, glucocorticoid treated, nephrectomized and control rats. Basal plasma renin activity (PRA) was undetectable in the nephrectomized group and suppressed in the DOCA/salt treated rats, but was increased in the rats treated with glucocorticoid. The Basal plasma ANG II concentration changed comparably with PRA in all four groups of rats. In the control rats, ANG II was released from the mesenteric arteries at a rate of 43.0 +/- 12.0 pg/h, and it was not decreased by nephrectomy. In DOCA/salt rats and glucocorticoid rats, ANG II release significantly decreased to 12.8 +/- 7.1 and 6.9 +/- 1.5 pg/h, respectively. Captopril treatment significantly reduced ANG II release from the mesenteric arteries in both controls and nephrectomized rats, but did not influence ANG II output in DOCA/salt rats or in glucocorticoid treated rats. In nephrectomized rats, captopril lowered blood pressure in association with a significant reduction in the mesenteric ANG II formation. These results indicate that the renal and vascular renin-angiotensin system (RAS) may be independently regulated, and in nephrectomized animals the vascular RAS contributes in part to the maintenance of blood pressure. The present results also suggest that volume expansion per se and/or pharmacological intervention by DOCA and glucocorticoid could modulate vascular ANG II generation.     

Altered regulation of renal sodium transporters and natriuretic peptide system in DOCA–salt hypertensive rats

Although deoxycorticosterone acetate (DOCA)–salt hypertension is a volume dependent model of hypertension, it shows polyuria and natriuresis. It is expected that dysregulation of aquaporin water channels (AQPs) and sodium transporters associated with natriuretic peptide (NP) system may play an escape role in sodium retaining state. One week after left unilateral nephrectomy, rats were subcutaneously implanted with silastic DOCA (200 mg/kg) strips. Physiologic saline was supplied as a drinking water to all animals. 4 weeks after operation, the protein expression of AQPs, sodium transporters, and endopeptidase (NEP) was determined in the kidneys by semiquantitative immunoblotting and immunohistochemistry. The mRNA expression of NP system was determined by real-time polymerase chain reaction. The amount of urinary ANP excretion was measured by radioimmunoassay. In DOCA–salt rats, urine osmolality was decreased while urinary excretion of sodium was increased. The expression of AQP1-3 as well as that of α-1 subunit of Na,K–ATPase, NHE3, NKCC2 and NCC was decreased in the kidney. The mRNA expression of ANP, brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP) was increased in the kidney. The expression of NEP was decreased, and urinary ANP excretion was increased. Downregulation of AQPs and sodium transporters may contribute to mineralocorticoid escape in DOCA–salt hypertension. Increased expression of natriuretic peptides associated with downregulation of NEP may play a role in natriuresis.