Serotonergic mechanism of the lateral parabrachial nucleus and relaxin-induced sodium intake

It has been shown that central or peripheral injections of the peptide relaxin induces water intake, not sodium intake in rats. Important inhibitory mechanisms involving serotonin and other neurotransmitters in the control of water and NaCl intake have been demonstrated in the lateral parabrachial nucleus (LPBN). In the present Study, we investigated the effects of bilateral injections of methysergide (serotonergic receptor antagonist) into the LPBN on intracerebroventricular (i.c.v.) relaxin-induced water and NaCl intake in rats. Additionally, the effect of the blockade of central angiotensin AT(1) receptors with i.c.v. losartan on relaxin-induced water and NaCl intake in rats treated with methysergide into the LPBN was also investigated. Male Holtzman rats with cannulas implanted into the lateral ventricle (LV) and bilaterally in the LPBN were used. Intracerebroventricular injections of relaxin (500 ng/l mul) induced water intake (5.1+/-0.7 ml/120 min), but not significant 1.8% NaCl intake (0.5+/-0.4 ml/120 min). Bilateral injections of methysergide (4 mug/0.2 mul) into the LPBN strongly stimulated relaxin-induced 1.8% NaCl intake (34.5+/-10.9 ml/120 min) and slightly increased water intake (10.5+/-4.9 ml/120 min). The pretreatment with i.c.v. losartan (100 mug/l mul) abolished the effects of i.c.v. relaxin combined with LPBN methysergide on 1.8% NaCI intake (0.5+/-0.4 ml/120 min). Losartan (100 mug/l mul) also abolished relaxin-induced water intake in rats injected with methysergide into the LPBN (1.6+/-0.8 ml/120 min) or not (0.5+/-0.3 ml/120 min). Losartan (50 mug/l mul) partially reduced the effects of relaxin. The results show that central relaxin interacting with central angiotensinergic mechanisms induces NaCl intake after the blockade of LPBN serotonergic mechanisms. (C) 2004 Elsevier B.V. All rights reserved.

Activation of paraventricular nucleus of hypothalamus 5-HT1A receptor on sodium intake

Hypothalamic paraventricular nucleus (PVN) has an important role in the regulation of water and sodium intake. Several researches described the presence of 5-HT1 receptors in the central nervous system. 5-HTIA was one of the prime receptors identified and it is found in the somatodendritic and post-synaptic forms. Therefore, the aim of this study was to investigate the participation of serotonergic 5-HT1A receptors in the PVN on the sodium intake induced by sodium depletion followed by 24 h of deprivation (injection of the diuretic furosemide plus 24 h of sodium-deficient diet). Rats (280-320 g) were submitted to the implant of cannulas bilaterally in the PVN. 5-HT injections (10 and 20 mu g/0.2 mu l) in the PVN reduced NaCl 1.8% intake. 8-OH-DPAT injections (2.5 and 5.0 fig/0.2 mu l) in the PVN also reduced NaCl 1.8% intake. pMPPF bilateral injections (5-HT1A antagonist) previously to 8-OH-DPAT injections have completely blocked the inhibitory effect over NaCl 1.8% intake. 5-HT1A antagonists partially reduced the inhibitory effect of 5-HT on NaCl 1.8% intake induced by sodium depletion. In contrast, the intake of palatable solution (2% sucrose) under body fluid-replete conditions was not changed after bilateral PVN 8-OH-DPTA injections. The results show that 5HT(1A) serotonergic mechanisms in the PVN modulate sodium intake induced by sodium loss. The finding that sucrose intake was not affected by PVN 5-HT1A activation suggests that the effects of the 5-HT1A treatments on the intake of NaCl are not due to mechanisms producing a nonspecific decrease of all ingestive behaviors. (c) 2006 Elsevier B.V. All rights reserved.

Alpha(2)-adrenergic activation in the lateral parabrachial nucleus induces NaCi intake under conditions of systemic hyperosmolarity

The inhibition of sodium intake by increased plasma osmolarity may depend on inhibitory mechanisms present in the lateral parabrachial nucleus. Activation of alpha(2)-adrenergic receptors in the lateral parabrachial nucleus is suggested to deactivate inhibitory mechanisms present in this area increasing fluid depletion-induced 0.3 M NaCl intake. Considering the possibility that lateral parabrachial nucleus inhibitory mechanisms are activated and restrain sodium intake in animals with increased plasma osmolarity, in the present study we investigated the effects on water and 0.3 M NaCl intake produced by the activation of alpha(2)-adrenergic receptors in the lateral parabrachial nucleus in rats with increased plasma osmolarity. Male Holtzman rats with stainless steel cannulas implanted bilaterally into the lateral parabrachial nucleus were used. One hour after intragastric 2 M NaCl load (2 ml), bilateral injections of moxonidine (alpha(2)-adrenergic/imidazoline receptor agonist, 0.5 nmol/0.2 mu l, n=10) into the lateral parabrachial nucleus induced a strong ingestion of 0.3 M NaCl intake (19.1 +/- 5.5 ml/2 h vs. vehicle: 1.8 +/- 0.6 ml/2 h), without changing water intake (15.8 +/- 3.0 ml/2 h vs. vehicle: 9.3 +/- 2.0 ml/2 h). However, moxonidine into the lateral parabrachial nucleus in satiated rats not treated with 2 M NaCl produced no change on 0.3 M NaCl intake. The pre-treatment with RX 821002 (alpha(2)-adrenergic receptor antagonist, 20 nmol/0.2 mu l) into the lateral parabrachial nucleus almost abolished the effects of moxonidine on 0.3 M NaCl intake (4.7 +/- 3.4 ml/2 h). The present results suggest that alpha(2)-adrenergic receptor activation in the lateral parabrachial nucleus blocks inhibitory mechanisms, thereby allowing ingestion of hypertonic NaCl under conditions of extracellular hyperosmolarity. We suggest that during cell dehydration, circuits subserving sodium appetite are activated, but at the same time strongly inhibited through the lateral parabrachial nucleus. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.

Participation of alpha-1 and alpha-2 adrenoceptors of the lateral hypothalamic area in water intake, and renal sodium, potassium and urinary Volume excretion induced by central administration of angiotensin II

The circumventricular structures and the lateral hypothalamus (LH) have been shown to be important for the central action of angiotensin II (ANGII) on water and electrolyte regulation. Several anatomical findings have demonstrated neural connection between circumventricular structures and the LH, the present experiments were conducted to investigate the role of the alpha-adrenergic antagonists and agonistic injected into the LH on the water intake, sodium and potassium excretion elicited by injections of ANGII into the lateral ventricle (LV), the water intake was measured every 30 min over a period of 120 min. The sodium, potassium and urinary volume were measured over a period of 120 min in water-loaded rats. The injection of ANGII into the LV increased the water intake, which was reduced by previous injection of clonidine (an alpha-2-adrenergic agonist) into the LH. The injection of yohimbine (an alpha-2-adrenergic antagonist) and prazosin (an alpha-l-adrenergic antagonist) into the LH, which was done before injecting ANGII into the LV, also reduced the water intake induced by ANGII. The injection of ANGII into the LV reduced the sodium, potassium and urinary volume. Previous treatment with clonidine attenuated the action of ANGII in reducing the sodium, potassium and urinary volume, whereas previous treatment with yohimbine attenuated the effects of ANGII but with less intensity than that caused by clonidine. Previous treatment with prazosin increased the inhibitory effects of ANGII in those parameters. The injection of yohimbine and prazosin, which was done before the injection of clonidine, attenuated the effect of clonidine on the ANGII mechanism. The results of this study led us to postulate that when alpha-2-adrenergic receptors are blocked, the clonidine may act on the imidazoline receptors to produce its effects on the ANGII mechanism. We may also conclude that the LH is involved with circumventricular structures, which present excitatory and inhibitory mechanisms. Such mechanisms are responsible for regulating the renal excretion of sodium, potassium and water, (C) 2000 Elsevier B.V.

Moxonidine and central alpha(2) adrenergic receptors in sodium intake

Central injections of the alpha(2) adrenergic/imidazoline receptor agonist moxonidine inhibit water and NaCl intake in rats. In the present study, we investigated the possible involvement of central alpha(2) adrenergic receptors on the inhibitory effect of moxonidine in 0.3 M NaCl intake induced by 24 h sodium depletion. Male Holtzman rats with stainless-steel cannulas implanted into the lateral ventricle (LV) were used. Sodium depletion was produced by the treatment with the diuretic furosemide (20 mg/kg of body weight) injected subcutaneously + 24 h of sodium-deficient diet. Intracerebroventricular (icv) injections of moxonidine (20 nmol/l mul) reduced sodium depletion-induced 0.3 M NaCl intake (6.6 +/- 1.9 ml/120 min vs. vehicle: 12.7 +/- 1.7 ml/120 min). Pre-treatment with the alpha(2) adrenoreceptor antagonists RX 821002 (80 nmol/l mul), SK&F 86466 (640 nmol/l mul) and yohimbine (320 nmol/3 mul) injected icv abolished the inhibitory effect of icv moxonidine on sodium depletion-induced 0.3 M NaCl intake (13.3 +/- 1.4, 15.7 +/- 1.7 and 11.8 +/- 2.2 ml/120 min, respectively). The results show that the activation of alpha(2) adrenoreceptors is essential for the inhibitory effect of central moxonidine on sodium depletion-induced NaCl intake. (C) 2003 Elsevier B.V. All rights reserved.

L-Type calcium channels mediate water intake induced by angiotensin injection into median preoptic nucleus

Calcium ions are widely accepted as critically important in responses of neurons to a stimulus. We have show previously the central involvement of angiotensin II (ANGII) in water intake. This study determined whether voltage-dependent calcium channels are involved in ANGII-induced behavioral drinking implicating nitrergic mechanism. The antidipsogenic actions of L-type calcium channel antagonists nifedipine, on ANGII-induced drinking behavior were studied when it is injected into the median preoptic nucleus (MnPO). The influence of nitric oxide (NO) on nifedipine antidipsogenic action was also studied by utilizing the N-W-nitro-L-arginine methyl ester (L-NAME) a constitutive nitric oxide synthase inhibitor constitutive (cNOSI) and 7-nitroindazol (7-NIT) a specific neuronal nitric oxide synthase inhibitor (nNOSI) and L-arginine a NO donor. Rats 200-250 g, with cannulae implanted into MnPO, pre-treated into MnPO with either nifedipine, followed by ANGII, drank significantly less water than controls during the first 15 min after injection. However, L-NAME potentiated the dipsogenic effect of ANGII that is blocked by prior injection of nifedipine and L-arginine. 7-NIT injected prior to ANGII into MnPO also potentiated the dipsogenic effect of ANGII but with a less intensity than L-NAME that it is also blocked by prior injection of nifedipine. The results described in this paper provide evidence that calcium channels play important roles in the ANGII-induced behavioral water intake. The structures containing NO in the brain such as MnPO include both endothelial cells and neurons might be responsible for the influence of nifedipine on dipsogenic effect of ANGII. These data shows the correlation between L-type calcium channel and a free radical gas NO produced endogenously from amino acids L-arginine by endothelial and neuronal NO synthase in the control of ANGII-dipsogenic effect. This suggests that an L-type calcium channel participates in both short- and longer-term neuronal actions of ANGII by nitrergic way. (c) 2006 Elsevier B.V. All rights reserved.

Effects of V-1 and angiotensin receptor subtypes of the paraventricular nucleus on the water intake induced by vasopressin injected into the lateral septal area

In this study, we investigated the influence of d(CH2)(5)-Tyr (Me)-AVP (AAVP) an antagonist of V-1 receptors of arginine(8)-vasopressin (AVP) and the effects of losartan and CGP42112A (selective ligands of the AT, and AT, angiotensin receptors, respectively) injections into the paraventricular nucleus (PVN) on the thirst effects of AVP stimulation of the lateral septal area (LSA). AVP injection into the LSA increased the water intake in a dose-dependent manner. AAVP injected into the PVN produced a dose-dependent reduction of the drinking responses elicited by LSA administration of AVP. Both the AT(1) and AT(2) ligands administered into the PVN elicited a concentration-dependent inhibition in the water intake induced by AVP injected into the LSA, but losartan was more effective than CGP42112A the increase in the AVP response. These results indicate that LSA dipsogenic effects induced by AVP are mediated primarily by PVN AT(1) receptors. However, doses of losartan were more effective when combined with CGP42112A than when given alone, suggesting that the thirst induced by AVP injections into LSA may involve activation of multiple angiotensin II (ANG II) receptor subtypes. These results also suggests that facilitatory effects of AVP on water intake into the LSA are mediated through the activation of V-receptors and that the inhibitory effect requires V-receptors. Based on the present findings, we suggest that the administration of AVP into the LSA may play a role in the PVN control of water control. (C) 2003 Elsevier B.V. All rights reserved.

Effects of subtypes of adrenergic and angiotensinergic antagonists on the water and sodium intake induced by adrenaline injected into the paraventricular nucleus

The present experiments were conducted to investigate die role of the alpha(1A)-, alpha(1B)-, beta(1)-, beta(2)-adrenoceptors, and the effects of losartan and CGP42112A (selective ligands of the AT(1) and AT(2) angiotensin receptors, respectively) on the water and sodium intake elicited by paraventricular nucleus (PVN) injection of adrenaline. Male Holtzman rats with a stainless steel cannula implanted into the PVN were used. The ingestion of water and sodium was determined in separate groups submitted to water deprivation or sodium depletion with the diuretic furosemide (20 mg/rat). 5-Methylurapidil (an alpha(1A)-adrenergic antagonist) and ICI-118,551 (a beta(2)-adrenergic antagonist) injected into the PVN produced a dose-dependent increase, whereas cyclazosin (an alpha(1B)-adrenergic antagonist) and atenolol (a beta(1)-adrenergic antagonist) do not affect the inhibitory effect of water intake induced by adrenaline. on the other hand, the PVN administration of adrenaline increased the sodium intake in a dose-dependent manner. Previous injection of the alpha(1A) and beta(1) antagonists decreased, whereas injection of the alpha(1B) and beta(2) antagonists increased the salt intake induced by adrenaline. In rats with several doses of adrenaline into PVN, the previous administration of losartan increased in a dose-dependent manner the inhibitory effect of adrenaline and decreased the salt intake induced by adrenaline, while PVN CGP42112A was without effect. These results indicate that both appetites are mediated primarily by brain AT(1) receptors. However, the doses of losartan were more effective when combined with the doses of CGP42112A than given alone p < 0.05, suggesting that the water and salt intake effects of PVN adrenaline may involve activation of multiple angiotensin II (ANG II) receptors subtypes. (C) 2003 Elsevier B.V. All rights reserved.

Lateral hypothalamus lesions influences water and salt intake, and sodium and urine excretion, and arterial blood pressure induced by L-NAME and FK 409 injections into median preoptic nucleus in conscious rats

Male Holtzman rats weighting 200-250 g were anesthetized with zoletil 50 mg/Kg (tiletamine chloridrate 125,0 mg and zolazepan chloridrate 125,0 mg) into quadriceps muscle and submitted an electrolytic lesion of the lateral hypothalamus (LH) and a stainless steel cannula was implanted into their median preoptic nucleus (MnPO). We investigated the effects of the injection into the (MnPO) of FK 409 (20 mug/0.5 mul), a nitric oxide (NO) donor, and N-W-nitro-L-arginine methyl ester (L-NAME) 40 mug/0.5 mul, a nitric oxide synthase inhibitor (NOSI), on the water and sodium appetite and the natriuretic, diuretic and cardiovascular effects induced by injection of L-NAME and FK 409 injected into MnPO in rats with LH lesions. Controls were injected with a similar volume of 0.15 M NaCl. L-NAME injected into MnPO produced an increase in water and sodium intake and in sodium and urine excretion and increase de mean arterial pressure (MAP). FK 409 injected into MnPO did not produce any change in the hydro electrolytic and cardiovascular parameters in LH-sham and lesioned rats. FK 409 injected before L-NAME attenuated its effects. These data show that electrolytic lesion of the LH reduces fluid and sodium intake as well as sodium and urine excretion, and the pressor effect induced by L-NAME. LH involvement with NO of the MnPO excitatory and inhibitory mechanisms related to water and sodium intake, sodium excretion and cardiovascular control is suggested. (C) 2004 Elsevier B.V. All rights reserved.

Activation of serotonergic 5-HT1A receptors in the lateral parabrachial nucleus increases NaCl intake

Previous studies using non-specific serotonergic agonists and antagonists have shown the importance of serotonergic inhibitory mechanisms in the lateral parabrachial nucleus (LPBN) for controlling sodium and water intake. In the present study, we investigated whether the serotonergic 5-HTIA receptor subtype in the LPBN participates in this control. Male Holtzman rats had cannulas implanted bilaterally into the LPBN. Bilateral injections of the 5-HTIA receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.1, 1.25, and 2.5 mu g/ 0.2 mu l), into the LPBN enhanced 0.3 M NaCl and water intake of rats injected subcutaneously with the diuretic furosemide (10 mg/kg bw) and a low dose of the angiotensin-converting enzyme inhibitor, captopril (5 mg/kg bw). The increase in NaCl intake produced by 8-OH-DPAT injections was reduced in dose-related manner by pre-treating the LPBN with the selective 5-HTIA serotonergic antagonist, WAY-100635 (WAY, I and 2 mu g/0.2 mu l). In contrast, WAY did not affect water intake produced by 8-OH-DPAT. WAY-100635 injected alone into the LPBN had no effect on NaCl ingestion. Injections of 8-OH-DAPT (0.1 mu g/0.2 mu l) into the LPBN also increased 0.3 M NaCl intake induced by 24-h sodium depletion (furosemide, 20 mg/kg bw plus 24 h of sodium-free diet). Serotonin (5-HT, 20 mu g/0.2 mu l) injected alone or combined with 8-OH-DPAT into the LPBN reduced 24-h sodium depletion-induced 0.3 M NaCl intake. Therefore, the activation of serotonergic 5-HTIA receptors in the LPBN increases stimulated hypertonic NaCl and water intake, while 5-HT injections into the LPBN reduce NaCl intake and prevent the effects of serotonergic 5-HTIA receptor activation. (c) 2005 Elsevier B.V. All rights reserved.

Role of the alpha(1)- and alpha(2)-adrenoceptors of the paraventricular nucleus on the water and salt intake, renal excretion, and arterial pressure induced by angiotensin II injection into the medial septal area

In this study we investigated the influence of cu-adrenergic antagonists injections into the paraventricular nucleus (PVN) of the hypothalamus on the thirst and salt appetite, diuresis, natriuresis, and presser effects of angiotensin II (ANG II) stimulation of medial septal area (MSA). ANG II injection into the MSA induced water and sodium intake, diuresis, natriuresis, and presser responses. The previous injection of prazosin (an alpha (1)-adrenergic antagonist) into the PVN abolished, whereas previous administration of yohimbine (an alpha (2)-adrenergic antagonist) into the PVN increased the water and sodium intake, urinary, natriuretic, and presser responses induced by ANG ii injected into the MSA. Previous injection of a nonselective alpha -adrenergic antagonist, regitin, into the PVN blocked the urinary excretion, and reduced the water and sodium intake, sodium intake, and presser responses induced by ANG II injected into the MSA. The present results suggest that alpha -adrenergic pathways involving the PVN are important for the water and sodium excretion, urine and sodium excretion, and presser responses, induced by angiotensinergic activation of the MSA. (C) 2001 Elsevier B.V.

Effects of angiotensin and vasopressin V-1 receptors on water and sodium intake induced by injection of vasopressin into lateral septal area

The specific arginine(8)-vasopressin (AVP) V, receptors antagonist (AAVP) was injected (20, 40 and 80 nmol) into the lateral septal area (LSA) to determine the effects of selective septal V, receptor on water and 3% sodium intake in rats. Was also observed the effects of losartan and CGP42112A (select ligands of the AT(1) and AT(2) ANG II receptors, respectively) injected into LSA prior AVP on the same appetites. Twenty-four hours before the experiments, the rats were deprived of water. The volume of drug solution injected was 0.5 mul. Water and sodium intake were measured at 0.25, 0.5, 1.0 and 2,0 h. Injection of AVP reduced the water and sodium ingestion vs. control (0.15 M saline). Pre-treatment with AAVP (40, 80 and 160 nmol) did not alter the decrease in the water ingestion induced by AVP, whereas AAVP abolished the action of AVP-induced sodium intake. Losartan (40, 80 and 160 nmol) did not alter the effect of AVP on water and sodium intake, whereas CGP42112A (20, 40 and 60 nmol) at the first 30 min increased water ingestion. Losartan and CGP42112A together increased the actions of AVP, showing more pronounced effects than when the two antagonists were injected alone. The results showed that AVP inhibited the appetites and these effects were increased by the AAVP. The involvement of angiotensinergic receptors in the effects of AVP is also suggested. (C) 2004 Elsevier B.V. All rights reserved.

Lipopolysaccharide reduces sodium intake and sodium excretion in dehydrated rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)