Effect of losartan on sodium appetite of hypothyroid rats subjected to water and sodium depletion and water, sodium and food deprivation

The involvement of angiotensin AT1 receptors in sodium appetite was studied in hypothyroid rats treated with the angiotensin II antagonist losartan. Losartan was administered chronically by the oral route or acutely by the subcutaneous route after water and sodium depletion or water, sodium and food deprivation. Three days after addition of losartan to the food at the dose of 1.0 mg x g(-1), the rats significantly reduced (P < 0.02) their spontaneous intake of 1.8% NaCl. Increasing the dose of losartan to 2.0 and 4.0 mg x g(-1) did not reduce NaCl intake; in contrast, the intensity of the sodium appetite gradually returned to previous levels. The simultaneous administration of captopril, an angiotensin converting enzyme inhibitor, and losartan significantly increased (P < 0.05) NaCl intake and after captopril removal NaCl intake returned to the levels observed with losartan treatment alone. The administration of losartan 4 days after the beginning of captopril treatment significantly reduced (P < 0.0001) NaCl intake. Following acute administration of losartan, water- and sodium-depleted rats significantly reduced their NaCl and water intake (P < 0.001). The administration of losartan also induced a significant reduction in NaCl and water intake in water, NaCl and food-deprived rats (P < 0.0001 and P < 0.001, respectively). The present results show that chronic treatment with oral losartan inhibited spontaneous sodium appetite in hypothyroid rats. Continuation of treatment rendered rats resistant to the blockade of AT1 receptors. Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors.     

Ontogenetic role of angiontensin-converting enzyme in rats: Thirst and sodium appetite evaluation

We investigated the influence of captopril (an angiotensin converting enzyme inhibitor) treatment during pregnancy and lactation period on hydromineral balance of the male adult offspring, particularly, concerning thirst and sodium appetite. We did not observe significant alterations in basal hydromineral (water intake, 0.3 M NaCl intake, volume and sodium urinary concentration) or cardiovascular parameters in adult male rats perinatally treated with captopril compared to controls. However, male offspring rats that perinatally exposed to captopril showed a significant attenuation in water intake induced by osmotic stimulation, extracellular dehydration and beta-adrenergic stimulation. Moreover, captopril treatment during perinatal period decreased the salt appetite induced by sodium depletion. This treatment also attenuated thirst and sodium appetite aroused during inhibition of peripheral angiotensin II generation raised by low concentration of captopril in the adult offspring. Interestingly, perinatal exposure to captopril did not alter water or salt intake induced by i.c.v. administration of angiotensin I or angiotensin II. These results showed that chronic inhibition of angiotensin converting enzyme during pregnancy and lactation modifies the regulation of induced thirst and sodium appetite in adulthood.     

Renin-dependent water intake in hypovolemia

The role of the renin-angiotensin system as a mediator of water intake, induced by hypovolemia after polyethylene glycol (PEG) injection, was investigated. Blockade of angiotensin I converting enzyme and of angiotensin receptors was used as a pharmacological tool. A significant reduction of water intake was observed when angiotensin 1 converting enzyme was inhibited by captopril and enalapril. In PEG-treated rats with blockade of angiotensin I converting enzyme, hypertonic saline injection continued to elicit substantial drinking. Normalization of low blood pressure by vasopressin infusions in PEG and captopril treated rats did not interfere with the antidipsogenic effectiveness of converting enzyme blockade. The angiotensin II receptor antagonist, saralasin, also reduced PEG-induced drinking although less effectively than converting enzyme inhibitors. We conclude that water intake due to isotonic depletion of the extracellular fluid compartment may depend on the activity of the renin-angiotensin system.     

Characteristics of thirst and sodium appetite in mice (Mus musculus)

The intakes of water and sodium chloride (NaCl) solution were examined in mice following treatment with agents that either stimulate or mimic various components of the renin-angiotensin-aldosterone system. Injections of either angiotensin II (Ang II) or isoproterenol produced very little water intake compared with the robust responses to either intracellular dehydration or to extracellular dehydration induced by treatment with polyethylene glycol (PEG). In studies on appetite for NaCl solution, mice exhibited no spontaneous preference for 0.15 M NaCl solution over water and did not change this preference during treatment with deoxycorticosterone acetate (DOCA), a sodium-deficient diet, or after adrenalectomy. Plasma concentrations of aldosterone were increased in intact mice fed a sodium-deficient diet but were not eliminated by adrenalectomy. However, acute treatment with furosemide in combination with a sodium-deficient diet stimulated an appetite for NaCl solution. Chronic oral administration of an angiotensin I (Ang I) converting enzyme inhibitor failed to induce a NaCl appetite. These findings show that mice are refractory to the induction of either water or NaCl intake by stimuli of the renin-angiotensin-aldosterone system, stimulation that is highly effective in rats; this suggests that there may be major differences among rodents in the hormonal determinants of behaviors related to hydromineral homeostasis.     

Effects of exercise and anion on intake of sodium solutions in Syrian hamsters.

Previous studies have shown that hamsters have low spontaneous intakes of NaCl solutions and are refractory to induction of salt appetite. In order to examine the generality of these results, the intakes of NaCl and NaHCO3 solutions are reported for hamsters housed either in normal laboratory conditions (sedentary) or with free access to exercise wheels. Spontaneous salt intakes, as well as those induced by acute sodium depletion and treatment with either the angiotensin converting enzyme inhibitor, enalapril, or deoxycorticosterone acetate (DOCA), were measured. The intakes of NaCl and NaHCO3 were similar. Salt intakes tended to be lower in exercising than in sedentary groups. Neither acute sodium depletion nor administration of enalapril increased salt intake systematically, but treatment with DOCA increased intakes of both salt and water. These results are contrasted with the efficacy of all three treatments to induce salt appetite in rats.     

Sodium appetite decreased by central angiotensin blockade

Disturbances in body water and electrolytes that trigger sodium appetite, such as sodium depletion or hypovolemia, are potent activators of the renin-angiotensin system. In the absence of an actual deficit in body fluids, angiotensin injections are adequate to stimulate increased sodium ingestion. To assess whether angiotensin is a significant mediator of sodium appetite induced by acute alterations in body fluids, sodium intake was examined in rats during central or peripheral angiotensin blockade. Central blockade of angiotensin receptors by intracerebroventricular (ICVT) injection of the analogue antagonist saralasin decreased (but did not eliminate) sodium intake after polethylene glycol-induced hypovolemia or sodium depletion resulting from dialysis against glucose. Conversely, peripheral blockade of angiotensin converting enzyme with orally active captopril potentiated rather than decreased sodium appetite and stimulated water intake after sodium depletion. This increased water and salt intake after peripheral inhibition of converting enzyme was reversed, however, by concurrent central blockade of angiotensin receptors. These data support the hypothesis that angiotensin participates in sodium appetite associated with acute alteration in body fluids. Furthermore, the brain is the site at which angiotensin exerts its influence on sodium appetite. While the involvement of angiotensin of brain origin is not ruled out, the change in sodium appetite after peripheral blockade of converting enzyme suggests that circulating angiotensin derived from renal renin may interact with central angiotensin receptors regulating sodium appetite.     

Induction of an appetite for sodium in rats that show no spontaneous preference for sodium chloride solution--the Fischer 344 strain

Fischer 344 rats show no spontaneous preference for isotonic sodium chloride (NaCl) solution. These experiments indicate, however, that a strong appetite for this solution may be induced by various methods, including adrenalectomy, administration of a mineralocorticoid hormone, acute depletion of sodium, and treatment with inhibitors of the angiotensin I converting enzyme (ACE). These treatments were also shown to produce the expected changes in the renin-angiotensin-aldosterone system, which thus appears to be involved in the induction of an appetite for NaCl solution in this strain of rat. The intakes of NaCl induced in the Fischer 344 rats by these experimental paradigms are less than those that have been reported in either Sprague-Dawley or Wistar strains in similar paradigms. In the case of sodium depletion, the intake of NaCl solution by Fischer 344 rats appears to be more closely related to the deficit than in the other two strains. Thus, the Fischer 344 strain of rats may be a particularly good model for studies of need-related sodium appetite.     

The apparent dependence of salt appetite in the pigeon on endogenous angiotensin II

Blockade of endogenous angiotensin II (ANG II) biosynthesis by intramuscular administration of the angiotensin converting enzyme inhibitor captopril (1 or 10 mg/kg b.w.t.) completely suppressed salt appetite induced by sodium depletion in the pigeon. The effect was selective since captopril did not reduce deoxycorticosterone (DOCA)-induced salt appetite nor water drinking to ANG II and eledoisin. Blockade of brain ANG II receptors by pulse intracerebroventricular (pICV) injection of the ANG II receptor antagonist [Sarcosine1, isoleucine8] ANG II produced a marked, although partial, inhibition of salt appetite. The inhibition was quantitatively similar to the effectiveness of the ANG II receptor blockade, as measured by the suppression of drinking to pICV ANG II. Blockade of brain aldosterone (ALDO) receptors by pICV injections of the mineralocorticoid receptor antagonist RU-28318 did not significantly suppress depletion-induced appetite at doses that markedly reduced DOCA-induced salt appetite. These findings suggest that the pigeon might be completely dependent on ANG II for the expression of depletion-induced salt appetite. This is in contrast with what has been found in the rat, in which blockade of both ANG II and ALDO are necessary to suppress the appetite.     

Angiotensin converting enzyme inhibitor captopril modifies conditioned place preference induced by morphine and morphine withdrawal signs in rats.

Angiotensin II and angiotensin converting enzyme (ACE) inhibitors have analgesic, anticonvulsant and antidepressive effects and in some cases they can antagonize morphine. In the present study effects of angiotensin II and ACE inhibitor captopril administered intracerobroventricularily (icv) on conditioned place preference induced by morphine as well as on morphine withdrawal signs has been evaluated in rats. Icv canullas were implanted in anesthetized male rats. Rats were allowed to recover from the surgery and conditioned place preference was induced by morphine, and the time spent in morphine compartment was compared in saline, morphine, captopril and Ang II groups. Morphine withdrawal signs were compared in three other groups of rats: morphine alone, captopril+morphine and Ang II+morphine 4 days after morphine injections (three times in each day) with naloxone injection on 4th day. Results with rats conditioned place preference induced by morphine showed that icv captopril decreased significantly the time in morphine compartment (P<0.01) while Ang II had no effect. In morphine dependent rats captopril decreased some withdrawal signs after naloxone precipitation (P<0.05 and P<0.01). Ang II administration augmented some of withdrawal signs than in the morphine group (P<0.01 and P<0.001). In conclusion captopril reduced conditioned place preference induced by morphine and some withdrawal signs in morphine dependent rats.     

Salt appetite is enhanced by one prior episode of sodium depletion in the rat

A single sodium depletion enhances the salt appetite that is expressed after a second and subsequent sodium depletions. The enhanced salt intake, as measured by a decrease in latency to drink and an increase in volume of 3% NaCl ingested, is not accounted for by an increased sodium loss. The enhanced salt intake occurs even when the interval between first and second depletion is as long as 4 months. The enhanced salt appetite does not depend on the drinking of salt after the animal's first sodium depletion and is specific for NaCl but not for KCl. Moreover, it can be produced without sodium depletion by the actions of the hormones aldosterone and angiotensin on the brain. These results suggest that angiotensin and aldosterone, which are released in response to sodium depletion, (a) increase renal sodium conservation, (b) evoke a salt appetite to restore the lost sodium, and (c) produce enduring changes in the brain that prepare it for more rapid and more vigorous expression of salt appetite in response to future sodium depletions. Thus the neural mechanisms that govern salt appetite are not only activated by the hormones of sodium conservation but appear also to be organized by them for a lifelong increase in avidity for salty substances.     

Thirst and sodium appetite after colloid treatment in rats: role of the renin-angiotensin-aldosterone system

Recent experiments indicated that rats usually develop sodium appetite 5 hr after subcutaneous injection of polyethylene glycol (PEG) solution. However, sodium appetite appeared within 30 to 60 min if the rats had been maintained on sodium-deficient diet instead of Purina chow for 2-4 days previously. Elevated levels of aldosterone paralleled the appearance of NaCl consumption in both circumstances. In the present experiments, sodium appetite was no longer potentiated by pretreatment maintenance on sodium-deficient diet when the hypersecretion of aldosterone after PEG administration was prevented by prior hypophysectomy. Conversely, sodium appetite was enhanced in PEG-treated rats when angiotensin II (AII) was produced in unusually large amounts in the brain, owing to the systemic administration of captopril. This latter effect occurred even when drinking water was withheld and plasma sodium concentrations were markedly elevated. These and other findings raise the possibility that the normal secretion of aldosterone in rats after PEG treatment might permit physiological amounts of AII to be effective in stimulating sodium appetite. Such actions would complement the accepted physiological role of the renin-angiotension-aldosterone system in the maintenance of blood pressure and sodium balance.     

Comparison of the dipsogenic responsiveness of Long-Evans and Sprague-Dawley rats

The dipsogenic responsiveness of the Sprague-Dawley (albino) and Long-Evans (hooded) strains of rats was compared. The responsiveness of the angiotensin II pathway for induction of drinking was assessed by means of acute administration of the beta-adrenoceptor agonist, isoproterenol (25 micrograms/kg, SC), angiotensin I (150 micrograms/kg, SC), and angiotensin II (150 micrograms/kg, SC). The results show that rats of the Long-Evans (hooded) strain drink less water than those of the Sprague-Dawley strain in response to acute administration of either isoproterenol or angiotensin I. However, there was no difference between groups in water intake resulting from administration of angiotensin II. This suggests that the Long-Evans strain has less capacity to convert angiotensin I to angiotensin II than the Sprague-Dawley strain, but that responsiveness of the Long-Evans strain to angiotensin II is similar to that of the Sprague-Dawley strain. The responsiveness of the osmoreceptor pathway for induction of drinking was also assessed both by measurement of the drinking response to acute administration of hypertonic saline (1% body weight of 1 M NaCl solution, IP) and a 24-hour dehydration. The results show that rats of the Long-Evans strain drink less water in response either to administration of hypertonic saline or to dehydration than those of the Sprague-Dawley strain. This suggests that responsiveness to stimulation of the osmoreceptor pathway of the Long-Evans strain induces less drinking than in the Sprague-Dawley.(ABSTRACT TRUNCATED AT 250 WORDS)     

Operant drinking in pigs following intracerebroventricular injections of hypertonic solutions and angiotensin II

The effect on operant drinking of intracerebroventricular injections of the following solutions has been investigated; hypertonic saline, hypertonic sugars, angiotensin II (Ang II) dissolved in water or dextrose, and Ang II dissolved in saline. Hypertonic (0.85 M) NaCl caused drinking in all pigs tested, but hypertonic (1.7 M) xylose, glucose or sucrose were less effective, indicating involvement of a cerebrospinal fluid sodium receptor mechanism as well as an osmoreceptor mechanism in the drinking responses. Angiotensin II in 0.15 M NaCl caused drinking in all pigs but when dissolved in water or dextrose it was ineffective. Injection of Ang II with hypertonic NaCl produced drinking similar in volume to the sum of the amount drunk in response to the individual stimuli. These results indicate that, in the pig, drinking in response to Ang II requires the presence of sodium ions.     

Salt-Sensitive Hypertension Resulting From Nitric Oxide Synthase Inhibition is Associated with Loss of Regulation of Angiotensin II in the Rat

In the Dahl salt-sensitive hypertensive rat, a diet containing L-arginine, the natural substrate for nitric oxide synthase, abrogates the hypertension. We postulated that nitric oxide synthase inhibition might induce a salt-sensitive form of hypertension and that this salt sensitivity might be linked to a loss of the regulatory effect of sodium ingestion on angiotensin II (Ang II) and angiotensinogen. Male Wistar-Kyoto rats were randomised to a diet containing 0.008 %, 2.2 % or 4.4 % sodium chloride and to treatment with the NO synthase inhibitor L-NAME (10 mg kg(-1) day(-1)) in the drinking water, or drinking water alone (Controls) for 4 weeks. Blood pressure was measured by tail cuff plethysmography twice weekly. After 4 weeks, the rats were anaesthetised and truncal blood collected for determination of angiotensinogen, renin, angiotensin I (Ang I), Ang II and aldosterone concentrations as well as angiotensin-converting enzyme (ACE) activity. Systolic blood pressure increased with increasing dietary sodium intake in the L-NAME-treated rats (P < 0.05). Plasma renin and aldosterone concentrations decreased with increasing dietary sodium intake in both Control and L-NAME-treated rats. Ang I and ACE activity were unchanged by increasing dietary sodium intake. In contrast, the plasma concentration of Ang II and angiotensinogen increased with increasing dietary sodium (P < 0.05 and P < 0.005, respectively). Treatment with the Ang II receptor blocker, losartan, reversed the blood pressure increase. We conclude that treatment with L-NAME induces an increase in blood pressure that is at least in part salt sensitive. Further, the salt-sensitive component appears to be Ang II-dependent, as it was associated with increasing plasma Ang II levels and could be reversed by treatment with an Ang II receptor antagonist.     

Angiotensin does contribute to drinking induced by caval ligation in rat

In small (0.5 mg/kg) subcutaneous doses, the angiotensin-converting enzyme inhibitor, captopril, greatly enhanced drinking in response to caval ligation in the rat. Drinking was not secondary to urinary water loss since the rats developed a substantial positive fluid balance. High (50 mg/kg) subcutaneous doses of captopril reduced drinking to a level below that following caval ligation alone. This effect could be mimicked by giving repeated intracerebroventricular injections of captopril (total amount 110 micrograms) to rats treated with the lower subcutaneous dose of captopril. With this combination, therefore, not only did the lower dose enhancement disappear, the basal caval ligation drinking response was also reduced with a total dose of captopril of less than 2% of the higher subcutaneous dose alone. These results show that, when conversion of angiotensin I to angiotensin II is prevented in the brain as well as systemically, drinking in response to caval ligation is reduced although not entirely prevented. The original report that such drinking is multifactorial, depending on angiotensin as well as nonangiotensin mechanisms, is confirmed.     

Role of angiotensin-II in the polydipsia of diabetes insipidus in the Brattleboro rat

Captopril, an inhibitor of angiotensin converting enzyme which prevents conversion of angiotensin I (AI) to angiotensin II (AII), reduces the polydipsia of Brattleboro rats with hereditary hypothalamic diabetes insipidus (DI). In the present study, captopril (480 mg/kg-day) reduced DI polydipsia by 18% with no change in plasma osmolality; an equivalent (17%) reduction caused by quinine (0.02%) adulteration of drinking water increased plasma osmolality significantly. If captopril reduces water intake of DI rats because it removes a dipsogenic signal to the CNS, plasma osmolality should have increased during captopril treatment. Captopril probably reduces DI polydipsia because it reduces renal water loss by lowering blood pressure. Both furosemide and spironolactone, which reduce renal water loss and increase AII levels, also reduced DI polydipsia with no change in plasma osmolality. Thus, only a small fraction of DI polydipsia seems to be controlled by a dipsogenic effect of AII.     

FURO/CAP: A protocol for sodium intake sensitization

We investigated if a history of FURO/CAP, a protocol that increases brain angiotensin II (ANG II), sensitizes or enhances sodium intake. A subcutaneous injection of the diuretic furosemide (FURO, 10 mg/kg) was combined with a converting enzyme inhibitor captopril (CAP, 5 mg/kg) to induce a short latency stimulated sodium (0.3 M NaCl) and water intake in a 2 h FURO/CAP test. Repeated injections of only FURO/CAP, separated by one-week interval, enhanced stimulated and spontaneous (daily) sodium intake. Stimulated fluid intake was completely suppressed when FURO/CAP was combined with two intraperitoneal injections of the ANG II type-1 receptor antagonist losartan (10, 20, or 40 mg/kg each) given within 1 h prior to the FURO/CAP test. Losartan reduced by only 35% the FURO/CAP-induced natriuresis. A history of FURO/CAP, FURO/CAP + losartan (all doses), or vehicle produced similar stimulated fluid intake when all animals received only FURO/CAP in the third final FURO/CAP test. However, a history of vehicle or FURO/CAP + losartan 10 mg/kg precluded the enhancement in spontaneous sodium intake after the third final FURO/CAP. The FURO/CAP combined with losartan (all doses) also precluded the spontaneous sodium intake enhancement in the weeks that preceded the third final FURO/CAP test. A history of only FURO/CAP, but not vehicle, also enhanced water deprivation-induced sodium appetite. The results suggest that a history of FURO/CAP enhances stimulated and spontaneous sodium intake, as well as water deprivation-induced sodium appetite, and reinforce the role of ANG II as a peptide that mediates long-term effects on behavior.     

Is substance P released from slices of the rat spinal cord inactivated by peptidase(s) distinct from both 'enkephalinase' and 'angiotensin-converting enzyme'?

Studies on the effects of peptidase inhibitors on substance P-like immunoreactive material (SPLI) released by K(+)-induced depolarization from slices of the rat spinal cord showed that bacitracin was the most potent agent to protect SPLI from degradation. Captopril and thiorphan which inhibit, respectively, angiotensin I converting enzyme and endopeptidase-24.11 also protected SPLI from degradation. However other inhibitors of these two enzymes, kelatorphan for endopeptidase-24.11 and enalaprilat for angiotensin I converting enzyme were essentially inactive, indicating that both enzymes are probably not involved in the degradation of endogenous substance P. Instead, the non-additive protecting effect of bacitracin, captopril and thiorphan might be due to the blockade of some 'bacitracin-sensitive enzyme' playing a key role in the catabolism of SP within the rat spinal cord.     

Functional consequences of angiotensin-converting enzyme gene polymorphism on N-acetyl-Ser-Asp-Lys-Pro degradation and angiotensin II production

Studies analyzing the biochemical and hemodynamic consequences of the insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme gene on angiotensin I and bradykinin metabolism have provided divergent results. Twelve DD and 12 II normotensive subjects were infused for 15 min with angiotensin I (30 ng kg(-1) x min(-1)) and with another angiotensin I converting enzyme substrate not related to the renin-angiotensin system, N-acetyl-Ser-Asp-Lys-Pro (AcSDKP; 1.12 micro g kg(-1) x min(-1)), in the presence and absence of captopril. The infusion of the two peptides was repeated 15 days apart. In both the presence and the absence of captopril we found that DD and II subjects did not significantly differ in terms of endogenous plasma AcSDKP, angiotensin I, or angiotensin II concentrations, and that conversion of exogenous angiotensin I to angiotensin II was not faster in the DD subjects. Exogenously infused AcSDKP was metabolized slightly more rapidly in DD than in II subjects only when angiotensin I converting enzyme was not inhibited. The within-subject variability for angiotensin measurements was high, in contrast to AcSDKP measurements. This variability may account for the divergent results reported to date in the biochemical consequences of the I/D polymorphism of the angiotensin I converting enzyme gene. In conclusion, the I/D polymorphism of the angiotensin I converting enzyme gene has no effect on either endogenous AcSDKP metabolism or on the circulating renin-angiotensin system. It slightly affects the metabolism of exogenously infused AcSDKP and not that of angiotensin I.     

Angiotensin III-induced dipsogenic and pressor responses in rodents

Subcutaneous injections of [des-Asp1]-angiotensin I [( des-Asp1]-AI), angiotensin II (AII), and angiotensin III (AIII) induced drinking in the laboratory rat and the South American rodent Octodon degus, but not in the gerbil. In a second experiment, pretreatment with captopril, an angiotensin converting enzyme inhibitor, prevented the endogenous conversion of subcutaneously injected [des-Asp1]-AI to AIII and prevented drinking in rats and degus. The pharmacological artifact of hypovolemia caused by angiotensin-induced increases in vascular permeability was not observed in members of these species. In a final experiment blood pressure changes resulting from subcutaneous injections of AII and AIII in rats and gerbils were measured. Significant pressor elevations were seen following the administration of both analogues, although AII was more potent. These results demonstrate that AIII is dipsogenic in rats and degus and serves as a pressor agent in rats and gerbils. No ready explanation is available for the gerbil's relative lack of dipsogenicity to the presently tested angiotensins.