Histaminergic stimulation of prolactin secretion mediated via H1- or H2-receptors: dependence on routes of administration

Controversy exists regarding the involvement of H1- or H2-receptors in the PRL-releasing activity of histamine (HA). This could be due to differences in the route of administration of HA and histaminergic compounds. Therefore, we studied the effect on PRL secretion of HA and HA-agonists infused intracerebroventricularly (ICV) or systemically (IA) either alone or in combination with HA-antagonists in male rats. HA administered ICV as well as IA stimulated PRL secretion dose dependently. The stimulatory effect of ICV-infused HA was blocked by the H2-receptor antagonist cimetidine (CIM) and mimicked by the H2-receptor agonists 4-methylhistamine (4-MeHA) and dimaprit (DIM). In contrast, the H1-receptor antagonist mepyramine (MEP) enhanced the PRL-releasing effect of HA while the H1-receptor agonist 2-thiazolylethylamine (2-TEA) had no significant effect. The stimulatory effect of IA-infused HA was blocked by the H1-receptor antagonist MEP and mimicked by the H1-receptor agonist 2-TEA, whereas the H2-receptor antagonist CIM enhanced the PRL-stimulatory effect of HA and the H2-receptor agonist DIM was without effect. 4-MeHA stimulated PRL secretion, but this effect was unrelated to stimulation of H2-receptors. The effect of ICV administered HA was unaffected by IA infused antagonists and the effect of IA administered HA was not altered by ICV infused antagonists. HA had no effect on the PRL release from isolated adenohypophyses, and HA did not stimulate PRL secretion in pituitary stalk-sectioned rats following IA infusion. The findings indicate that HA administered ICV exerts its PRL releasing activity via H2-receptors while HA administered IA stimulates PRL secretion via H1-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine H1 receptor participation in the control of prolactin secretion in postpartum

It has been reported that cimetidine, an H2-receptor antagonist, stimulates PRL secretion in postpartum. In the present study, the PRL response to two H1-receptor antagonists, promethazine and d-chlorpheniramine, was studied in 38 normal puerperal women on day 1 after delivery. Serum PRL levels decreased significantly after a single dose of promethazine (100 mg) given im (5 women) or d-chlorpheniramine (20 mg) given iv (6 women). In contrast, no significant change in PRL levels was observed after only saline infusion (6 women). Promethazine, given concomitantly to an iv bolus injection of TRH (200 micrograms) (6 women) and d-chlorpheniramine, given at the onset of suckling (6 women), did not alter stimulation of PRL release induced by these challenges. These results suggest the involvement of histamine H1 receptors in the regulation of basal PRL secretion in postpartum and would indicate that they do not participate in the mechanisms underlying suckling-induced PRL release.     

Histamine H2 receptors and intrinsic factor secretion

Intrinsic factor (IF) secretion in healthy male subjects was studied in response to pentagastrin stimulation with and without cimetidine, and to impromidine, a histamine H2 receptor agonist. Peak and total IF output were reduced by cimetidine, but the concentration was unchanged and the response was unaffected by administration of the compound for 1 week. The IF secretory response to impromidine was similar to that to pentagastrin. It is suggested that the acid and IF components of the parietal cell secretory response are mediated via different intracellular pathways, that histamine H2 receptors do not fulfill and obligatory role in the secretion of IF and that synthesis of IF is probably not altered by cimetidine.     

Histamine-induced vasodilations mediated by H1- and H2-receptors in isolated rat common carotid arteries

Summary Using the cannula inserting method, the vasodilatory effects of histamine were analysed employing selective histamine H₁- and H₂-receptor agonists and antagonists in isolated, perfused rat common carotid arterial preparations which were preconstricted by a continuous infusion of phenylephrine with propranolol. Histamine, 2-pyridylethylamine (2-PEA) (a selective H₁-agonist) and dimaprit (a selective H₂-agonist) produced a vasodilation in a dose-related manner. The order of potency was histamine > dimaprit > 2-PEA. Histamine-induced dilations were significantly inhibited by either diphenhydramine (a selective H₁-antagonist) or cimetidine (a selective H₂-antagonist). 2-PEA-induced dilations were significantly inhibited by diphenhydramine but not by cimetidine. Dimaprit-induced dilations were significantly blocked by cimetidine but not by diphenhydramine. ACh-, histamine-, 2-PEA- and dimaprit-induced dilations were significantly suppressed by removal of the endothelium. From these results, it is concluded that (1) isolated rat common carotid arteries have both H₁-and H₂-receptors, (2) there are few vasoconstrictory H₁-receptors, (3) both H₁- and H₂-receptors mediate only vasodilation but not vasoconstriction, and (4) EDRF from the endothelium might participate in histamine-induced vasodilation via not only H₁- but also H₂-receptors.     

Cholinergic regulation of PP release is mediated through muscarinic M1-receptors

The effects of the selective muscarinic M1-receptor antagonist pirenzepine and the nonselective muscarinic antagonist atropine on bombesin- and peptone-stimulated release of pancreatic polypeptide (PP) were studied in healthy subjects. To exclude any effect of changes in intraduodenal pH continuous intragastric titration was performed during all tests. Both pirenzepine (i.v. bolus 0.6 mg/kg) and atropine (i.v. bolus 15 micrograms/kg, followed by an infusion of 5 micrograms/kg.h) significantly reduced peptone-induced integrated mean rise of plasma PP from 28 +/- 5 to 8 +/- 4 and -2 +/- 5 pmol/l, respectively (n = 4). Both drugs also reduced bombesin-induced rise of plasma PP in all 4 subjects, from 27 +/- 12 to 6 +/- 4 and 7 +/- 1 pmol/l (0.05 less than p less than 0.1). It is concluded that cholinergic regulation of PP release is mediated mainly through muscarinic M1-receptors.     

H1 and H2 histamine receptor participation in the brain control of prolactin secretion in lactating rats.

The aim of the present research was to evaluate the histaminergic regulation of prolactin secretion in the lactating rat and the possible involvement of H1 and H2 histamine receptors in this control. Prolactin was measured by radioimmunoassay in blood samples withdrawn through an intrajugular silastic catheter from undisturbed lactating mothers 10 to 15 days after delivery. In some of those rats a stainless steel cannula was placed in the third ventricle. The tested drugs, H1 and H2 receptor agonists and antagonists, were injected either by the intrasilastic route or intraventricularly immediately before the onset of suckling and after a basal sample was taken. New samples were withdrawn 10, 20, 30 and 60 min thereafter. Suckling caused a 12- to 18-fold increase in serum prolactin by 10 min in control saline-injected mothers. In non-suckled mothers (NSM) injected with saline, prolactin levels were low at all times. Systemic or intraventricular diphenhydramine and mepyramine, H1 receptor antagonists, suppressed the increment in prolactin observed in suckled mothers (SM). Intraventricular metiamide, an H2 receptor antagonist, did not modify prolactin secretion in SM but drastically increased serum prolactin in NSM. A small but significant increase in prolactin titers was observed in NSM injected intraventricularly with histamine. 4-Methylhistamine, an H2 agonist, was ineffective when used intraventricularly in NSM, but clearly suppressed prolactin enhancement in SM. It is postulated that in lactating mothers, brain histamine has a dual control on prolactin secretion. H2 receptors mediate events related to inhibition of prolactin release, since the agonist 4-methylhistamine blocked the prolactin rise in SM, while the antagonist metiamide promoted release of the hormone in NSM. H1 receptors seem to be related to a facilitatory mechanism since classical antihistamines suppress the serum prolactin increase that follows the onset of suckling, while histamine itself is able to release prolactin in NSM.     

Histamine tachyphylaxis in human airway smooth muscle. The role of H2-receptors and the bronchial epithelium.

The role of airway epithelium and H2-receptors in the development of histamine tachyphylaxis was studied using human isolated bronchial smooth muscle strips obtained from 18 patients undergoing thoracotomy. In epithelium-intact strips, a 38% reduction in the maximal contractile response (Emax) (p less than 0.002) and a 2.14-fold increase in the EC50 (p less than 0.02; n = 18) was observed after three separate histamine cumulative concentration effect curves (CCEC). In contrast, significant differences were not seen for either Emax (p greater than 0.4; n = 10) or EC50 (p greater than 0.26; n = 10) in epithelium-denuded strips. In separate experiments, both intact and denuded muscle strips were treated with the H2-receptor antagonist ranitidine (60 microM), either 30 min prior to the first or 30 min prior to the second histamine CCEC. In epithelium-intact strips, pretreatment with ranitidine caused a 1.8-fold increase in Emax in the initial CCEC (p less than 0.02), and both ranitidine schedules prevented tachyphylaxis (n = 8). In epithelium-denuded preparations, ranitidine did not enhance the responsiveness to histamine beyond that seen in untreated epithelium-denuded strips (n = 6). These data suggest that histamine-induced tachyphylaxis occurs in human airway smooth muscle and is mediated, at least in part, via H2-receptors resident on airway epithelium. In vivo, this may function as a protective mechanism, but damage to the epithelium and loss of H2-receptors may be significant in the development of histamine bronchial hyperreactivity as seen in asthma.     

The dopaminergic regulation of anterior pituitary 45Ca2+ homeostasis and prolactin secretion

A role for the regulation of cellular Ca2+ homeostasis in the dopaminergic control of prolactin secretion was investigated in rat anterior pituitary glands. Withdrawal of dopamine stimulated the uptake of 45Ca2+ into hemipituitary tissue by 48% after 3 min. Radioisotope desaturation from tissue prelabelled with 45Ca2+ was significantly retarded in the presence of dopamine. Withdrawal of dopamine rapidly stimulated 45Ca2+ efflux from prelabelled tissue by 79% and was accompanied by a three- to fourfold rise in prolactin secretion. The 45Ca2+ efflux response to dopamine withdrawal was reduced in tissue prelabelled in the presence of dopamine. Agonist displacement with metoclopramide mimicked the effect of dopamine withdrawal on 45Ca2+ efflux and prolactin secretion. These observations demonstrate that the stimulation of prolactin release by dopamine withdrawal is accompanied by a redistribution of cellular Ca2+ and support the hypothesis that dopamine inhibits secretion by decreasing Ca2+ influx in the mammotroph cell.     

Corticosteroid regulation of gonadotropin and prolactin secretion in the rat

The purpose of this study was to determine if glucocorticoids had any direct effects on the release of gonadotropin. In estrogen-primed ovariectomized immature rats, triamcinolone acetonide and deoxycorticosterone (1 mg/kg BW) caused a surge in both serum LH and FSH levels. Dexamethasone treatment (0.05 mg/kg BW) resulted in a highly significant selective release of FSH. Cortisol (1 mg/kg BW) suppressed serum FSH levels. A systematic dose-response study showed that triamcinolone acetonide significantly released LH and FSH and suppressed PRL at all doses tested (range, 0.25-4 mg/kg BW). Deoxycorticosterone was not as potent as triamcinolone acetonide and only doses greater than 0.8-1 mg/kg BW significantly released LH and FSH. Dexamethasone selectively released FSH at low doses (0.01, 0.02, 0.05, and 0.1 mg/kg BW) and inhibited LH at higher doses (0.5 and 1.0 mg/kg BW). A single low dose of dexamethasone (0.02 mg/kg BW) was found to significantly release LH. With respect to PRL secretion, a biphasic effect of dexamethasone was observed in that the lowest dose (0.01 mg/kg BW) stimulated PRL release while the highest dose (1.0 mg/kg BW) significantly inhibited PRL release. Triamicolone acetonide and deoxycorticosterone were found to require estrogen priming for their effects on gonadotropin secretion. The findings in this study raise the possibility that the beneficial effects seen with corticosteroids in inducing ovulation in polycystic ovarian syndrome may be due, in part, to their direct effects upon the release of gonadotropins.     

Serotonergic regulation of prolactin and growth hormone secretion in man

Controversy still exists regarding the role of serotonin in the regulation of prolactin (Prl) and growth hormone (GH) secretion in man. We gave healthy male volunteers three oral doses (0.5, 1.0 and 1.5 mg/kg) of fenfluramine, a serotonin-releasing agent and uptake inhibitor, and a corresponding placebo. There was a significant dose-response effect of fenfluramine on Prl but not on GH levels. Following the highest dose of fenfluramine, mean Prl levels increased from 9.7 ng/ml to 42.3 ng/ml. In a separate study, subjects were pre-treated with cyproheptadine, a serotonin antagonist, before the administration of fenfluramine. Cyproheptadine did not significantly affect basal Prl or GH levels, but it did blunt the response of Prl to fenfluramine. Cyproheptadine pre-treatment did not alter plasma levels of fenfluramine. Our findings support a stimulatory role for serotonin in the regulation of Prl secretion in man. They also suggest that serotonin does not have a major influence on GH secretion in man.     

Histamine H1 and H2 receptor activation stimulates ACTH and beta-endorphin secretion by increasing corticotropin-releasing hormone in the hypophyseal portal blood.

Histamine (HA) stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END) via activation of central postsynaptic H1 or H2 receptors. The effect of HA is indirect and may involve the hypothalamic regulating factors corticotropin-releasing hormone (CRH), arginine vasopressin, or oxytocin (OT). We studied the effect of specific HA H1 or H2 receptor agonists on the concentration of CRH and OT in hypophyseal portal blood in urethane-anesthetized male rats. In addition we investigated the effect of the agonists on ACTH and beta-END immunoreactivity in peripheral plasma in conscious male rats pretreated with antiserum to CRH. Intracerebroventricular administration of the H1 receptor agonist 2-thiazolylethylamine (2-TEA) or the H2 receptor agonist 4-methylhistamine (4-MeHA) increased the CRH concentration in pituitary portal blood by 80-90% when compared to preinfusion levels (p < 0.05). Central infusion of saline had no effect. The level of OT in the pituitary portal blood was not affected by 2-TEA or 4-MeHA when compared to saline-treated rats. Intracerebroventricular infusion of 2-TEA or 4-MeHA increased the ACTH concentration in peripheral plasma 3- or 4-fold, respectively (p < 0.01). Pretreatment with a specific CRH antiserum (abCRH) inhibited the responses by 50 and 70%, respectively (p < 0.01). Intracerebroventricular administration of 2-TEA or 4-MeHA increased the beta-END immunoreactivity in peripheral plasma 3- or 2-fold, respectively (p < 0.01). These effects were inhibited by 80-90%, when rats were pretreated with abCRH (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Histamine H2-receptor antagonists

The first histamine H2-receptor antagonists were developed in the early 1970s, and they have a dominant role in today's management of peptic ulceration. The original regimens using either cimetidine or ranitidine attempted to control acidity across the 24 hours, but more 'modern' regimens use a large single dose of the H2-blocker in the evening, which produces a pulse of decreased intragastric acidity during the night with a normal acidity in the daytime. High-dose regimens using a new generation of extremely potent histamine H2-receptor antagonists may improve ulcer healing rates at 4 weeks, and may be particularly useful for the management of either severe oesophagitis or intractable duodenal ulceration.     

Gonadotrophic regulation of prolactin mediated progesterone secretion in vitro

The effects of preincubating rat granulosa cells with FSH, LH, and Prl on subsequent Prl mediated progesterone secretion were investigated. Granulosa cells were isolated from ovarian follicles 50 h after injection of 5 IU PMSG and were then plated on poly-L-lysine coated coverslips in serum supplemented medium. Cells were preincubated for 24 h in the absence of hormones (control) or with the addition of either 0.25, 2.5, 25 ng/ml rat FSH or rat LH, or 1 microgram/ml rat Prl. Following the preincubation period, cells were maintained for an additional 6 or 8 days in the presence or absence of 1 microgram/ml Prl. When cells were preincubated with FSH or LH, only the two higher concentrations (2.5 and 25 ng/ml) stimulated significantly more progesterone secretion than control cultures during the 24 h preincubation period. For each series of preincubations, cells cultured for 6 or 8 days in the presence of Prl secreted significantly more progesterone at each day of culture than cells cultured without Prl. Cells preincubated and cultured with Prl secreted only 3-7-fold more progesterone than cells preincubated in control medium and then cultured with Prl. Preincubation with FSH or LH promoted a 20-45-fold increase in Prl mediated progesterone secretion compared to control preincubation cultures that also subsequently were cultured with Prl. The magnitude of Prl mediated progesterone secretion observed through 6 days of culturing was dose dependent on the preincubation concentration of FSH or LH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of histamine H1- and H2-receptor antagonists on thyrotrophin secretion in the rat

The effects of histamine H1- and H2-receptor antagonists on the pituitary-thyroid axis were studied in normal and thyroxine (T4)-treated rats. Acute administration (120 min before the test) of the H2 antagonist cimetidine induced a significant (P less than 0.01) increase in the TSH response to TRH, whereas treatment with histamine (30 min before the test) or with the H1-receptor blocker diphenhydramine (120 min before the test) was without effect. Treatment with cimetidine or ranitidine (another H2-receptor antagonist) for 5 days induced a marked decrease in basal plasma TSH concentrations (P less than 0.01), with no changes in pituitary concentrations of TSH. Plasma prolactin concentrations were similarly decreased by cimetidine (P less than 0.01), though not by ranitidine. Neither antihistaminic altered pituitary prolactin concentrations. Despite decreasing basal concentrations of plasma TSH, cimetidine augmented the response to TRH above baseline values (P less than 0.01) in control rats as well as in animals with T4-induced suppression of plasma TSH. Administration of cimetidine or ranitidine for 5 days was followed by a reduced concentration of plasma T4 and triiodothyronine (T3) (P less than 0.05 and P less than 0.01 respectively), perhaps as a result of the declining plasma TSH levels. These results provide the first evidence for the reduction of plasma TSH concentrations by H2-receptor blockers, and may indicate that histamine can physiologically regulate TSH and prolactin secretion through H2 receptors in the anterior pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)     

Control of gastric acid secretion. Histamine H2-receptor antagonists and H+K(+)-ATPase inhibitors.

Gastric acid secretion is regulated by an intricate interplay of neural (acetylcholine), hormonal (gastrin), and paracrine (histamine, somatostatin) mechanisms. Receptors for each of these agents and the signal transduction pathways to which these receptors are coupled have been identified on the parietal cell. The stimulatory effect of acetylcholine and gastrin is mediated by an increase in cytosolic calcium, whereas that of histamine is mediated by activation of adenylate cyclase and generation of cAMP. Strong potentiation between histamine and either gastrin or acetylcholine reflects postreceptor interaction between the distinct pathways as well as the ability of acetylcholine and gastrin to release histamine from mucosal ECL cells. The inhibitory effects of somatostatin on acid secretion are mediated by receptors coupled by guanine nucleotide-binding proteins to inhibition of adenylate cyclase activity. All the pathways converge on and modulate the activity of the luminal enzyme, H+K(+)-ATPase, the proton pump of the parietal cell. Precise information on the mechanisms involved in gastric acid secretion has led to the development of potent drugs capable of inhibiting acid secretion. These include competitive antagonists that interact with stimulatory receptors (e.g., histamine H2-receptor antagonists) as well as noncompetitive inhibitors of H+K(+)-ATPase (e.g., omeprazole). The histamine H2-receptor antagonists (cimetidine, ranitidine, famotidine, and nizatidine) continue as first-line therapy for peptic ulcer disease and are effective in preventing relapse. Although they are generally well tolerated, histamine H2-receptor antagonists may cause untoward CNS, cardiac, and endocrine effects as well as interference with the absorption, metabolism, and elimination of various drugs. Omeprazole is a weak base that reaches the parietal cell through the bloodstream, diffuses through the cytoplasm, and becomes activated and trapped as a sulfenamide in the acidic canaliculus of the parietal cell. It covalently binds to H+K(+)-ATPase, thereby irreversibly blocking acid secretion in response to all modes of stimulation. The main drawback to its use is its extreme potency, which leads to virtual anacidity, gastrin and ECL cell hyperplasia, hypergastrinemia, and, in rats, to the development of carcinoid tumors.     

Effect of blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 receptors on catecholamine-induced stimulation of ACTH and prolactin secretion

The effect of inhibition of the neuronal histaminergic system by blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 autoreceptors on the ACTH and prolactin responses to the catecholamines epinephrine and norepinephrine was investigated in conscious male rats. Intracerebroventricular infusion of epinephrine and norepinephrine stimulated ACTH and prolactin secretion. Prior intracerebroventricular infusion of the H1 receptor antagonist, mepyramine, or the H2 receptor antagonist, cimetidine, had no effect on the ACTH response to epinephrine or norepinephrine, while these responses were inhibited by pretreatment with the H3 receptor agonist, imetit. The prolactin response to norepinephrine was significantly inhibited by pretreatment with mepyramine, cimetidine or imetit whereas the three histaminergic compounds had no effect on the prolactin response to epinephrine. The findings suggest that the histaminergic system exerts a mediating or permissive action on the norepinephrine-induced stimulation of prolactin secretion, whereas an intact histaminergic system may not be required for catecholamines to stimulate ACTH secretion. The inhibitory effect of imetit on catecholamine-induced release of ACTH may be due to an activation of H3 receptors located presynaptically on non-histaminergic neurons, e.g. aminergic neurons. The study further indicates an important role of histamine in the neuroendocrine regulation of prolactin secretion.     

Histaminergic regulation of prolactin secretion: involvement of serotoninergic neurons

The possible involvement of the serotoninergic system in histamine-induced PRL secretion was studied in urethane anesthetized male rats. Intracerebroventricular infusion of histamine (30 micrograms) stimulated PRL secretion 10-fold. This effect was mimicked by the H2-receptor agonist dimaprit (300 micrograms), while the H1-receptor agonist 2-thiazolylethylamine (140 micrograms) had no effect. Pretreatment with the serotonin receptor blockers methysergide (2.5 mg/kg i.p.) or ketanserin (2.5 or 10.0 mg/kg i.p.) reduced the PRL peak response to histamine 75, 54, or 58%, respectively. During serotonin receptor blockade, dimaprit had a stimulatory effect similar to that of histamine, while 2-thiazolylethylamine had no effect. Intraarterial infusion of histamine (420 micrograms) stimulated PRL secretion 6-fold. This effect was mimicked by the H1-receptor agonist 2-thiazolylethylamine (1,900 micrograms), while the H2-receptor agonist dimaprit (3,000 micrograms) had no effect. Pretreatment with methysergide (2.5 mg/kg i.p.) or ketanserin (2.5 or 10.0 mg/kg i.p.) reduced the peak response to histamine 54, 54, or 51% respectively. The effect of histamine was mimicked by 2-thiazolylethylamine, while dimaprit slightly inhibited the PRL secretion. The antiserotoninergic activity of methysergide and ketanserin was demonstrated by their ability to prevent the PRL-releasing effect to serotonin. The effects of methysergide and ketanserin were not due to dopamine-like activity, since none of the drugs affected basal PRL secretion and since the dopamine receptor antagonist pimozide did not prevent the inhibitory effect of methysergide on the histamine-induced PRL release. The findings indicate that histamine-stimulated PRL secretion is mediated in part by serotoninergic neurons.     

Cimetidine, an H2-antihistamine, stimulates prolactin secretion in man.

Intravenous administration of cimetidine, a histamine (H2) receptor antagonist, provoked an immediate 2 to 3-fold rise in serum prolactin concentrations in 8 normal men; serum thyrotropin, growth hormone, thyroxine, and triiodothyronine were not significantly affected. Diphenhydramine, an H1-antagonist, was without effect on any of the hormones measured. The results suggest that histamine may have an important function in the regulation of prolactin secretion in man.