Cholecystokinin actions in the parabrachial nucleus: effects on thirst and salt appetite

The present study investigated the effects of bilateral injections of the nonselective CCK receptor antagonist proglumide or CCK-8 into the lateral parabrachial nuclei (LPBN) on the ingestion of 0.3 M NaCl and water induced by intracerebroventricular injection of ANG II or by a combined treatment with subcutaneous furosemide (Furo) + captopril (Cap). Compared with the injection of saline (vehicle), bilateral LPBN injections of proglumide (50 mu g . 200 nl(-1). site(-1)) increased the intake of 0.3 ill NaCl induced by intracerebroventricular ANG II (50 ng/1 mu l). Bilateral injections of proglumide into the LPBN also increased ANG II-induced water intake when NaCl was simultaneously available, but not when only water was present. Similarly, the ingestion of 0.3 M NaCl and water induced by the treatment with Furo (10 mg/kg) + Cap (5 mg/kg) was increased by bilateral LPBN proglumide pretreatment. Bilateral CCK-8 (0.5 mu g . 200 nl(-1). site(-1)) injections into the LPBN did not change Furo + Cap-induced 0.3 M NaCl intake but reduced water consumption. When only water was available after intracerebroventricular ANG II, bilateral LPBN injections of proglumide or CCK-8 had no effect or significantly reduced water intake compared with LPBN vehicle-treated rats. Taken together, these results suggest that CCK actions in the LPBN play a modulatory role on the control of NaCl and water intake induced by experimental treatments that induce hypovolemia and/or hypotension or that mimic those states.

LATERAL PARABRACHIAL SEROTONERGIC MECHANISMS - ANGIOTENSIN-INDUCED PRESSOR AND DRINKING RESPONSES

This study investigated the effects of bilateral injections of serotonergic receptor ligands into the lateral parabrachial nucleus (LPBN) on the presser and dipsogenic responses induced by intracerebroventricular (icv) injection of angiotensin II (ANG II). Rats with stainless steel cannulas implanted bilaterally into the LPBN and into the left lateral ventricle were used to study icy ANG II-induced water intake and presser responses. Pretreatment with the serotonergic 5-HT1/5-HT2 receptor antagonist methysergide (1-8 mu g/200 nl) bilaterally injected into the LPBN increased the water intake induced by icv ANG II (50 ng/mu l) administered via the lateral ventricle, but pretreatment with methysergide (4 mu g/200 nl) did not change the presser response produced by icy ANG II. After bilateral injection of either serotonin (5-HT, 5 mu g/200 nl) or the serotonergic 5-HT2a/5-HT2c receptor agonist (+/-)-2,5-dimetoxy-4-iodoamphetamine hydrochloride (DOI; 0.5-10 mu g/200 nl) into the LPBN, the water intake induced by ANG II was significantly reduced. These results are consistent with other observations indicating that the LPBN is associated with inhibitory mechanisms controlling water intake induced by ANG II treatment and suggest that serotonergic pathways may be involved in this effect.

DIFFERENT EFFECTS ON RAT ARTERIAL-PRESSURE AND HEART-RATE WHEN LOSARTAN IS INJECTED INTO THE 3RD-VENTRICLE OR 4TH-VENTRICLE

Cardiovascular responses to central losartan (LOS), a non-peptide angiotensin II (ANG II) receptor antagonist, were investigated by comparing the effects of LOS injection into the 3rd and 4th cerebral ventricles (3rdV, 4thV) on mean arterial pressure (MAP) and heart rate (HR). Adult male Holtzman rats were used (N = 6 animals per group). Average basal MAP and HR were 114 +/- 3 mmHg and 343 +/- 9 bpm (N = 23), respectively. LOS (50, 100 or 200 nmol/2 mu l) injected into the 3rdV induced presser (peak of 25 +/- 3 mmHg) and tachycardic (peak of 60 +/- 25 bpm) responses. LOS injected into the 4thV had no effect on MAP, but it induced bradycardia (peak of -35 +/- 15 bpm). KCl (200 nmol/2 mu l) injected into the 3rdV or into the 4thV had no effect on either MAP or HR compared to 0.9% saline injection. The results indicate that LOS injected into the third ventricle acts on forebrain structures to induce its presser and tachycardic effects and that bradycardia, likely dependent on hindbrain structures, is obtained when LOS is injected into the fourth ventricle.

Endothelial dysfunction in DOCA-salt hypertension - Possible involvement of prostaglandin endoperoxides

The effects of the arachidonic acid metabolism inhibitors on the acetylcholine responses of aortae from control (CR) and deoxycorticosterone acetate (DOCA)-salt hypertensive (HR) rats were investigated. The acetylcholine decreased response observed in HR [relaxation (%): CR 95.5 +/- 2.7, n = 4; HR 52.0 +/- 6.3, n = 5, p < 0.05] was restored by the cyclooxygenase inhibitor piroxicam [relaxation (%): CR 99.8 +/- 0.2, n = 4; HR 86.0 +/- 4.0, n = 5] and by the thromboxane synthetase inhibitor and the thrombox ane A(2)/prostaglandin H-2 receptor antagonist ridogrel [relaxation (%): CR 92.1 +/- 4.4, n = 7; HR 93.1 +/- 2.0, n = 7] but not by the inhibitors of thromboxane synthetase, prostacyclin synthetase, cytochrome P-450 monooxygenase, and lipoxygenase. So, endoperoxide intermediates seem to be involved in the decreased endothelium-dependent relaxation to acetylcholine in DOCA-salt hypertension. (C) 1999 Elsevier B.V. All rights reserved.

The antiepileptic activity of JSTX-3 is mediated by N-methyl-D-aspartate receptors in human hippocampal neurons

We analyzed the effect of the acylpolyaminetoxin JSTX-3 on the epileptogenic discharges induced by perfusion of human hippocampal slices with artificial cerebrospinal fluid lacking Mg2+ or N-methyl-D-aspartate. Hippocampi were surgically removed from patients with refractory medial temporal lobe epilepsy, sliced in the surgical room and taken to the laboratory immersed in normal artificial cerebrospinal fluid. Epileptiform activity was induced by perfusion with Mg2+-free artificial cerebrospinal fluid or by iontophoretically applied N-methyl-D-aspartate and intracellular and field recordings of CAI neurons were performed. The ictal-like discharges induced by Mg2+-free artificial cerebrospinal fluid and N-methyl-D-aspartate were blocked by incubation with JSTX-3. This effect was similar to that obtained with the N-methyl-D-aspartate receptor antagonist DL(-)2-amino-5 phosphonovaleric acid. Our findings suggest that in human hippocampal neurons, the antiepileptic effect of JSTX-3 is mediated by its action on N-methyl-D-aspartate receptor.

Lateral parabrachial nucleus serotonergic mechanisms and salt appetite induced by sodium depletion

This study investigated the effects of bilateral injections of a serotonin (5-HT) receptor agonist into the lateral parabrachial nucleus (LPBN) on the intake of NaCl and water induced by 24-h water deprivation or by sodium depletion followed by 24 h of sodium deprivation (injection of the diuretic furosemide plus 24 h of sodium-deficient diet). Rats had stainless steel cannulas implanted bilaterally into the LPBN. Bilateral LPBN injections of the serotonergic 5-HT1/2 receptor antagonist methysergide (4 mu g/200 nl at each site) increased hypertonic NaCl intake when tested 24 h after sodium depletion and after 24 h of water deprivation. Water intake also increased after bilateral injections of methysergide into the LPBN. In contrast, the intake of a palatable solution (0.06 M sucrose) under body fluid-replete conditions was not changed after bilateral LPBN methysergide injections. The results show that serotonergic mechanisms in the LPBN modulate water and sodium intake induced by volume depletion and sodium loss. The finding that sucrose intake was not affected by LPBN serotonergic blockade suggests that the effects of the methysergide treatment on the intakes of water and NaCl are not due to a mechanism producing a nonspecific enhancement of all ingestive behaviors.

Central moxonidine on water and NaCl intake

In this study we investigated: (a) the effects of intracerebroventricular (i.c.v.) injections of moxonidine (an alpha(2)-adrenergic and imidazoline receptor agonist) on the ingestion of water and NaCl induced by 24 h of water deprivation; (b) the effects of i.c.v. injection of moxonidine on central angiotensin II (ANG II)- and carbachol-induced water intake; (c) the effects of the pre-treatment with i.c.v, idazoxan (an alpha(2)-adrenergic and imidazoline receptor antagonist) and RX 821002 (a selective alpha(2)-adrenergic antagonist) on the antidipsogenic action of central moxonidine. Male Holtzman rats had stainless steel cannulas implanted in the lateral cerebral ventricle. Intracerebroventricular injection of moxonidine (5 and 20 nmol/1 mu l) reduced the ingestion of 1.5% NaCl solution (4.1 +/- 1.1 and 2.9 +/- 2.5 ml/2 h, respectively vs. control = 7.4 +/- 2.1 ml/2 h) and water intake (2.0 +/- 0.6 and 0.3 +/- 0.2 ml/h, respectively vs. control = 13.0 +/- 1.4 ml/h) induced by water deprivation, Intracerebroventricular moxonidine (5 nmol/1 mu l) also reduced i.c.v. ANG Ii-induced water intake (2.8 +/- 0.9 vs. control = 7.9 +/- 1.7 ml/1 h) and i.c.v. moxonidine (10 and 20 nmol/1 mu l) reduced i.c.v. carbachol-induced water intake (4.3 +/- 1.7 and 2.1 +/- 0.9, respectively vs. control = 9.2 +/- 1.0 ml/1 h). The pre-treatment with i.c.v. idazoxan (40 to 320 nmol/1 mu l) abolished the inhibitory effect of i.c.v, moxonidine on carbachol-induced water intake. Intracerebroventricular idazoxan (320 nmol/1 mu l) partially reduced the inhibitory effect of moxonidine on water deprivation-induced water intake and produced only a tendency to reduce the antidipsogenic effect of moxonidine on ANG Ii-induced water intake. RX 821002 (80 and 160 nmol/1 mu l) completely abolished the antidipsogenic action of moxonidine on ANG Ii-induced water intake. The results show that central injections c: moxonidine strongly inhibit water and NaCl ingestion. They also suggest the involvement of central alpha(2)-adrenergic receptors in the antidipsogenic action of moxonidine. (C) 1999 Elsevier B.V.

Forebrain angiotensin type 1 receptors and parabrachial serotonin in the control of NaCl and water intake

This study investigated the roles of serotonin (5-HT) receptors in the lateral parabrachial nucleus (LPBN), and brain angiotensin type 1 (AT(1)) receptors in the intake of 0.3 M NaCl and water induced by angiotensin II (ANG II). Rats were implanted with stainless steel cannulas for injections into tho subfornical organ (SFO) and into the LPBN. Bilateral LPBN pretreatment with the nonselective serotonergic 5-HT1/5-HT2 receptor antagonist methysergide (4 mu g/200 nl) markedly enhanced 0.3 M NaCl intake induced by injections of ANG II (20 ng/200 nl) into the SFO. Pretreatment of the SFO with the AT(1) receptor antagonist losartan (1 mu g/200 nl) blocked the intake of 0.3 M NaCl induced by ANG II in combination with LPBN methysergide injections. These results suggest that serotonergic mechanisms associated with the LPBN inhibit the expression of salt appetite induced by ANG II injections into Ihs SFO. In addition, the results indicate that the enhanced NaCl intake generated by central administration of ANG II in the presence of LPBN 5-HT blockade is mediated bg brain ATI receptors.

Hindbrain serotonin and the rapid induction of sodium appetite

Both systemically administered furosemide and isoproterenol produce water intake (i.e., thirst). Curiously, however, in light of the endocrine and hemodynamic effects produced by these treatments, they are remarkably ineffective in eliciting intake of hypertonic saline solutions (i.e., operationally defined as sodium appetite). Recent work indicates that bilateral injections of the serotonin receptor antagonist methysergide into the lateral parabrachial nuclei (LPBN) markedly enhance a preexisting sodium appetite. The present studies establish that a de novo sodium appetite can be induced with LPBN-methysergide treatment under experimental conditions in which only water is typically ingested. The effects of bilateral LPBN injections of methysergide were studied on the intake of water and 0.3 M NaCl following acute (beginning 1 h after treatment) diuretic (furosemide)-induced sodium and water depletion and following subcutaneous isoproterenol treatment. With vehicle injected into the LPBN, furosemide treatment and isoproterenol injection both caused water drinking but essentially no intake of hypertonic saline. In contrast, bilateral treatment of the LPBN with methysergide induced the intake of 0.3 M NaCl after subcutaneous furosemide and isoproterenol. Water intake induced by subcutaneous furosemide or isoproterenol was not changed by LPBN-methysergide injections. The results indicate that blockade of LPBN-serotonin receptors produces a marked intake of hypertonic NaCl (i.e., a de novo sodium appetite) after furosemide treatment as well as subcutaneous isoproterenol.

5-HT1A, but not 5-HT2 and 5-HT7, receptors in the nucleus raphe magnus modulate hypoxia-induced hyperpnoea

Aim: In the present study, we assessed the role of 5-hydroxytryptamine (5-HT) receptors (5-HT1A, 5-HT2 and 5-HT7) in the nucleus raphe magnus (NRM) on the ventilatory and thermoregulatory responses to hypoxia.Methods: To this end, pulmonary ventilation (V-E) and body temperature (T-b) of male Wistar rats were measured in conscious rats, before and after a 0.1 mu L microinjection of WAY-100635 (5-HT1A receptor antagonist, 3 mu g 0.1 mu L-1, 56 mM), ketanserin (5-HT2 receptor antagonist, 2 mu g 0.1 mu L-1, 36 mM) and SB269970 (5-HT7 receptor antagonist, 4 mu g 0.1 mu L-1, 103 mM) into the NRM, followed by 60 min of severe hypoxia exposure (7% O-2).Results: Intra-NMR microinjection of vehicle (control rats) or 5-HT antagonists did not affect V-E or T-b during normoxic conditions. Exposure of rats to 7% O-2 evoked a typical hypoxia-induced anapyrexia after vehicle microinjections, which was not affected by microinjection of WAY-100635, SB269970 or ketanserin. The hypoxia-induced hyperpnoea was not affected by SB269970 and ketanserin intra-NMR. However, the treatment with WAY-100635 intra-NRM attenuated the hypoxia-induced hyperpnoea.Conclusion: These data suggest that 5-HT acting on 5-HT1A receptors in the NRM increases the hypoxic ventilatory response.

Contribution of the rostral ventromedial medulla to post-anxiety induced hyperalgesia

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Ionotropic Glutamate Receptors in Hypothalamic Paraventricular and Supraoptic Nuclei Mediate Vasopressin and Oxytocin Release in Unanesthetized Rats

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

Different effects on rat arterial pressure and heart rate when losartan is injected into the third or fourth ventricle

Cardiovascular responses to central losartan (LOS), a non-peptide angiotensin II (ANG II) receptor antagonist, were investigated by comparing the effects of LOS injection into the 3rd and 4th cerebral ventricles (3rdV, 4thV) on mean arterial pressure (MAP) and heart rate (HR). Adult male Holtzman rats were used (N=6 animals per group). Average basal MAP and HR were 114±3 mmHg and 343±9 bpm (N=23), respectively. LOS (50, 100 or 200 nmol/2 μl) injected into the 3rdV induced pressor (peak of 25±3 mmHg) and tachycardic (peak of 60±25 bpm) responses. LOS injected into the 4thV had no effect on MAP, but it induced bradycardia (peak of -35±15 bpm). KCl (200 nmol/2 μl) injected into the 3rdV or into the 4thV had no effect on either MAP or HR compared to 0.9% saline injection. The results indicate that LOS injected into the third ventricle acts on forebrain structures to induce its pressor and tachycardic effects and that bradycardia, likely dependent on hindbrain structures, is obtained when LOS is injected into the fourth ventricle.

Effects of intracerebroventricular injections of losartan or PD123319 on arterial pressure and heart rate of sodium replete and sodium deplete rats

Angiotensin II (Ang II) non-peptide antagonists were injected i.c.v. (6.25-200 nmol, n = 5-8 rats/group): In sodium replete rats, losartan (AT1 receptor antagonist) induced an increase in mean arterial pressure (MAP) and in heart rate (HR) by 3rd ventricular (3rdV) injection, and a weaker pressor response and bradycardia by 4th ventricular (4thV) injection. PD123319 (AT2 receptor antagonist) induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and no alteration in HR by 4thV injection. In sodium deplete (furosemide plus removal of ambient sodium for 24 h) rats, losartan induced an increase in MAP and no alteration in HR by 3rdV injection, and no alteration in MAP and bradycardia by 4thV injection. PD123319 induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and bradycardia by 4thV injection. Thus, there was no fall in MAP by central injections of Ang II antagonists. Intravenous injection of losartan, but not of PD123319, induced a fall in MAP in both sodium replete and sodium deplete animals. Therefore, losartan and PD123319 can have similar effects on MAP and HR when injected intracerebroventricularly, although some differences are also present. The bradycardia is consistent with an withdrawal of Ang II inhibitory action on baroreflex.

On a dual role for clonidine stimulation of the ventromedial nucleus of the hypothalamus in sodium and potassium renal excretions of rats

The effects of clonidine on sodium and potassium excretions were examined after previous administration of prazosin (an α 1-adrenergic receptor antagonist) and yohimbine (an α 2-adrenergic receptor antagonist) into the ventromedial nucleus of the hypothalamus of conscious rats. Clonidine injected into the ventromedial nucleus of the hypothalamus induced inhibitory and facilitatory effects on the urinary sodium and potassium excretions. The results suggest that facilitatory effects of clonidine on natriuresis and kaliuresis are mediated through activation of α 1-adrenoceptors and that inhibitory effects require α(2A)-adrenoceptors.