Effect of naloxone on somatostatin inhibition of arginine vasopressin response to physical exercise in normal men

To establish whether somatostatin (SRIH) and/or endogenous opioids play a role in the control of arginine-vasopressin (AVP) response to physical exercise, eight healthy men underwent four bicycle-ergometer tests until exhaustion: exercise control test; exercise plus SRIH, naloxone or SRIH plus naloxone. Serum AVP levels, physiological and biochemical variables were measured during tests. Physiological and biochemical variables were similar in all tests. During control test exercise significantly increased serum AVP levels, with a peak value 4.1 times higher than baseline. The AVP response to exercise was similar in the presence of naloxone, whereas it was significantly reduced by SRIH (AVP peak was only 2.8 times higher than baseline). When SRIH and naloxone were given together, the exercise-induced AVP rise was comparable to that observed in the control test. Results indicate a somatostatinergic involvement in the regulation of the AVP response to physical exercise. Furthermore, naloxone-sensitive endogenous opioids appear to play a role in the mechanism underlying SRIH inhibitory action, but not in mediation of the AVP response to physical exercise.     

Depletion of central catecholamines reduces pressor responses to arginine vasopressin

Previous reports that central administration of arginine vasopressin (AVP) increases turnover of brain catecholamines raise the possibility that the pressor responses which follow central administration of AVP may be mediated, in part, by central catecholamines. To test this hypothesis, rats were given intraventricular injections of vehicle, or of the neurotoxin, 6-hydroxydopamine, which resulted in significant depletions of hypothalamic and medulla oblongata noradrenalin and hypothalamic dopamine, but not of medullary dopamine or of hypothalamic and medullary 5-hydroxytryptamine. Following a one week recovery, these conscious rats, fitted with indwelling arterial catheters, were given intraventricular injections of AVP; the increases in arterial pressure and heart rate were significantly reduced in the catecholamine-depleted animals. These data support the hypothesis that the pressor and tachycardia responses to intraventricular AVP are mediated, in part, by central catecholamine-containing neurons.     

Effects of intravenous infusion of substance P on arginine vasopressin and oxytocin secretion in normal men.

In order to establish possible stimulatory effects of increasing plasma concentrations of substance P (SP) on the arginine vasopressin (AVP) and/or oxytocin (OT) secretion, successively increasing doses of SP(0.5, 1 and 1.5 pmol/kg-1/min-1; each dose for 20 min) were infused in 7 normal men. Plasma AVP and OT levels were measured before infusion and every 20 min, just before increasing the infusion dose of SP. During tests, SP infusion did not produce untoward side effects or changes in blood osmolality and/or pressure. Plasma OT levels did not change during SP infusion. Plasma AVP concentrations were not modified by the infusion of the lowest dose of SP, whereas they were significantly increased in a dose response fashion when higher amounts of SP were given. These findings demonstrate for the first time in humans that the systemic administration of SP exerts stimulatory effects on AVP, but not on OT secretion.     

Role of arginine vasopressin and corticotropin-releasing factor in mediating alcohol-induced adrenocorticotropin and vasopressin secretion in male rats bearing lesions of the paraventricular nuclei

In male rats, lesions of the paraventricular nucleus (PVN) of the hypothalamus attenuate, but do not abolish, adrenocorticotropin (ACTH) secretion in response to acute alcohol injection. As the PVN is the major source of corticotropin-releasing factor (CRF) in the median eminence, this observation suggests that extra-PVN brain regions, and/or ACTH secretagogues other than CRF (e.g. arginine vasopressin (AVP)), mediate ACTH stimulation by alcohol. This hypothesis was tested by examining the effect of AVP immunoneutralization in PVN-lesioned (PVNx) rats. Removal of endogenous AVP diminished alcohol-evoked ACTH secretion in both sham-operated and PVNx animals, indicating that AVP from outside the PVN partially mediates the hypothalamic-pituitary-adrenal (HPA) axis response to alcohol. This led us to determine whether alcohol might also regulate AVP steady-state gene expression in the supraoptic nucleus (SON) and PVN, and/or CRF mRNA in the PVN and the central nucleus of the amygdala (AMY). In the magnocellular portion of the PVN, sham-operated animals showed significantly increased PVN levels of both CRF and AVP mRNAs 3 h after alcohol. In the SON, alcohol administration tended to decrease AVP gene expression in PVNx rats, while the drug increased AVP mRNA levels in the SON of sham-operated rats. AMY levels of CRF mRNA were unaffected by these manipulations. Finally, since the regulation of alcohol-induced AVP mRNA levels in the SON appeared to depend on the presence of the PVN, we measured peripheral levels of AVP in both sham-operated and PVNx animals after injection of vehicle or alcohol. Although AVP decreased in all groups, alcohol depressed AVP secretion to a greater extent in PVNx animals, suggesting that AVP systems are more sensitive to inhibition in the absence of the PVN. Our results demonstrate that although AVP of PVN origin may participate in regulating the stimulatory effect to AVP on ACTH secretion, AVP from areas other than the PVN also plays a role. Additionally, regulation of both AVP gene expression in the SON and secretion in the systemic circulation are altered in rats bearing lesions of the PVN.     

Reversible parkinsonism with normal beta-CIT-SPECT in patients exposed to sodium valproate

After reports of reversible parkinsonism and cognitive impairment with sodium valproate (VPA), the authors examined 50 consecutive patients taking VPA and 20 patients taking carbamazepine. Three patients taking VPA exhibited unequivocal parkinsonism with Unified Parkinson Disease Rating Scale scores >30. VPA was withdrawn from two patients with improvement of symptoms. Reduction in VPA dosage in the third patient produced no improvement. beta-CIT-SPECT scans were normal, suggesting dopaminergic neuronal loss is not the underlying mechanism.     

The effectiveness of arginine vasopressin and sodium salicylate as antipyretics in the Brattleboro rat

The infusion of either 30 micrograms/microliters (approx. 100 micrograms/kg/h) of sodium salicylate or 10 ng/microliters (10(-5) M) arginine vasopressin within the ventral septal area of the Brattleboro rat brain reduced a centrally induced prostaglandin E1 (PGE1) hyperthermia when compared with infusions of artificial cerebrospinal fluid. Conversely, the infusion of a related peptide, oxytocin (10 ng/microliters (10(-5) M), or 33 ng/kg/h) failed to alter the rise in core temperature following the PGE1 injection. These results suggest that the vasopressin receptors reported to be present in the Brattleboro rat may respond normally to exogenously administered vasopressin, thus allowing for the antipyretic action. Moreover, the antipyretic effects of sodium salicylate suggest that aspirin-like drugs may induce the release of alpha-melanocyte-stimulating hormone which, in turn, attenuates the PGE1-evoked fever. Given recent evidence, however, which suggests that the Brattleboro rat may contain vasopressin both peripherally and within the brain, the antipyretic action of sodium salicylate may be alternatively explained through the endogenous release of vasopressin.     

Localization of angiotensin-converting enzyme, angiotensin II, angiotensin II receptor subtypes, and vasopressin in the mouse hypothalamus

The hypothalamic angiotensin II (Ang II) system plays an important role in pituitary hormone release. Little is known about this system in the mouse brain. We studied the distribution of angiotensin-converting-enzyme (ACE), Ang II, Ang II receptor subtypes, and vasopressin in the hypothalamus of adult male mice. Autoradiography of binding of the ACE inhibitor [¹²⁵I]351A revealed low levels of ACE throughout the hypothalamus. Ang II- and vasopressin-immunoreactive neurons and fibers were detected in the paraventricular, accessory magnocellulary, and supraoptic nuclei, in the retrochiasmatic part of the supraoptic nucleus and in the median eminence. Autoradiography of Ang II receptors was performed using [¹²⁵I]Sar¹–Ang II binding. Ang II receptors were present in the paraventricular, suprachiasmatic, arcuate and dorsomedial nuclei, and in the median eminence. In all areas [¹²⁵I]Sar¹–Ang II binding was displaced by the AT₁ receptor antagonist losartan, indicating the presence of AT₁ receptors. In the paraventricular nucleus [¹²⁵I]Sar¹–Ang II binding was displaced by Ang II (K_i=7.6×10⁻⁹) and losartan (K_i=1.4×10⁻⁷) but also by the AT₂ receptor ligand PD 123319 (K_i=5.0×10⁻⁷). In addition, a low amount of AT₂ receptor binding was detected in the paraventricular nucleus using [¹²⁵I]CGP 42112 as radioligand, and the binding was displaced by Ang II (K_i=2.4×10⁻⁹), CGP 42112 (K_i=7.9×10⁻¹⁰), and PD 123319 (K_i=2.2×10⁻⁷). ACE, Ang II, and AT₁ as well as AT₂ receptor subtypes are present in the mouse hypothalamus. Our data are the basis for further studies on the mouse brain Ang II system.     

Excitotoxic lesions of the ventral anteroventral third ventricle and pressor responses to central sodium, ouabain and angiotensin II

To clarify the role of neurones in the anteroventral third ventricle (AV3V) area in cardiovascular responses to CSF sodium, ouabain and angiotensin II (ANG II), we employed excitotoxic lesions of the ventral AV3V (vAV3V). In conscious lesioned Wistar rats with systemic vasopressin blockade, pressor and tachycardiac responses to intracerebroventricular (i.c.v.) artificial CSF containing 0.3 M NaCl or ouabain were significantly attenuated by 26–32% whereas responses to ANG II were not affected. Thus, in rats with systemic blockade of vasopressin mechanisms, the vAV3V region partially mediates acute pressor responses to i.c.v. sodium and ouabain but not to ANG II.     

Aldosterone responses to angiotensin II in anorexia nervosa.

Patients with anorexia nervosa (AN) tend to have renin-angiotensin-aldosterone (RAA) abnormalities caused by abnormal behaviors such as strict dieting, fasting, vigorous exercise, self-induced vomiting and abuse of laxatives and/or diuretics. Adrenal responsiveness to angiotensin II (A II) was studied in 13 AN patients before and after therapy and in 6 normal sex- and age-matched controls: adrenal responses to postural change (1 h of walking following 1 h in a supine position) and to exogenous A II injection (A II: 10 ng/kg/min intravenous infusion for 30 min). The 24-h urine sodium concentration was significantly lower in AN patients before therapy than after therapy. Plasma aldosterone secretory response to A II was significantly higher in AN patients before therapy in both postural change and exogenous A II injection tests compared with after therapy response and that of controls. On the other hand, there was no significant difference in adrenal response to postural change or to exogenous A II between AN patients after therapy and controls. In conclusion, increased A II sensitivity caused by chronic sodium deficiency in AN patients normalized over time as the patients recovered.     

The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin.

Angiotensin II (Ang II) given centrally produces an increase in blood pressure and motivation to drink. The physiological mechanisms that mediate the pressor response include release of vasopressin (AVP) and activation of the sympathetic nervous system. Using 2 new Ang II receptor antagonists, we were able to investigate the role of AT1 or AT2 receptors in mediating these effects. Adult male Sprague-Dawley rats were cannulated in the lateral ventricle and 5 days later catheterized in the carotid artery for blood pressure measurements. All experiments were carried out in conscious rats. Three treatments were given intraventricularly (i.v.t.), in 2 microliters artificial cerebrospinal fluid (ACSF) at 30 min intervals: (1) 50 ng Ang II, (2) 0.7 micrograms AT1 antagonist Losartan or 7.0 micrograms AT2 antagonist PD123177, followed by 50 ng Ang II, and (3) 50 ng Ang II, to test for recovery. Blood pressure and drinking measurements were recorded. Also, blood samples for assay of AVP were drawn at 1 or 3 min post-injection in 2 separate groups of rats. We found that both Losartan and PD123177 significantly reduced release of AVP to Ang II 1 min post-injection. Losartan significantly blocked the pressor response (P less than 0.001), while PD123177 had no significant effect. Drinking was also antagonized by Losartan (P less than 0.05) and reduced (n.s.) by PD123177. The results suggest that the pressor response to Ang II (i.v.t.) is predominantly AT1 mediated, while the drinking and AVP responses may be mediated by both receptor subtypes.     

Stimulation of area postrema by vasopressin and angiotensin II modulates neuronal activity in the nucleus tractus solitarius

There is an abundance of evidence suggesting that the area postrema (AP) is involved in the central actions of argininevasopressin (AVP) and angiotensin II (Ang II) on cardiovascular regulation. Furthermore, recent studies have shown that activation of the AP facililates the response of nucleus tractus solitarius (NTS) neurons to tractus stimulation. In the present study, using the perfused rabbit brain slice preparation, we examined the response of NTS neurons when AVP and Ang II were microinjected onto the AP. Spontaneous or solitary tract stimulation-induced neuronal activity was recorded extracellularly from the medial NTS before, during and after AVP or Ang II application. An increase or decrease in activity by more than 30% of the baseline value was considered excitatory or inhibitory. The effects of AVP were studied in 57 NTS cells, 14 of which were spontaneously active and 43 were driven by tract stimulation. Of the cells with evoked activity, 49% were excited, 19% were inhibited, and 32% did not respond. The percentage of cells responding to AVP was similar in spontaneously active cells. The effects of Ang II were tested in 85 cells including 54 with evoked activity and 31 with spontaneous activity. In NTS cells with evoked activity, AP application of Ang II caused inhibition in 37%, excitation in 7%, while 56% did not respond. The proportion of cells responding to Ang II was similar in spontaneously active cells. These results suggest that AVP may act on the AP to increase the excitatory response of NTS neurons while the actions of Ang II result in an inhibitory influence.     

Differential prolactin responses to Haloperidol and TRH in normal adult men

(1) Prolactin (PRL) responses to low dose intravenous (i.v.) haloperidol differed among individuals, but PRL responses to 25 μg and 500 μg i.v. thyrotropin-releasing hormone (TRH) in the same subjects were similar. (2) Serum concentrations of haloperidol accounted for only 36% of the variability in PRL response. (3) It is concluded that the inter-individual variability in PRL response to haloperidol does not result from differences in pituitary PRL-secreting capacity, nor can it be attributed in a major way to differences in drug metabolism. It is proposed that the variable PRL responses to haloperidol reflect individual differences in dopamine receptor sensitivity to blockade by this drug.     

Influence of arginine vasopressin receptors and angiotensin receptor subtypes on the water intake and arterial blood pressure induced by vasopressin injected into the lateral septal area of the rat

In this study we investigated the influence of d(CH2)5-Tyr(Me)-[Arg8]vasopressin (AAVP) and [adamanteanacetyl1,0-ET-d-Tyr2,Val4,aminobutyryl6,Arg8,9]-[Arg8]vasopressin (ATAVP), which are antagonists of vasopressin V1 and V2 receptors, and the effects of losartan, a selective angiotensin AT1 receptor antagonist, and CGP42112A, a selective AT2 receptor antagonist, injected into the lateral septal area (LSA) on thirst and hypertension induced by [Arg8]vasopressin (AVP). AAVP and ATAVP injected into the LSA reduced the drinking responses elicited by injecting AVP into the LSA. Both the AT1 and AT2 ligands administered into the LSA elicited a concentration-dependent decrease in the water intake induced by AVP injected into the LSA, but losartan was more effective than CGP42112A. The increase in MAP, due to injection of AVP into the LSA, was reduced by prior injection of AAVP from 18 +/- 1 to 6 +/- 1 mm Hg. Losartan injected into the LSA prior to AVP reduced the increase in MAP to 7 +/- 0.8 mm Hg. ATAVP and CGP42112A produced no changes in the pressor effect of AVP. These results suggest that the dipsogenic effects induced by injecting AVP into the LSA were mediated primarily by AT1 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 AVP and angiotensin II receptor subtypes. The pressor response of AVP was reduced by losartan and by AAVP. CGP42112A and ATAVP did not change the AVP pressor response. These results suggest that facilitator effects of AVP on water intake are mediated through the activation of V1 receptors and that the inhibitory effect requires V2 receptors. The involvement of AT1 and AT2 receptors can be postulated. Based on the present findings, we suggest that the AVP in the LSA may play a role in the control of water and arterial blood pressure balance.     

A direct comparison of the rat and bovine arginine vasopressin/neurophysin II common precursor

Translation of polyA+ RNA from rat hypothalami in a reticulocyte lysate system yields a 19 000 dalton (19k) preproform which reacts with antibodies against bovine neurophysin II (Np II) and arginine vasopressin (AVP). Co-translational addition of canine microsomal membranes gives rise to a glycosylated 22 000 (22k) proform which co-migrates with an $\text{AVP}\text{Np II}$ common precursor extracted from rat hypothalamus. These rat precursors correspond to those obtained by translation of bovine mRNA except that the latter have molecular weights of 21 000 (21k) and 23 000 (23k), respectively (Schmale and Richter, 1981). Also as in the bovine system a second precursor with a molecular weight of 16 000 (16k) is synthesized from rat mRNA which reacts with anti Np II but not with anti AVP.     

Blood-borne angiotensin II acts in the brain to influence behavioral and endocrine responses to psychogenic stress

This study elucidates the neural circuits by which circulating angiotensin II (ANGII) acts in the brain to influence humoral and behavioral responses to psychological stressors. To test the hypothesis that systemic ANGII mediates stress responding via the subfornical organ (SFO), we first found that the timing of increased systemic ANGII in response to 60 min restraint coincides with increased c-fos mRNA expression in the SFO. Next, we administered an anterograde neuronal tract tracer into the SFO and found that fibers originating there make appositions onto neurons in the paraventricular nucleus of the hypothalamus that are also c-fos positive following restraint stress. To determine whether circulating ANGII stimulates the release of stress hormones via activation of angiotensin type 1 receptors (AT1R) within the SFO, we delivered lentivirus to knockdown AT1R expression locally in the SFO. Inhibition of AT1R specifically within the SFO blunted the release of adrenocorticotrophin-releasing hormone and corticosterone in response to restraint stress and caused rats to spend more time in the open arms of an elevated-plus maze than controls, indicating that inhibition of AT1R within the SFO is anxiolytic. Collectively, these results suggest that circulating ANGII acts on AT1R in the SFO to influence responding to psychological stressors.     

Evaluation for roles of periventricular cholinoceptors in vasopressin secretion in response to angiotensin II and an osmotic stimulus

In conscious rats, intracerebroventricular (i.c.v.) injections (10 microliters) of carbachol (1.4 nmol), angiotensin II (AII; 48.2 pmol) or a hypertonic solution (990 mOsm/kg) produced increases of plasma vasopressin (AVP) and arterial pressure. The effects of carbachol were inhibited not by a nicotinic cholinergic blocker hexamethonium (28 nmol), but by a muscarinic cholinergic blocker atropine (28 nmol). However, neither hexamethonium nor atropine affected the AVP and pressor responses to AII or the hypertonic solution. We concluded that periventricular cholinoceptors may not be involved in the central actions of AII and hypertonicity on AVP release and blood pressure.     

Responses of adrenocorticotropin and vasopressin to hemorrhage after lesions of the caudal ventrolateral medulla in rats

Hormonal responses to hemorrhage were examined in urethane-anesthetized rats 48 h after electrolytic lesions of the caudal ventrolateral medulla. Bilateral A1-lesions (A1X) inhibited the response of plasma adrenocorticotropin relative either to other lesions (XX) or to sham lesions. A1X inhibited the response of plasma vasopressin relative to XX but not to sham lesions. A1X and XX destroyed similar areas that were dorsal or caudal to A1. No lesion blocked either response completely. A hemodynamic pathway controlling the release of both hormones may pass through A1. However, other pathways may bypass this area.     

Diurnal growth hormone responses to dextroamphetamine in normal young men and postmenopausal women

(1) D-amphetamine stimulates growth hormone (GH) secretion, probably through its catecholaminergic effects. (2) In normal post-menopausal women we found the GH response to dextroamphetamine to be small and significantly less than that seen in young normal men. (3) In post-menopausal women but not in young men, the GH response to amphetamine was significantly higher in the evening than in the morning. (4) The reduced GH responses to dextroamphetamine in postmenopausal women may be due to sex difference, hypoestrogenism, or to reduced brain catecholamines associated with age. (5) The diurnal variation of the GH response to d-amphetamine in post-menopausal women may reflect a diurnal variation in hypothalamic nor-adrenergic activity higher in the evening, which was not masked by a reciprocal variation in estradiol levels.     

Effect of metergoline on the diurnal prolactin responses to insulin-induced hypoglycemia in normal men

(1) Insulin tolerance tests were performed at 0900 and 1800 hr on six young healthy men, under basal conditions and after metergoline pretreatment. (2) The hypoglycemia induced by insulin during the two tests was not significantly different. (3) Both morning and evening basal prolactin (PRL) levels were significantly lowered by metergoline. (4) Insulin hypoglycemia-induced PRL release was significantly inhibited by metergoline, both in the morning and in the evening. (5) Although dopaminergic mechanisms may account for these effects of metergoline, serotonergic mechanisms cannot be ruled out.     

A case of anorexia nervosa associated with epileptic seizures showing favorable responses to sodium valproate and clonazepam

We reported the case of a 13-year-old anorectic girl with epileptic seizures who showed marked favorable responses to sodium valproate and clonazepam. These two anticonvulsants were effective not only for controlling her epileptic seizures, but also against anorexia nervosa itself. The mechanism of their action to anorexia nervosa is unknown, but repeated EEGs and a trial of sodium valproate with or without clonazepam may be useful in evaluating the diverse pathologies of anorexia nervosa which seems to be a heterogeneous clinical entity.