Central H1 and H2 receptor participation in the control of water and salt intake in rats

The aim of the present study was to evaluate the participation of brain H1 and H2 histaminergic receptors on water and salt intake induced by water deprivation (24 h), furosemide-induced sodium depletion and central angiotensinergic pharmacological stimulation in rats. Third ventricle injections of the H1 and H2 receptor antagonists, mepyramine (50, 100, 200 and 400 nmol) and cimetidine (100, 200 and 400 nmol), were unable to modify water intake induced by water deprivation and sodium depletion. Salt intake elicited by water deprivation and sodium depletion was reduced by the central administration of mepyramine, while intracerebroventricular administration of cimetidine had no effect. Water and salt intake evoked by central angiotensinergic stimulation (10 ng) was diminished by third ventricle injections of both mepyramine and cimetidine. Inhibition of the ingestive behaviors observed here is not a result of any illness-like effect produced by the intracerebroventricular injections of the histaminergic antagonists used, as demonstrated by an avoidance test. It was also shown that third ventricle injections of these compounds were unable to modify the hedonic behavior that leads rats to drink a tasty saccharin solution. We conclude that central histaminergic receptors participate in the control of salt intake induced by distinct physiological and pharmacological stimuli.     

Central 5-HT(3) receptors and water intake in rats

In the present paper, we studied in rats the effect of third ventricle administration of m-chlorophenylbiguanide hydrochloride (1-(3-chlorophenyl)biguanide (m-CPBG), a selective 5-HT(3) agonist, on water intake induced by three different physiological stimuli: water deprivation, acute salt load and hypovolemia. Central acute m-CPBG injections in the doses of 80 and 160 nmol significantly reduced water intake elicited by an acute salt load. Third ventricle injections of m-CPBG in the dose of 160 nmol significantly inhibited water intake in hypovolemic animals, whereas third ventricle injections of m-CPBG in a higher dose (320 nmol) were necessary to decrease water intake in water-deprived rats. Pretreatment with 1-methyl-N-[8-methyl-8-azabicyclo(3.2.1)-oct-3-yl]-1H-indazole-3-carboxamide (LY-278,584), a selective 5-HT(3) antagonist, abolished the inhibitory effect on water intake seen after central administration of m-CPBG in all groups studied. The central administration of m-CPBG was also able to inhibit water intake induced by pharmacological activation of central cholinergic and angiotensinergic pathways. Third ventricle injections of m-CPBG in the highest dose employed in this study (320 nmol) were unable to modify food intake in food-deprived rats. An aversion test has shown that acute third ventricle injections of m-CPBG do not induce illness-like effects that could explain the water intake inhibition here observed. Also, central administration of m-CPBG did not modify the intake of a "dessert" meal consisting of diluted condensed milk. It is concluded that central 5-HT(3) receptor activation exerts a specific inhibitory effect on water intake.     

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.     

Inhibition of drinking in water-deprived rats by combined central angiotensin II and cholinergic receptor blockade.

The effect of blockade of central angiotensin II (AII) receptors and cholinergic receptors on thirst induced by water deprivation was studied in Sprague-Dawley rats and rats with hereditary hypothalamic diabetes insipidus (DI). Neither central AII nor cholinergic blockade alone affected drinking. Antagonism of both receptors simultaneously, however, significantly inhibited water intake of both Sprague-Dawley and DI rats. This inhibitory effect was not observed in water-deprived, nephrectomized rats. The combined antagonism on water intake was specific, since milk intake in hungry rats was not affected by simultaneous AII and cholinergic blockade. Isorenin concentrations in brain tissue were at control levels in water-deprived, nephrectomized, and non-nephrectomized Sprague-Dawley rats but were increased in water-deprived DI rats. The results suggest that angiotensin and cholinergic receptors in the brain have a physiological role in thirst. Thirst is maintained when either receptor is intact, but reduced when both receptors are inhibited by antagonists. They are independently capable of maintaining thirst.     

Central administration of zinc reduces salt intake in rats

The aim of the present study was to investigate the effect of third ventricle injections of zinc on salt intake in rats in the three different experimental models where sodium appetite is increased: fluid deprivation, central angiotensinergic stimulation and sodium depletion. Adult Wistar male rats received third ventricle injections of Zn(Ac)2 in three different doses (0.03, 0.3 and 3.0 nmol/rat). Central angiotensinergic stimulation was achieved by third ventricle injections of angiotensin II in the dose of 25 ng/rat 30 min before central zinc administration. As expected, fluid deprivation, central angiotensinergic stimulation and sodium depletion significantly increased sodium appetite. Water intake was also enhanced after fluid deprivation and central angiotensinergic stimulation. After sodium depletion, no increase in water intake was observed. Third ventricle injections of zinc inhibited salt intake in all three experimental models studied. Water intake was also inhibited by central zinc administration after fluid deprivation and central angiotensinergic stimulation. Conversely, third ventricle injections of zinc were unable to modify food intake or body temperature. It is suggested that zinc, acting on central structures related to the control of body fluid homeostasis, inhibits the drive for salt intake that is normally observed during fluid deprivation, central angiotensinergic stimulation and sodium depletion.     

Some central mechanisms of thirst in the dog.

Measurements of water intake were made on a population of trained conscious dogs of both sexes prepared with chronic third ventricle cannulae. 2. Injection of 100 ng angiotensin II into the third ventricle lead to a prompt stimulation of drinking, the mean water intake over a 5 min period being 503 +/- 89 ml. (n=6) compared with controls. This dipsogenic effect of angiotensin II was abolished by prior central administration of 10 mug saralasin acetate or 100 ng atropine. 3. Injection of 1 mug carbachol into the third ventricle produced a small, variable increase in drinking. 4. Injection of 0-2 ml. 5% NaCl into the third ventricle stimulated drinking, a response that was not affected by prior administration of 10 mug saralasin acetate or 100 ng atropine. 5. Following a 24 hr period of water deprivation there was an increase in plasma osmolality and plasma-renin activity. The drinking following this period of water deprivation was not affected by prior control administration of either 10 mug saralasin acetate or 100 ng atropine. 6. In two acute dogs, intracarotid infusion of 125I angiotensin II was not followed by significant appearance of radioactivity in the third ventricle or cisterna magna c.s.f. 7. The relevance of these results to the control of water intake is discussed.     

Interaction between the lateral hypothalamic area (LHA) and the medial septal area (MSA) in the control of sodium and potassium excretion in rats

In studies of the role of the hypothalamus in regulating body ionic balances it was found that carbachol injected into the lateral hypothalamic area (LHA) and medial septal area (MSA) elicited an increase in natriuresis and kaliuresis. This efflux reached its peak between 40 and 60 minutes after such injections. A blockage of this response was observed when LHA stimulation by carbachol was performed in animals whose MSA had been blocked previously by atropine or destroyed by electrolytic lesion. Similarly, stimulation of the MSA after pharmacological blockade or destruction of the LHA elicited a response of greatly decreased intensity. On the basis of these results it was concluded that the natriuretic-kaliuretic response elicited by cholinergic stimulation of the LHA depends in part on synapses located in MSA; the response elicited by cholinergic stimulation of the MSA utilized also synapses located in the LHA, unilaterally and bilaterally.     

Effect of furosemide treatment on the central and peripheral pressor responses to cholinergic and adrenergic agonists, angiotensin II, hypertonic solution and vasopressin.

The present study was performed to investigate the effect of treatment with furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injections of cholinergic (carbachol) and adrenergic (norepinephrine) agonists, angiotensin II (ANGII) and hypertonic saline (HS, 2 M NaCl). The changes induced by furosemide treatment on the pressor response to intravenous (i.v.) norepinephrine, ANGII and arginine vasopressin (AVP) were also studied. Rats with a stainless-steel cannula implanted into the lateral ventricle (LV) were used. Two injections of furosemide (30 mg/kg b.wt. each) were performed 12 and 1 h before the experiments. Treatment with furosemide reduced the pressor response induced by carbachol, norepinephrine and ANGII i.c.v., but no change was observed in the pressor response to i.c.v. 2 M NaCl. The pressor response to i.v. ANGII and norepinephrine, but not AVP, was also reduced after treatment with furosemide. These results show that the treatment with furosemide impairs the pressor responses induced by central or peripheral administration of adrenergic agonist or ANGII, as well as those induced by central cholinergic activation. The results suggest that the treatment with furosemide impairs central and peripheral pressor responses mediated by sympathetic activation and ANGII, but not those produced by AVP.     

Separate controls for conditioned cephalic phases of acid secretion and drinking in the rat

Adult male Sprague-Dawley rats, surgically equipped with a stainless steel gastric cannula, were tested in a paradigm known to support conditioning of cephalic phase gastric acid secretion. Rats were tested first under (a) baseline conditions--prepared to sham feed, but no food was offered and none should have been expected; then (b) 5 conditioning trials--prepared and allowed to sham feed sweetened milk; and finally (c) extinction trials--prepared to sham feed milk, but milk was not offered. Combined antagonism of H1 and H2 histamine receptors (using intraperitoneal dexbrompheniramine plus cimetidine) prevented the acquisition of conditioned cephalic phase of acid secretion, but had no effect on acquisition of conditioned water intake. Such histaminergic antagonism also blocked the expression of an established conditioned acid secretory response without effect on conditioned water intake; peripheral cholinergic blockade using atropine methyl nitrate had virtually the same effect as did histaminergic antagonism. The converse was observed following blockade of angiotensin II synthesis using subcutaneous captopril: Established conditioned secretion was unaffected, but conditioned water intake was inhibited. These results dissociate the physiological controls for conditioned responses which occur simultaneously in rats anticipating eating: Peripheral histamine mediates the acquisition and expression of the conditioned cephalic phase of acid secretion, whereas angiotensin II appears to mediate at least the expression of conditioned water intake.     

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.     

Behavioral and pharmacological specificity of the feeding elicited by cholinergic stimulation of the substantia nigra in the rat

Microinjections of the cholinergic agonist carbachol into anterior substantia nigra dose dependently increased food intake in satiated rats. This resulted from a prolongation of the duration of eating. In the absence of food, those doses of carbachol that stimulated food intake (.1 and .5 microgram) had no effect on any other response examined, including gnawing, drinking, locomotion, grooming, sniffing, and rearing. The effect of carbachol depended on the degree of prior food deprivation, but supra-additive effects of carbachol and deprivation were not observed. These results are contrasted with those of previous studies demonstrating the nonspecific behavioral effects of electrical stimulation of the brain and of studies showing that carbachol has radically different behavioral effects at other central nervous system sites. Microinjection of an acetylcholine/eserine sulfate mixture also significantly increased food intake. This response was abolished by prior microinjection of the muscarinic receptor antagonist atropine into the substantia nigra, a result that provides evidence for pharmacological specificity of the behavioral effects. These data provide further evidence for the hypothesis that a functional cholinergic system is present within substantia nigra.     

Central kappa opioid receptors modulate salt appetite in rats

The role of the central opioid system in the control of water and salt intake is complex, with both stimulatory and inhibitory effects having been observed. The aim of the present study was to investigate the participation of the central κ-opioid receptors in the control of salt appetite. Male Wistar rats were submitted to two different experimental protocols: sodium deficit produced by the diuretic, furosemide, and brain angiotensinergic stimulation in rats under normal sodium balance. Lateral ventricle (LV) injections of Nor-binaltorphimine (Nor-BNI) at different doses (5, 10 and 20 nmol) inhibited hypertonic saline solution (1.5%) intake in sodium-depleted rats. The salt appetite induced by an LV injection of angiotensin II (Ang II) (10 ng) was also blocked by Nor-BNI injections into the LV, while no significant change was observed in water intake. Furthermore, the decrease in salt intake seems not to have been due to a general inhibition of locomotor activity or to any change in palatability, since central administration of Nor-BNI failed to modify the intake of a 0.1% saccharin solution when the animals were submitted to a "dessert test" or to induce any significant locomotor deficit in the open-field test. Also the central administration of Nor-BNI was unable to modify blood pressure in sodium-depleted animals. The present results suggest that activation of endogenous κ-opioid receptors modulates salt appetite induced by sodium depletion and by central angiotensinergic stimulation in rats.     

The role of the central serotonergic system in pilocarpine-induced seizures: receptor mechanisms

Modification of central serotonergic transmission resulted in alterations of pilocarpine convulsive activity in male Wistar rats. Seizure activity was increased after pizotifen injection and the latency period to onset of convulsions was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in seizure protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced seizures. In conclusion, the present study suggests that the inhibition of pilocarpine-induced seizures may be mediated by stimulation of 5-HT1A and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals.     

Naloxone antagonizes a central histaminergic stimulation of corticosterone secretion in rats

The interaction of central opioid receptors with histaminergic stimulation of the hypothalamo-pituitary-adrenocortical axis, evaluated indirectly through corticosterone secretion, was investigated in conscious unstressed rats. To avoid any possible direct action on the adrenal cortex, all drugs were given intracerebroventricularly (i.c.v.). Histamine, 2-pyridylethylamine (PEA), a histamine H₁-receptor agonist, and 4-methyl-histamine (MeHA) and dimaprit, the H₂-receptor agonists, considerably increased the serum corticosterone levels 1 h after adminstration. Naloxone, an opioid receptor antagonist, almost abolished the corticosterone response to PEA and considerably reduced the responses to MeHA, dimaprit and histamine. The maximum inhibitory effects of naloxone on corticosterone responses induced by histamine and histamine agonists were comparable with those of the H₁-and H₂-receptor antagonists, mepyramine and cimetidine.These results strongly suggest that a major part of the histaminergic stimulation of the hypothalamopituitary-adrenal axis is mediated by central opioid receptorsThe study was supported by the Polish Academy of Sciences, grant No 06.03.     

Intraseptal microinjections of carbachol and angiotensin II in rats: effects on taste preferences

The present study examined the effects of carbachol and angiotensin II injected into the medial and lateral septal areas (MSA and LSA) on the ingestion of primary taste solutions in a free-choice situation. The injection of carbachol or angiotensin II into MSA and LSA of water sated rats evoked a preference for the sweet tasting saccharin solution and water. The lateral septal rats also preferred acetic acid solution. Only the total fluid intake differed significantly among the four groups. In the water deprived rats injection of chemical to the respective groups induced the ingestion of NaCl solution. The MSA rats on injection of carbachol also preferred saccharin apart from NaCl. There was a significant difference in the NaCl intake among the four groups. The quinine solution was not consumed by all the groups. These results indicate that both the carbachol and angiotensin II induce the ingestion of saccharin, NaCl and water. The MSA might be more sensitive in inducing NaCl intake as compared with LSA during deprivation schedule and cholinergic stimulation. The LSA also evokes a preference for the sour tasting acetic acid. Furthermore, the data also suggest that the neurons sensitive to angiotensin are more potent than cholinergic neurons of LSA in producing salt preference.     

Role of histaminergic H1 and H2 receptors in prolactin release in humans

Histamine is considered as a neurotransmitter, since it is present in hypothalamus and pituitary gland. It has been reported to stimulate prolactin (PRL) release in rats and humans; it seems to be involved in the control of LH release in rats. But cimetidine, an H2 antagonist also induces PRL release in humans. To investigate the relationship between the PRL secretion and possible histaminergic pathways, the response of PRL and LH was studied for 180 minutes in 10 normal subjects (5 men, 5 women) after H1 antagonist (diphenhydramine 50 mg iv), H2 antagonist (cimetidine 300 mg iv) and placebo. Diphenhydramine and placebo injection resulted in a decrease of PRL from 0800 until 11.00 hours, suggesting a spontaneous diurnal variation. Cimetidine induced a short but significant rise of PRL before a similar diurnal secretory pattern. LH levels were unaffected by H1 and H2 antagonists. These data suggest that PRL and LH secretion in humans is unresponsive to H1 histaminergic pathways. The specific action of cimetidine remains to be defined.     

Antidipsogenic action of alpha-human atrial natriuretic polypeptide administered intracerebroventricularly in rats

Intracerebroventricular (i.c.v.) administration of alpha-human atrial natriuretic polypeptide (alpha-hANP) in a dose of 5 micrograms did not change water intake in normal rats, while 0.1 micrograms of angiotensin II (AII) and 0.5 micrograms of carbachol caused a marked increase in water intake for 30 min after i.c.v. injections. The water intake induced by 0.1 micrograms of AII was significantly suppressed by the simultaneous administration of 2 and 5 micrograms of alpha-hANP. However, alpha-hANP did not affect the water intake caused by 0.5 micrograms of carbachol. In 24-h water-deprived rats, alpha-hANP in doses of 2 and 5 micrograms pronouncedly inhibited the water intake. alpha-hANP did not change the food intake in 24-h fasted rats nor the locomotor activity in normal rats. These findings suggest that alpha-hANP in the central nervous system may play an important role in controlling drinking behavior, interacting with AII.     

Mechanisms of stimulation of acid production in parietal cells isolated from the pig gastric mucosa

Sequential incubations with pronase and collagenase of pig gastric mucosa resulted in single cell preparations containing 10-20% parietal cells, which could be enriched further to 85-95% purity by density-gradient centrifugation followed by elutriation. Acid production of the isolated cells was measured by means of aminopyrine accumulation in their acid compartments. When small pieces of the mucosa were pretreated for 1 h in the presence of either histamine, pentagastrin or carbachol before preparation of cells, the ability of the subsequently isolated cells to produce acid was increased. In parietal cells isolated from resting (not pretreated) mucosa pentagastrin, carbachol and also adrenaline increased the histamine-stimulated aminopyrine accumulation (50-90% increase). Adrenaline alone had no significant effect on the aminopyrine accumulation. In the presence of 10(-4) M histamine the apparent EC50 for adrenaline was 5 X 10(-7) M. Adrenaline, histamine, forskolin and isobutylmethylxanthin (IBMX) increased the formation of cAMP in purified parietal cells. The three 'classical' secretagogues histamine, pentagastrin and carbachol, but also IBMX and forskolin, increased the cytosolic free Ca2+ from approximately 1.5 X 10(-7) M to 2.2-3.5 X 10(-7) M but adrenaline and dibutyryl cyclic AMP did not. Thus the present results indicate that there are - in addition to histaminergic H2 receptors - specific cholinergic, gastrinergic and adrenergic receptors on the plasma membrane and that there are separate cAMP and Ca2+-dependent stimulatory pathways in the parietal cell.     

Increased responsiveness of the cerebral cortical phosphatidylinositol system to noradrenaline and carbachol in senescent rats

The responsiveness of cerebral cortical alpha 1-adrenoceptors and cholinergic muscarinic M1 receptors was assessed in young (3 months) and aged (24 months) male Sprague-Dawley rats. The measure of responsiveness was the accumulation of inositol phosphate (IP) formed in [3H]myo-inositol-preloaded cerebral cortical slices in the presence of lithium, following stimulation with various concentrations of noradrenaline (1-300 microM) and carbachol (5-1000 microM). In old rats the maximum response to noradrenaline was higher by 80%, and that to carbachol by 33%, indicating an increased responsiveness of the investigated receptors in senescence.     

Selective blockade of central M1 muscarinic cholinergic receptors with pirenzepine impairs cardiovascular and respiratory function in rats with acute hemorrhage

Ultrasound studies showed that selective antagonist of central M1 muscarinic cholinergic receptors pirenzepine (50 mg/kg intravenously) causes transitory hypotension and respiratory depression in anesthetized intact rats. The M1 receptor antagonist had no effect on cardiac output and portal blood flow. Pretreatment with pirenzepine increased the sensitivity of rats with acute massive hemorrhage to circulatory hypoxia. After blockade of central M1 muscarinic cholinergic receptors, the posthemorrhagic period was characterized by primary decompensation of blood pressure, portal blood flow, and respiration and development of low cardiac output syndrome. The animals died over the first minutes after bleeding arrest. Our results indicate that central M1 muscarinic cholinergic receptors act as shock-limiting cholinergic structures under conditions of posthemorrhagic changes in systemic and portal blood flow, as well as during respiratory dysfunction.