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P Navarra

Publications and source records attributed to P Navarra.

At least 73 records · Page 4Linked to original sources
PubMed1994

Release of immunoreactive interleukin-1-alpha from rat hypothalamic explants is increased by bacterial lipopolysaccharide and high KCL concentrations.

It has previously been shown that interleukin (IL)-1-like bioactivity is released from rat hypothalamic explants in short-term incubations. Experiments conducted with antiserum against IL-1 alpha or IL-1 beta showed that IL-1 alpha is released more abundantly under basal conditions. For the present study, we developed a specific radioimmunoassay to investigate the release of immunoreactive (ir) IL-1 alpha from the rat hypothalamus in short-term experiments, and observed that release of irIL-1 alpha increased with time and was significantly increased by high KCL concentrations. The stimulatory effect of 28 mM KCL was significantly inhibited by verapamil. Subsequent investigation of the effects of putative modulators of IL-1 alpha secretion, bacterial lipopolysaccharide (LPS) and the prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha), showed that irIL-1 alpha release was stimulated by 100 ng/ml LPS, but not by higher concentrations, PGE2 had no effect and PGF2 alpha caused dose-dependent inhibition. However, the latter did not seem to exert a tonic inhibitory influence on irIL-1 alpha release, since blockade of cyclo-oxygenase activity by indomethacin had no effect on cytokine release under basal conditions. We conclude that LPS stimulates and PGF2 alpha inhibits basal release of hypothalamic IL-1 alpha, the characteristics of the secretion of which suggest that it may be, at least in part, of neuronal origin.

Animals↗
PubMed1994

Endothelin-1 stimulates the in vitro release of neurohypophyseal hormones, but not corticotropin-releasing hormone, via ETA receptors.

The endothelins consist of a family of vasoconstrictor peptides originally isolated from endothelial tissue which are now known to be involved in neuroendocrine regulation. However, while there are data indicating the involvement of endothelins in the modulation of the hypothalamo-pituitary-adrenal (HPA) axis, the precise mechanisms involved have been unclear. We have therefore used a previously validated rat hypothalamic explant system in order to investigate the possible modulation of the neurohypophyseal hormones vasopressin and oxytocin, and corticotropin-releasing hormone (CRH), by endothelin-1 (ET-1) and endothelin-3 (ET-3). Following a period of stabilisation, the release of vasopressin, oxytocin and CRH remained approximately constant in successive 20-min incubations. Addition of ET-1 stimulated the release of vasopressin at a dose of 0.1 nmol/l (p < 0.05), and both vasopressin and oxytocin at 10 nmol/l (p < 0.01 and 0.05, respectively). The release of vasopressin and oxytocin induced by 10 nmol/l ET-1 were both totally blocked by co-incubation with either 1 or 10 mumol/l of the specific ETA receptor subtype antagonist cyclo (D-Trp-D-Asp-Pro-D-Val-Leu) (BQ-123). ET-1 had no effect on CRH release in the dose range of 0.1-1,000 nmol/l. In case any possible stimulation of CRH might be masked by simultaneous generation of nitric oxide (NO), an inhibitor of CRH secretion, addition of ET-1 was also carried out in the presence of the NO synthase inhibitor, L-NO-Arg: ET-1 was again without effect in this dose range.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Carbon monoxide as a novel neuroendocrine modulator: inhibition of stimulated corticotropin-releasing hormone release from acute rat hypothalamic explants.

Although recent evidence suggests that the gas nitric oxide (NO) can modulate the secretion of corticotropin-releasing hormone (CRH) from acute rat hypothalamic explants, another gas, carbon monoxide (CO), has been suggested to play a role in neural signaling in the brain; CO may complement the activity of NO in long term potentiation. In this study, we have investigated whether CO shares with NO the ability to modify the release of CRH from the rat hypothalamus. Hemin, a specific CO precursor through the enzyme heme oxygenase (the enzymatic pathway synthesizing endogenous CO), was found to inhibit in a dose-dependent manner KCl-stimulated CRH release, with a maximal effect at 1 microM, while showing no effect on basal CRH secretion. The stimulation of CRH by interleukin-1 beta (100 ng/ml) was also significantly antagonized by hemin (1 microM). An inhibitor of heme oxygenase, zinc-protoporphyrin-9, had no effect on basal or stimulated CRH release up to a maximal dose of 10 microM. When hemin and zinc-protoporphyrin-9 were given together, the hemin-induced inhibition of CRH release was completely antagonized by the enzyme inhibitor. These findings provide evidence that endogenous CO may play a role in the control of CRH release; by analogy with NO, CO may represent a major new neuroendocrine modulator.

Animals↗
PubMed1994

Lipopolysaccharide modulation of eicosanoid and corticotrophin-releasing hormone release from rat hypothalamic explants and astrocyte cultures in vitro: evidence for the involvement of prostaglandin E2 but not prostaglandin F2 alpha and lack of effect of nerve growth factor.

Bacterial lipopolysaccharide (LPS) and prostaglandins (PG) E2 and F2 alpha are putative activators of the hypothalamo-pituitary-adrenal axis. Certain of the biological effects of LPS may be mediated by cytokines such as interleukin-1 beta (IL-1 beta), while IL-1 beta itself may operate via induction of the prostaglandins and/or nerve growth factor (NGF). As IL-1 beta stimulates the release of corticotrophin-releasing hormone (CRH) from acute rat hypothalamic explants directly, the effects of these substances on the release of CRH in vitro were investigated in short- and medium-term (20 and 60 min) incubations. The effect of LPS on the release of PGE2 and PGF2 alpha from these explants, as well as from cortical astrocyte cultures, was also studied. LPS did not modify the release of CRH, PGE2 or PGF2 alpha in 20-min incubations. In 60-min incubations, LPS stimulated the release of PGE2, whereas the release of CRH was weakly, but significantly, reduced; PGF2 alpha was not altered. PGE2 significantly stimulated CRH release in the 60-min but not in the 20-min experiments. This effect appeared to be selective for PGE2, since PGF2 alpha did not modify CRH release, alone or in combination. LPS also selectively released PGE2 but not PGF2 alpha from cortical astrocyte cultures after 24-h incubation. NGF had no effect on the release of explant CRH, regardless of the length of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Interleukin-1 alpha and tumour necrosis factor inhibit rat gastric fundus motility in vitro.

In this study, the effects of tumour necrosis factor (TNF) and interleukins 1 alpha and 6 (IL-1 alpha and IL-6) on rat gastric fundus motility were investigated in vitro. IL-1 alpha and TNF induced rapid dose-dependent inhibition of stomach motility, with maximal relaxation equal to that induced by 100 microM papaverin, and respective EC50s of 20 and 450 pg/ml. IL-6 had no effect on gastric motility up to a 3 ng/ml concentration.

Animals↗
PubMed1993

The regulation of hypothalamic corticotropin-releasing factor release: in vitro studies.

Although there are various ways in which the regulation of hypothalamic corticotropin-releasing factor (CRF) may be investigated, the most direct is by the study of CRF secretion from rat hypothalami incubated in vitro. Using this technique, we have found stimulation of secretion by noradrenaline, acetylcholine, serotonin, neuropeptide Y, and interleukins 1 and 6; inhibitory modulation was shown by GABA, substance P, atrial natriuretic peptide, opioid peptides and precursors of nitric oxide. Studies of these interactions demonstrated certain non-linear characteristics which may allow appropriate mathematical models to be devised; this may aid in our understanding of clinical disorders associated with CRF excess.

Animals↗
PubMed1993

Prostaglandin E2 and bacterial lipopolysaccharide stimulate bioactive interleukin-1 release from rat hypothalamic explants.

While interleukin-1 (IL-1) is intimately involved in locally modulating the acute inflammatory response, it is also able to influence processes at remote sites, i.e., in an endocrine manner. While there is as yet little evidence that IL-1 can cross the blood-brain barrier, many effects such as fever, increased slow-wave sleep, anorexia and the modulation of neuroendocrine function suggest an action of circulating IL-1 at regulatory sites within the hypothalamus. However, there is accumulating evidence for IL-1 originating within the central nervous system (CNS), and it is currently unclear as to whether the neurally mediated manifestations of the acute inflammatory response are due to activation of central or peripheral (circulating) IL-1. In this study we have characterized the release of IL-1 from rat hypothalamic explants, and we have investigated the effects of putative modulators of IL-1 release, lipopolysaccharide (LPS) and the prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha). After 1 h of incubation, IL-1-like activity in hypothalamic supernatants ranged between 175 and 2,304 munits/mg of protein; this was substantially inhibited by the addition to the bioassay system of antibodies (1:200) against IL-1 alpha, but not against IL-1 beta. LPS and PGE2 significantly stimulated IL-1 release at 100 and 1 ng/ml respectively, whereas PGF2 alpha had no effect in the range of doses tested. It is therefore concluded that the control of hypothalamic IL-1 release may be investigated by means of acute rat hypothalamic explants.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The effects of 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon.

In the present study, the emetic effect of the anticancer drug cisplatin, and the protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental set-up involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and the number of emetic episodes per vomiting animal. It was observed that cisplatin induced dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists afforded partial protection against cisplatin emesis, although some of them, i.e. indole, indole-like derivatives and zacopride, displayed intrinsic emetic activity. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (pCPA), prevented vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists provide pharmacological evidence of species differences in the properties of 5-HT3 receptors.

Animals↗
PubMed1992

A dual effect of some 5-HT3 receptor antagonists on cisplatin-induced emesis in the pigeon.

In the present study, the emetic effect of the anticancer drug cisplatin, and protective effects of 5-HT3 receptor antagonists against cisplatin emesis were investigated in the pigeon. The experimental setting involved the i.v. administration of drugs and subsequent observation of the percentage of vomiting animals and number of emetic episodes per vomiting animal over a period of 5 h. In some experiments, the 5-HT and 5-HIAA content in tissues was estimated by the HPLC technique. It was observed that cisplatin (2.5-10 mg/kg) is able to induce dose-dependent emesis in the pigeon. 5-HT3 receptor antagonists (500 micrograms/kg) afford partial protection against cisplatin emesis, although some of them, i.e. indolic derivatives and zacopride, display intrinsic emetic activity at doses of 50-500 micrograms/kg. A serotonergic mechanism appears to be involved in both cisplatin- and 5-HT3 receptor antagonist-induced emesis, since pretreatment with an inhibitor of 5-HT synthesis, para-chlorophenylalanine (300 mg/kg x 3 days), is able to hamper vomiting induced by either cisplatin or 5-HT3 receptor antagonists. It is concluded that the intrinsic emetic effects of 5-HT3 receptor antagonists in the pigeon provide pharmacological evidence of species differences in the properties of 5 HT3 receptors.

Animals↗
PubMed1992

The effects of (+/-)-idazoxan and its stereoisomers on mouse vas deferens motility in vitro. A comparison with yohimbine.

The effects of idazoxan (IDZ) and its stereoisomers were compared to that of a classical alpha 2-antagonist, yohimbine (YOH), on para-aminoclonidine (PAC)- and norepinephrine (NE)-mediated inhibition of the twitch response evoked in the mouse vas deferens by low-frequency (0.1 Hz) field stimulation. (+/-)-IDZ and (+)-IDZ antagonized the inhibitory effects of PAC, (+)-IDZ being twice as potent as (+/-)-IDZ; in contrast, antagonism by (-)-IDZ failed to meet Schild criteria for a competitive mechanism. YOH completely reversed the inhibition of twitch response induced by NE, but not that induced by PAC; in the latter case, residual inhibition was almost fully reversed by (+)-IDZ and to a lesser extent by (+/-)-IDZ, while (-)-IDZ proved ineffective. These results provide pharmacological evidence of alpha 2-receptor heterogeneity at the vas deferens level. A possible additional mechanism involving imidazoline binding sites is discussed.

Adrenergic alpha-Antagonists↗
PubMed1992

Interleukin-1 beta and interleukin-6 specifically increase the release of prostaglandin E2 from rat hypothalamic explants in vitro.

It has previously been shown that the cytokines interleukin-1 beta and interleukin-6 (IL-1 beta and IL-6) stimulate directly the release of corticotrophin-releasing-hormone-41 from the rat hypothalamus in vitro, while IL-1 beta can also stimulate the release of somatostatin. These effects can be antagonized by drugs which block prostaglandin (PG) synthesis. PGs are also involved in the control of hypothalamic neuropeptides by other neurotransmitters. In the present study, we have characterized the production of PGs from the rat hypothalamus in vitro, and investigated the effects of IL-1 beta and IL-6, as well as the neurotransmitters norepinephrine, acetylcholine and 5-hydroxytryptamine, on the acute release of PGs, using a well-validated acute hypothalamic incubation system. The rate of release of PGs [PGE2, PGF2 alpha, 6-keto-PGF1 alpha (6KPGF1 alpha) and thromboxane B2 (TXB2) in the medium was found to stabilize after 60 min of preincubation and thereafter remain constant, with TXB2 being the predominant species. Twenty-minute incubation in the presence of human recombinant IL-1 beta or IL-6, in the dose range 1-100 U/ml, had no effect on the release of PGF2 alpha, 6KPGF1 alpha or TXB2; however, the release of PGE2 was significantly increased by both IL-1 beta and IL-6. The effect of IL-1 beta was antagonized by both indomethacin and dexamethasone. None of the other neurotransmitters tested had any effect on the release of any of the PGs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Inhibition of CRH-41 release by substance P, but not substance K, from the rat hypothalamus in vitro.

Substance P is one of a series of tachykinins which is present throughout the central nervous system, and has potent effects on neuroendocrine function. Recent studies have suggested that it inhibits pituitary-adrenal activity at a site above the level of the pituitary. We have therefore used a well-validated rat hypothalamic incubation system to investigate the effects of substance P on the release of the principal corticotrophin-releasing hormone, CRH-41. Substance P caused a dose-dependent inhibition of the 28-mM KCl-stimulated release of CRH-41, with a maximum effect at 100 nM (P less than 0.01). This effect was attenuated by 10 microM of the substance P antagonist (D-Pro2,-D-Trp7,9)-substance P. No statistically significant effect of substance K was seen at 1 or 100 nM. Substance P, at a dose of 100 nM, did not alter the 28-mM KCl-stimulated release of CRH-41 from isolated median eminences in vitro. It is concluded that substance P is a potent inhibitor of the stimulated release of CRH-41, probably acting at a site within the hypothalamic paraventricular nucleus.

Animals↗
PubMed1991

Idazoxan inhibits hyperprolactinaemia in ovariectomized estrogen-treated rats.

The alpha 2-antagonist idazoxan (IDZ) has previously been shown to inhibit hyperprolactinaemia triggered by various stimuli such as lactation, stress, serotonergic agents and morphine (Preziosi, Martire, Navarra, Pistritto and Vacca 1989; Krulich, Jurcovicova and Le 1989). In this study, we investigated the PRL-lowering activity of IDZ in ovariectomized estrogen-treated (OET) rats; since a PRL surge usually occurs in normal cycling rats on the day of proestrus, the effect of IDZ on pulsatile PRL release in intact female rats was also studied. IDZ significantly lowered plasma PRL levels in OET rats; no elevated PRL values were observed in normal cycling rats, indicating that IDZ might inhibit PRL surges in these animals. It is concluded that IDZ is an effective PRL-lowering agent in a number of physiological and pharmacological hyperprolactinaemic models.

Animals↗
PubMed1991

Alpha 2-adrenoceptor-mediated inhibition of prolactin release in suckling- or fenfluramine-induced hyperprolactinemia.

It has recently been shown that the specific and selective alpha 2-antagonist idazoxan (IDZ) displays prolactin-lowering activity on hyperprolactinemia induced in the rat either by suckling or serotonergic drugs. In an attempt better to understand the role of alpha 2-adrenoceptors under the above conditions, experiments were carried out to compare the effects of IDZ with that of the classic alpha 2-antagonist yohimbine (YOH), and also of the alpha 2-agonists clonidine (CLO) and B-HT 920, on prolactin (PRL) release during lactation and in hyperprolactinemia induced in male rats by the serotonergic drug fenfluramine (FEN). In lactating rats, both alpha 2-agonists decreased PRL release; this effect was enhanced by prior separation of the animals from their pups for several hours. A decrease of plasma PRL levels was also induced by IDZ but not by YOH, which tended further to increase hyperprolactinemia. In male rats treated with FEN, IDZ and CLO, a significant decrease of plasma PRL was produced, but YOH further enhanced PRL secretion. It is concluded that the alpha 2-agonists tested and also the alpha 2-antagonist IDZ display a unique inhibitory activity on PRL release during suckling or serotonergic-induced hyperprolactinemia.

Adrenergic alpha-Agonists↗
PubMed1991

Interleukins-1 and -6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via the eicosanoid cyclooxygenase pathway.

It has previously been shown that interleukin-1 (IL-1) directly stimulates the release of CRH-41 from rat hypothalamus in vitro, suggesting that cytokines may mediate the effects of changes in immune state on the hypothalamo-pituitary adrenal axis (HPA). However, it is likely that several cytokines can cause changes in neuroendocrine function, and we have now investigated a series of others for central activity on the HPA: IL-2, IL-6, IL-8, tumor necrosis factor (cachectin), interferon-alpha 2, and interferon-gamma. The static rat hypothalamic incubation system used involves fresh hypothalamic explants with consecutive 20-min incubation, and estimation of CRH-41 concentrations in the medium by a specific RIA; the acute effects of cytokines on ACTH release from rat dispersed pituitary cells were also measured. IL-6 increased hypothalamic CRH-41 secretion in the range 10-100 U/ml, but had no effect on isolated median eminences incubated in vitro under the same conditions. IL-6 (1-1000 U/ml) also had no effect on the secretion of ACTH from freshly dispersed rat anterior pituitary cells when administered in 10-min pulses. The effects of both IL-1 and IL-6 were antagonized by blockade of the eicosanoid cyclooxygenase pathway, but not by lipooxygenase blockade. Neither IL-2 (1-10000 U/ml), IL-8 (0.1-10 nM), tumor necrosis factor (10-1000 U/ml), interferon-alpha 2 (10-1000 U/ml) nor interferon-gamma (10-1000 U/ml) had any effect on hypothalamic CRH-41 release or pituitary ACTH release. It is therefore concluded that IL-6, like IL-1, can exert a potent enhancing effect on the HPA by acutely stimulating the secretion of CRH-41 from the hypothalamus at a site above the level of the median eminence, at concentrations known to occur in human plasma and cerebrospinal fluid. These effects are probably mediated by cyclooxygenase products. Acute stimulatory effects of the other cytokines investigated on the HPA are unlikely to be exerted through changes in either CRH-41 or ACTH directly.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1991

Interleukin-1 beta modulates the acute release of growth hormone-releasing hormone and somatostatin from rat hypothalamus in vitro, whereas tumor necrosis factor and interleukin-6 have no effect.

There is clear evidence for communication between the immune and neuroendocrine systems. However, the effect of cytokines as major immune mediators on the hypothalamic growth peptides, GHRH and somatostatin (SRIH), is not well established. To investigate a possible hypothalamic action of the cytokines interleukin-1 beta (IL-1), interleukin-6, and tumor necrosis factor-alpha, on the release of GHRH and SRIH, we used a previously validated acute rat hypothalamic explant system. IL-1 caused a pronounced dose-dependent stimulation of SRIH in the dose-range 1-100 U/ml (P less than 0.01). GHRH showed a slight, but significant, increase in response to IL-1 tested in the dose-range 10-100 U/ml. Similar studies with mediobasal hypothalamic (GHRH and SRIH) or median eminence (SRIH) fragments produced no change in either GHRH or SRIH release. The effects of IL-1 were antagonized by the cyclo-oxygenase inhibitor, indomethacin (10 micrograms/ml). Stimulation of GHRH and SRIH could not be blocked by the CRH-antagonist alpha-helical CRH (9-41) at 10(-6) M. Interleukin-6, in the dose range 10-100 U/ml, and tumor necrosis factor-alpha, in the dose range 10-10,000 U/ml, had no effect on the acute hypothalamic release of either GHRH or SRIH. It is concluded that IL-1 stimulates the acute hypothalamic release of GHRH and SRIH, and that this effect is mediated by cyclo-oxygenase products. The marked IL-1 stimulation of hypothalamic SRIH release may override the minor increase of GHRH increase, and may thus contribute to disturbances in growth seen in the presence of chronic inflammation.

Animals↗
PubMed1990

Hydroxyurea: relationship between toxicity and centrally-induced adrenal activation.

The anticancer drug hydroxyurea (HU) at doses of 300-800 mg/kg/day causes a dramatic lethality (up to 100% after a 5-day treatment) in hypophysectomized as well as in adrenalectomized rats drinking physiological saline + 5% glucose. Mortality in controls was less than 10% over a 5-day period. Adrenal stimulatory or replacement therapies protect pituitary- or adrenal-ablated rats against HU toxicity. They also counteract white blood cell changes induced by the drug. HU (30-800 mg/kg) induces a dose-dependent increase of plasma corticosterone in normal rats after single or repeated treatments that is not observed in hypophysectomized animals. HU also increases plasma levels of epinephrine, although this finding cannot account for the rise in plasma corticosterone; indeed, it is secondary to a strong rise in plasma corticosterone. The stimulation of the hypothalamic-hypophyseal-adrenal axis induced by HU is responsible for the drug-induced adrenocortical activation. This activation appears to be a valuable defence mechanism protecting intact rats against HU lethality, and its failure causes the dramatic HU lethality in pituitary- or adrenal-ablated animals.

Adrenal Glands↗