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A N Epstein

Publications and source records attributed to A N Epstein.

At least 55 records · Page 3Linked to original sources

Interference with central actions of angiotensin II suppresses sodium appetite.

We have proposed that sodium appetite is aroused by a synergy in the brain of angiotensin II and aldosterone. This hypothesis was tested with 1) chronic intracerebroventricular infusion of captopril, which blocks the conversion of angiotensin I to angiotensin II, or 2) intracerebroventricular injection of eight-substituted analogues of angiotensin II, which block its receptors. Both treatments resulted in a suppression of the sodium appetite induced by sodium deficiency. The suppression was specific for the deficiency-induced appetite, because spontaneous ingestive behaviors were not changed nor was sodium excretion. In addition, the rats continued to express a sodium appetite aroused by pharmacological doses of deoxycorticosterone acetate when they received the highest dose of chronic intracerebroventricular captopril. These results offer compelling evidence for the idea that angiotensin II action in the brain is necessary for expression of sodium appetite.

Angiotensin II↗

Ontogeny of epinephrine-induced anorexia in rats.

Intraperitoneal or intraportal epinephrine elicits a strong inhibition of food intake in adult rats and dogs but has no effect when injected intramuscularly or intrajugularly, in spite of production of larger hyperglycemia and cardiovascular changes. These facts suggest that the effect of epinephrine on feeding is elicited via the liver. Ontogeny of this adrenergic control of food intake was studied in newborn and weanling rats. Anorexic effect of intraperitoneal epinephrine was clearly observed in dam-deprived 3-day-old neonatal rats (youngest in which it was tested), both when they were offered enriched milk through an anterior oral cannula while they were isolated from their dam and when they were allowed to suckle from her. However, anorectic effect was less in neonatal rats (day 3-13) than in adults. Weanling rats, 21-26 days old, were as sensitive to intraperitoneal epinephrine as adults. In 3- to 4-day-old rats it also reduced water intake, but this effect disappeared by day 12 and was not observed in mildly water-deprived adults. Peripheral adrenergic control of intake appears very early in ontogeny of rats. First, it affects food and water intake equally, but by day 12 it affects only food intake. Increase in sensitivity to epinephrine after weaning is probably due to an increase in number of hepatocytic adrenergic receptors and/or increase in enzymes necessary for hepatic effects of epinephrine.

Aging↗

Salt appetite is suppressed by interference with angiotensin II and aldosterone.

Blockade of central but not peripheral mineralocorticoid receptors, with the antimineralocorticoid RU-28318, reduces but does not suppress salt appetite aroused by sodium depletion in the rat. When central mineralocorticoid blockade is combined with captopril treatment to prevent formation of endogenous angiotensin II the appetite is completely suppressed. Suppression of the appetite occurred without changes in the animals' spontaneous ingestive behaviors, sodium excretion, or insulin-induced food intake. These results demonstrate that a synergy of angiotensin II and aldosterone is responsible for the expression of depletion-induced salt appetite in the rat.

Aldosterone↗

Together intracranial angiotensin and systemic mineralocorticoid produce avidity for salt in the rat.

Rats that have no need for sodium will run to small rewards of 3% NaCl solution in a runway after they have been treated with both a mineralocorticoid and angiotensin II. When given alone at the low doses used here, neither the mineralocorticoid nor the angiotensin produce the behavior. This result encourages the idea that it is a synergy of the hormones of sodium conservation, angiotensin and aldosterone, that apprises the brain of the need for salt and generates the appetite for the taste of salt.

Angiotensin II↗

The failure of ventricular sodium to control sodium appetite in the rat.

Dilution of CSF sodium by infusion of hyperosmotic mannitol into the cerebral ventricles of the rat does not evoke a salt appetite, nor does the addition of sodium to the CSF of the rat suppress the preexisting salt appetites produced by the hormones of sodium conservation or by adrenalectomy. CSF sodium concentration does not control sodium appetite in the rat. The proposal that it does so in sheep should not be generalized to other species without caution.

Adrenal Glands↗

Involvement of the renin-angiotensin system in captopril-induced sodium appetite in the rat.

The angiotensin converting enzyme inhibitor, captopril, given to rats in their drinking water (about 40 mg/day) for 6 days caused an increase in intake of hypertonic NaCl solution which began 1-2 days after the captopril was started and reached a plateau after 4-5 days. Twice-daily subcutaneous injections of captopril (15 mg per injection) elicited a sodium appetite similar in pattern to that seen with oral administration. The rats remained in sodium and fluid balance during oral captopril treatment and the haematocrit did not alter. Captopril infused directly into the ventricles (12 micrograms/h), or captopril reaching the brain from the periphery across a leaky blood-brain barrier, suppressed the sodium appetite which normally follows oral captopril. Continuous intravenous infusion of captopril at rates high enough to block angiotensin converting enzyme in the brain (25, 50 or 500 mg/day) did not cause sodium appetite. As soon as the rate was reduced to a low value (5 mg/day), NaCl intake increased. In conclusion, moderate levels of circulating captopril which do not cross the blood-brain barrier in sufficient amounts to block cerebral angiotensin converting enzyme, result in an increase in circulating angiotensin I which stimulates sodium appetite when it is converted to angiotension II in the brain.

Angiotensin-Converting Enzyme Inhibitors↗

Sodium appetite during captopril blockade of endogenous angiotensin II formation.

Angiotensin II and aldosterone increase in response to sodium deficiency to promote sodium and water conservation. In addition, they may act synergistically to arouse a sodium appetite. If so, then blockade of endogenous angiotensin should decrease the appetite. In experiments reported here, captopril (SQ 14,225) was given peripherally to rats to block conversion of angiotensin I to angiotensin II. It both enhanced and suppressed sodium depletion-induced sodium appetite. The appetite was suppressed when captopril was given in high doses, which block conversion centrally as well as peripherally. The same doses of captopril had no effect on urinary sodium excretion or on sodium appetite aroused by mineralocorticoid treatment. Low doses, which block conversion only in the periphery, enhanced salt intake elicited by depletion, and the enhancement was abolished by captopril given directly into the brain. Therefore the enhancement was probably due to a captopril-induced increase of peripheral angiotensin I, which gained access to the brain and was converted there to angiotensin II.

Administration, Oral↗

The dependence of the salt appetite of the rat on the hormonal consequences of sodium deficiency.

Richter's discovery of the salt appetite that follows adrenalectomy (1936) raised the question: how does the brain appreciate the need for sodium so that it can mobilize the search for and ingestion of salty substances? It remains unanswered. Recent work suggests that the answer may come from an understanding of the behavioral effects of the hormones of sodium conservation. Fluharty and I have found (Behavioral Neuroscience, 1983) that treatment of salt replete rats with low doses of both angiotensin (Ang II) and a mineralocorticoid (DOCA) evokes a rapid, reliable, and specific appetite for sodium solutions, and we have proposed that the hormones of renal sodium conservation are also the hormones for the behavioral defense against sodium deficiency. We can now report: That the same combined endocrine treatment will compel rats that do not need salt to search for it in a runway. That is, sodium replete rats that have been primed for 3 days with DOCA (500 micrograms/day), which does not produce an appetite for salt, and are then given a pulse intracerebroventricular (ICV) injection of Ang II (60 ng), which by itself does not produce an appetite for salt, will run in an alleyway in order to ingest small drops of 3% NaCl. The hormones act together to make the rat avid for salt and their action is sufficient to drive it to seek salt at a distance and to ingest it at a concentration that untreated rats avoid.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

The arousal of ingestive behaviors by chemical injection into the brain of the suckling rat.

Three neurochemical agents known to arouse ingestion in adult rats were studied in milk-sated rat neonates ingesting fluids away from their dams. All were given intracerebroventricular (ICV) injection. Drinking of both milk and water by 2-day-olds injected with angiotensin II (Ang II) was confirmed. The characteristic adult dipsogenic response, intake of water greater than that of milk, appeared at 8 days. ICV carbachol (Carb), on the other hand, did not elicit drinking before 4 days, despite the fact that these dipsogens (Carb and Ang II) may both affect receptors in the subfornical organ. ICV norepinephrine (NE) increased milk intake beginning at 9 to 10 days, which coincides with the age at which central adrenergic receptors believed to mediate NE's orexigenic effect are appearing in the developing forebrain. NE had no effect on water intake at any age. The effects of all three agents on ingestive behaviors were dose-dependent. These data suggest that the neural systems utilized by Ang II, Carb, and NE are competent for mediation of specific ingestive behaviors before they reach full anatomical and biochemical maturity. Last, NE did not increase milk intake of pups suckling from their dam at any age. The noradrenergic system that is developing in the rat brain during the suckling period appears to be a nascent control of subsequent adult feeding rather than a functioning control of ongoing suckling.

Angiotensin II↗

Sodium appetite elicited by intracerebroventricular infusion of angiotensin II in the rat: II. Synergistic interaction with systemic mineralocorticoids.

Angiotensin and mineralocorticoids, the hormones of sodium conservation, acted together to arouse a sodium appetite with shorter latency and greater magnitude than is produced by larger amounts of each acting alone. This potentiation was selective for sodium ingestion and occurred in the absence of significant changes in sodium balance. Therefore, because endogenous angiotensin and mineralocorticoids are concurrently elevated during sodium deficiency, sodium appetite may be aroused by a synergy of the peptide and the steroid.

Angiotensin II↗

Differential effects of upper gastrointestinal fill on milk ingestion and nipple attachment in the suckling rat.

Milk intake and nipple attachment behaviors were studied in the natural suckling situation after gastrointestinal preloading. Rat pups, deprived of their dam for 9 hr at 1, 10, or 20 days of age, were preloaded by gavage with volumes ranging from 2 to 16% of their body weight and returned to suckle. Preloads of artificial bitch's milk decreased the intake of mother's milk in a volume-related manner at all ages. At 1 and 10 days 4% preloads decreased milk intake without affecting attachment behaviors; larger preloads of 8 and 16% decreased intake and reduced the incidence of attachment. At 20 days of age small and large preloads decreased both incidence of attachment and milk intake. Preloads up to 8% of body weight had no effect on latency to attach at any age. Complete subdiaphragmatic bilateral vagotomy increased milk intake of 7-9 day-old pups fed automatically through an anterior mouth cannula in a nonsuckling situation. Vagotomy combined with spinal cordotomy (T2-T3) resulted in a synergistic hyperphagia and massive distension of the upper GI tract. The results indicate that suckling rats can control their intake of mother's milk while remaining attached to a nipple as early as 1 day of age. The suppression of ingestion in response to GI filling appears to be mediated by visceral afferent activity. Conversely, attachment behaviors are less affected by GI fill. This suggests that ingestive behaviors and attachment behaviors have different controls during the 1st 10 days of postnatal development.

Age Factors↗

The site of the dipsogenic action of angiotensin II in the North American opossum.

Adult North American opossums (Didelphis virginiana), predominantly nocturnal water drinkers, were found to respond by drinking to water deprivation, cellular dehydration produced by intravenous infusion of hypertonic saline, and to both intravenous and intracerebroventricular administration of angiotensin II (AII). By taking advantage of the absence of the corpus callosum, an anatomical characteristic of the marsupial, we removed the subfornical organ and implanted a cannula into the anterior third ventricle under direct visual guidance. In these animals: (1) spontaneous drinking, and responses to water deprivation and cellular dehydration were unaffected; (2) after a postoperative period of unresponlsiveness, attenuated and unreliable responses only to high doses of intracerebroventricular AII could be elicited; and (3) the dipsogenic effect of intravenous AII was abolished. We conclude that the subfornical organ is necessary for the physiologically appropriate effect of AII on drinking but that, in the absence of the subfornical organ, the brain can mediate the dipsogenic effect of intracranially administered AII, although the physiological significance of the latter phenomenon is unclear.

Angiotensin II↗

Development of angiotensin-induced drinking in the rat.

The suckling rat responds from birth to intraventricular angiotensin, and the drinking behavior elicited by the hormone achieves adult characteristics of reliability and sensitivity at 4--5 days of age. Additional testing of 5-day-old rats injected with a range of doses showed that the threshold dose lies between 0.1--1.0 ng, which is comparable to the adult sensitivity to intraventricular injections. The hormone also increases milk intake in neonates, but the animals choose water over milk as early as 17 days.

Angiotensin II↗

Arousal of a specific and persistent sodium appetite in the rat with continuous intracerebroventricular infusion of angiotensin II.

1. Prolonged exposure of the brain of the normal Na-replete rat to angiotensin II produced a marked and persistent Na appetite. In a first series of experiments, short-term, repeated systemic injections of isoprenaline or renin (both of which raise circulating angiotensin levels), and repeated intracranial injections of angiotensin II evoked increased ingestion of 2 . 7% NaCl. In the second series of experiments, continuous infusions of angiotensin II directly into the brain evoked extremely large intakes of 3% NaCl. 2. In addition to large intakes of hypertonic NaCl some rats drank daily volumes of water that exceeded their body weight. 3. Not only did the animals drink large volumes of 3% NaCl some rats drank daily volumes of water that exceeded their body weight. 3. Not only did the animals drink large volumes of 3% NaCl during continuous angiotensin II infusion, but after termination of the infusion they continued to ingest NaCl at a rate comparable to that of the adrenalectomized rat. In most of the animals the persistent NaCl intake diminished over several days, but other animals continued to drink NaCl for as long as their intake was measured (up to 7 months). 4. The response to continuous infusion of angiotensin II was dose-dependent. Both water and 3% NaCl intake increased over a dose range of 6 ng h-1 to 6000 ng h-1. The persistence of the sodium appetitite was also dose-dependent across the same range of doses. 5. Angiotensin-induced salt appetite is specific for Na. Animals did not drink 0 . 5 M-NH4Cl and only occasionally drank minimal amounts of 0 . 5 M-KCl during continuous infusion. 6. The large water turnover was not responsible for the Na appetite. Rats given access to 3% NaCl only during infusion of angiotensin copiously. Animals that were not infused but were given saccharine-flavoured water in order to increase their water intakes did not drink 3% NaCl offered at the same time even though fluid intake was high. Rats that did not receive intracranial infusions but were infused intragastrically with volumes of water equal to or exceeding the amounts that were drunk during angiotensin infusion did not drink the 3% NaCl but did drink some water. 7. Records of the drinking by rats infused with angiotensin show that firstly the onset of drinking after the start of angiotensin infusion varied from animal to animal, secondly, NaCl drinking was not temporally linked to water intake, although this was observed occasionally, and thirdly, most of the drinking occurred during the night although angiotensin was infused continuously throughtout the nychthemeron. 8. Therefore, increases in angiotensin levels, probably with other factors such as increased levels of aldosterone or ACTH, result in Na appetite. The hormonal changes may alter the animals' preception of salt making it more acceptable. By means that are not yet understood the increased accceptability of salt persists after the termination of angiotensin infusion.

Angiotensin II↗