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Ulrich Knigge, Steen Matzen and Jørgen Warberg

Abstract. The effects on prolactin secretion of histamine H2-receptor antagonists infused intracerebroventricularly were studied in urethane anaesthetized male rats. A dose of 1.6 μmol cimetidine stimulated basal prolactin secretion and did not affect the histamine-induced release, whereas 0.4 μmol cimetidine inhibited basal and histamine-stimulated prolactin secretion. 0.1 μmol cimetidine had no effect. The more potent H2-receptor antagonist ranitidine at doses of 0.1, 0.4, 1.6 μmol had no effect on basal prolactin secretion, whereas 0.4 and 1.6 μmol inhibited the histamine-stimulated secretion completely. SKF-92408, a compound resembling cimetidine in chemical structure but devoid of H2-receptor antagonist activity, stimulated basal prolactin secretion at a dose of 1.6 μmol, but had no effect on the histamine-induced release or at a dose of 0.4 μmol. The H2-receptor antagonists metiamide and oxmetidine (1.6 μmol) stimulated basal prolactin secretion and did not prevent the response to histamine. A dose of 0.4 or 1.6 μmol imidazole (the ring structure contained in cimetidine, SKF-92408, metiamide, and oxmetidine) had no effect on basal or histamine-stimulated prolactin secretion. The findings indicate that cimetidine stimulates prolactin secretion by a non-specific action when infused centrally at high doses. In contrast, when infused at lower doses cimetidine inhibits the basal and histamine-stimulated secretion by blockade of H2-receptors. The prolactin-stimulatory action of cimetidine was not due to an H2-agonist effect, since ranitidine did not prevent the response. Cimetidine did not stimulate prolactin secretion via an effect on the dopaminergic system, since the drug had no effect on the dopamine concentration in hypophysial portal blood or in hypothalamic tissue and since inhibition of the dopamine synthesis by α-methyl-p-tyrosine did not prevent the cimetidine-induced prolactin release.

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Steen Matzen, Ulrich Knigge and Jørgen Warberg

Abstract. General anaesthesia has been reported to interact with neuroendocrine functions leading to large variations in basal and stimulated plasma levels of several hormones, but the findings are often contradictory. In the present investigation we have attempted to clarify the importance of the experimental procedure when evaluating the influence of anaesthetics on the secretion of PRL and LH in male rats. One group of rats (non-adapted) were anaesthetized (ip) with pentobarbital (P), urethane (U), ketamine (A), or althesin (A) without being accustomed to the laboratory environment prior to anaesthesia. Another group of rats (adapted) were kept for 90 min in their individual cages before induction of anaesthesia with P or U. In non-adapted rats the plasma concentration of PRL declined rapidly during the first 30 min following administration of all anaesthetics or saline (controls) and attained a steady level after 60 min. Except for a brief rise following U injection, the LH concentration was not affected by anaesthesia in the non-adapted rats. In adapted rats, the concentration of both PRL and LH declined markedly during the pre-anaesthetic adaptation period and had stabilized at the end of that period. Following administration of U, P or saline, no further changes in the hormone concentrations were observed. Injection of the dopamine receptor antagonist pimozide prevented the decrease in plasma PRL during the adaptation period, but had no effect on LH secretion. In pimozide-treated rats, U caused a 5-fold increase in the PRL concentration. This effect of U was inhibited by the serotonin receptor antagonist methysergide. The PRL response to 30 μg of histamine was similar in conscious and U-anaesthetized rats, whereas P anaesthesia caused a reduction in the response. It is concluded that the anaesthetics used here have no significant influence on the basal secretion of PRL and LH, and that the change in PRL secretion observed in non-adapted animals is not caused by the anaesthetic agents, but is due to the routine manipulation of the animals preceding induction of anaesthesia. We recommend that neuroendocrine experimentation be not initiated until 60 min after administration of anaesthetics.

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Andreas Kjær, Ulrich Knigge, Steen Matzen and Jørgen Warberg

Kjær A, Knigge U, Matzen S, Warberg J. β-Adrenergic receptors are involved in histamine-induced secretion of proopiomelanocortin-derived peptides and prolactin in rats. Eur J Endocrinol 1995;132: 223–8. ISSN 0804–4643

The neurotransmitter histamine (HA) is involved in central regulation of secretion of prolactin (PRL) and the proopiomelanocortin (POMC)-derived peptides adrenocorticotropin (ACTH), β-endorphin (β-END) and α-melanocyte-stimulating hormone (α-MSH). The effect of HA on POMC-derived peptides and PRL release is, at least in part, indirect and may involve activation of catecholaminergic systems. Therefore, we investigated the effect of β-adrenergic receptor blockade on HA or HA agonist-induced release of ACTH, β-END, α-MSH and PRL. Central administration of HA, the H1-receptor agonist 2-thiazolylethylamine (2-TEA) or the H2-receptor agonist 4-methylhistamine (4-MeHA) stimulated the secretion of ACTH, β-END, α-MSH and PRL. Pretreatment with the β-adrenergic antagonist propranolol inhibited secretion of the POMC peptides in response to HA, 2-TEA or 4-MeHA. Propranonol only inhibited the PRL response to HA or 2-TEA, but had no effect on the PRL response to 4-MeHA. Administration of the β-receptor agonist isoproterenol stimulated ACTH, β-END, α-MSH and PRL two to five-fold. This effect was totally blocked by pretreatment with propranolol. We conclude that HA-induced secretion of POMC-derived peptides from the anterior and intermediate lobe of the pituitary gland and of PRL from the anterior lobe is, at least in part, mediated via catecholamines. β-Adrenergic receptors are involved in the mediation of the POMC response to H1- as well as H2-receptor activation, whereas β-receptors are involved only in the mediation of the PRL response to H1-receptor activation.

Andreas Kjær, Department of Medical Physiology, Division of Endocrinology and Metabolism, The Panum Institute (Building 12.3), University of Copenhagen, Blegdamsvej 3c, DK-2200 Copenhagen N, Denmark

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Ulrich Knigge, Flemming W. Bach, Steen Matzen, Peter Bang and Jørgen Warberg

Abstract. In conscious male rats intracerebroventricular infusion of histamine increased the plasma concentrations of ACTH and β-endorphin immunoreactivity 2.5-fold (P < 0.01). Gel filtration of plasma revealed two peaks of β-endorphin immunoreactivity corresponding to β-endorphin and β-lipotropin. The two fractions increased almost equally in histamine-stimulated animals, whereas most of the circulating β-endorphin immunoreactivity in control animals corresponded to β-endorphin. Central infusion of the H1-receptor agonist 2-thiazolylethylamine and of the H2-receptor agonists dimaprit or 4-methylhistamine increased the plasma ACTH and β-endorphin immunoreactivity concentrations 2- and 3-fold, respectively (P < 0.01). Infused intracerebroventricularly, the H2-receptor antagonists cimetidine or ranitidine prevented the histamine-induced increase in plasma ACTH and β-endorphin immunoreactivity (P < 0.01), whereas the H1-receptor antagonist mepyramine inhibited the peptide responses by 70% (P < 0.01). Infused intra-arterially cimetidine or ranitidine inhibited the histamine-induced increase in plasma ACTH by 80% (P < 0.01) and plasma β-endorphin immunoreactivity by 45% (P < 0.05), whereas mepyramine or the other H1-receptor antagonist SKF-93944 inhibited the ACTH response by 50% (P < 0.05), but had no effect on the β-endorphin immunoreactivity. The results indicate that histamine increases the release of the pro-opiomelanocortin derived peptides ACTH, β-lipotropin and β-endorphin from the anterior pituitary lobe, whereas an effect of histamine on the release of β-endorphin from the neurointermediate lobe is possible. The effect of histamine seems primarily mediated by H2-receptors, whereas H 1-receptors appear to play a minor role.

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Ulrich Knigge, Steen Matzen, Flemming W. Bach, Peter Bang and Jørgen Warberg

Abstract. Histamine, which acts as a neurotransmitter, stimulates the release of the pro-opiomelanocortin derived peptides ACTH, β-lipotropin, and β-endorphin. Since stress affects the hypothalamic turn-over of neuronal histamine, we investigated the role of histaminergic neurons in the mediation of the stress-induced release of ACTH and β-endorphin immunoreactivity in male rats. In control animals histamine receptor antagonists had no effect on the release of ACTH or β-endorphin immunoreactivity. Restraint and ether stress increased plasma ACTH 3- and 2-fold, respectively. The responses were almost prevented by intracerebroventricular or intra-arterial infusion of the H2-receptor antagonists cimetidine and ranitidine. Infused intracerebroventricularly the H1-receptor antagonist mepyramine inhibited the ACTH response to restraint by 45% (P< 0.01), but had no effect on the response to ether. Infused intra-arterially the H1-receptor antagonists mepyramine or SKF-93944 had no effect. Restraint and ether stress increased plasma β-endorphin immunoreactivity 6- and 5-fold, respectively. Sephadex G-50 gel chromatography of plasma showed that the β-endorphin immunoreactivity in stressed rats coeluted with β-lipotropin and β-endorphin, whereas the immunoreactivity in control animals co-eluted almost exclusively with β-endorphin. The H2-receptor antagonists cimetidine and ranitidine infused intracerebroventricurlarly inhibited the responses of β-endorphin immunoreactivity to restraint and ether stress by 90 and 70%, respectively, whereas intra-arterial infusion of these antagonists inhibited the responses by only 50 and 60%, respectively. The H1-receptor antagonist mepyramine infused intracerebroventricularly inhibited the β-endorphin immunoreactivity response to restraint and ether stress by 40 and 25%, respectively, whereas intra-arterial infusion of mepyramine or the other H1-receptor antagonist SKF-93944 prevented the response to restraint stress, but had no effect on the response to ether stress. We suggest that hypothalamic histamine is involved in the mediation of the stress-induced release of the proopiomelanocortin-derived peptides ACTH, β-endorphin and β-lipotropin. The effect is mediated preferentially via H2-receptors, but H1-receptors may also play a role.