Naloxone-induced prolactin secretion in women: evidence against a direct prolactin stimulatory effect of endogenous opioids

Because both opioids and ovarian steroids influence PRL secretion, the relationship between these inputs to PRL control was investigated. Infusion of the opiate receptor antagonist naloxone (1.6 mg/h for 4-8 h) failed to alter serum PRL levels in hypogonadal women or normal women in the early follicular or late luteal phase. In contrast, a prompt and sustained naloxone-induced release of PRL was found in the late follicular and midluteal phases of the cycle, with maximum increments (mean +/- SE) of 16.9 +/- 5.3 and 9.7 +/- 3.2 ng/ml, respectively. In the luteal phase women, the number of PRL pulses was significantly (P less than 0.001) greater during naloxone than during saline infusion (3.4 vs. 1.6 pulses/8 h), and a positive linear correlation was found between the integrated PRL response to naloxone and the levels of circulating estradiol (r = 0.62) and progesterone (r = 0.95). When serum LH concentrations were determined in the same samples, a significantly (P less than 0.001) greater synchrony of PRL with LH pulses during naloxone infusion (96%) compared to that during saline infusion (36%) was found in the luteal phase women. Thus, naloxone infusion induced an increase in pulsatile PRL release which was synchronized with LH pulses. These findings, not previously reported, suggest that a common neuroendocrine mechanism is involved in the opioidergic control of PRL and LH secretion and that this effect of naloxone is manifested only during high ovarian steroid environments.     

Decreased central dopaminergic activity in essential hypertension

Baseline serum prolactin (PRL) was found to be similar in 35 men with untreated essential hypertension (149 +/- 2/98 +/- 1 mmHg; means +/- s.e.) and 44 healthy normotensive men (126 +/- 1/80 +/- 1 mmHg), all 40 years old. A correlation between baseline PRL and aldosterone was found in the normotensive (r = 0.534, P less than 0.001), but not in the hypertensive group (r = -0.011, NS). Ten subjects from each group received intravenous metoclopramide, a competitive dopamine antagonist, while another 12 normotensive subjects were given saline only, and the effect on PRL, vasopressin (AVP) and catecholamines was followed. An exaggerated PRL response to metoclopramide was observed in the hypertensive group compared with the normotensive (P less than 0.05), and the mean normotensive peak value never exceeded the hypertensive. Plasma noradrenaline increased significantly compared with baseline (P less than 0.05) and the control group (P less than 0.001), concomitant with increased heart rate (P less than 0.05), after the administration of metoclopramide both in the hypertensive and normotensive group. After intravenous injection of metoclopramide, forearm blood flow increased significantly by 50% in the hypertensive (P less than 0.001), and 80% in the normotensive group (P less than 0.001) compared with the control group. Mean blood pressure remained unchanged as did plasma AVP, dopamine and adrenaline. The present study indicates an altered central dopaminergic activity in essential hypertension. Even at rest, endogenous dopamine exerts a modulating effect on noradrenaline release in both hypertensive and normotensive men.     

Histaminergic regulation of prolactin secretion: involvement of tuberoinfundibular dopaminergic neurons

It has been shown that histamine (HA) stimulates prolactin (PRL) secretion via H2 receptors following intra-cerebroventricular infusion and via H1 receptors following systemic (intra-arterial) infusion. Since the effect of HA appears to be exerted at a suprapituitary level, we investigated the involvement of the tuberoinfundibular dopaminergic (TIDA) system in HA-induced PRL secretion in urethane-anesthetized male rats. HA infused intracerebroventricularly (30 micrograms) or intra-arterially (420 micrograms) decreased the dopamine (DA) concentration in pituitary portal blood by 30 and 23%, respectively. Blockade of DA receptors by pimozide did not prevent the stimulation of PRL secretion induced by intracerebroventricular infusion of HA or the H2 receptor agonist dimaprit. Furthermore, during DA receptor blockade intracerebroventricular infusion of the H1 receptor agonist 2-thiazolylethylamine inhibited PRL secretion. In contrast, pimozide prevented the stimulation of PRL secretion induced by intra-arterial infusion of HA and the H1 receptor agonist 2-thiazolylethylamine. In fact, under these conditions intra-arterial infusion of HA or the H2-receptor agonist dimaprit inhibited PRL secretion. During treatment with alpha-methyl-p-tyrosine, which reduced the hypothalamic DA content by 50%, HA infused intracerebroventricularly stimulated PRL secretion, while HA infused intra-arterially inhibited the secretion, which is in accordance with the results obtained during pimozide treatment. Cholinergic blockade by atropine did not prevent the HA-induced PRL release, excluding the possibility that the observed effect of pimozide is due to its anticholinergic property. We suggest that intracerebroventricular infusion of HA by activation of H2 receptors may stimulate PRL secretion partly via inhibition of the TIDA system and partly via other mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dynamic evaluation of prolactin secretion by successive TRH and metoclopramide stimulations

We evaluated the clinical applicability of a 2-h test in which the prolactin (Prl) responses to thyrotrophin releasing hormone (TRH)(200 micrograms iv) and the dopamine antagonist, metoclopramide (MC; 10 mg iv) were studied successively, 1 h apart. Nine healthy women were studied with TRH-MC test and with another test in which MC alone was used or the drugs were given in opposite order. The preceding TRH injection did not affect the Prl responses to MC, nor did preceding MC affect the Prl response to TRH. With the TRH-MC test, Prl responses to TRH and MC were significantly lowered in amenorrhoea (N = 8) and hyperprolactinaemia (N = 15) regardless of whether or not treated with bromocriptine, and to MC only in oligomenorrhoea (n = 11). In normoprolactinaemic galactorrhoea (N = 7) the responses were similar as in healthy women. The ratio between Prl responses to TRH and MC was significantly higher in women with bromocriptine-treated hyperprolactinaemia (1.06 +/- 0.8, SD) than in healthy controls (0.34 +/- 0.13). The capacity of pituitary lactotrophs to secrete Prl in response TRH and MC can be evaluated with a 2-h test which has potential for investigation of pituitary Prl dynamics in gynaecological endocrine disorders, particularly in amenorrhoea and hyperprolactinaemia.     

Decreased dopaminergic control of prolactin secretion in male obesity: normalization by fasting

To test whether short-term fasting has a different effect on hormone release from lactotrophs and thyrotrophs in normal-weight men compared with obese men, 10 mg metoclopramide (MET) was administered orally to seven normal and six obese men before and after a 56-hour fast. In the normal subjects, MET raised the serum prolactin (PRL) level before fasting from 5.1 +/- 1.3 to 58.6 +/- 9.5 micrograms/L in 60 minutes (P less than .02), but left the thyrotropin (TSH) level unaffected. An almost identical hormone response was seen after fasting. Obese men responded differently. Their lactotrophs were initially refractory to MET stimulation (PRL increase from 9.5 +/- 5.1 to 17.5 +/- 5.7 micrograms/L, NS), but became sensitive to such stimulation after fasting (PRL increase from 8.2 +/- 4.5 to 46.3 +/- 6.7 micrograms/L, P less than .01). The thyrotrophs were unaffected by MET before, as well as after, the fast. Although decreased PRL synthesis, reduced cell membrane permeability, and inadequate MET stimulation are plausible mechanisms by which the reduced PRL responsiveness to MET could be explained in the obese patients, neither is likely in view of the fact that the lactotrophs responded promptly to thyrotropin-releasing hormone (TRH), administered intravenously (IV) 60 minutes after MET, in the fed obese patients (PRL increase after TRH from 17.5 +/- 5.7 to a maximum of 48.0 +/- 8.7 micrograms/L, P less than .05). Furthermore, a 50% reduction of the MET dose (5 mg) resulted in a significant PRL response in non-obese healthy men (PRL increase from 3.1 +/- 1.1 to 40.3 +/- 0.9 micrograms/L, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of L-dopa and apomorphine on glucagon secretion in man: evidence against central dopaminergic stimulation of glucagon

In 6 normal subjects, L-dopa (500 mg PO) and apomorphine (0.6 mg sc) increased circulating growth hormone and suppressed prolactin levels in a parallel and quantitatively similar fashion, but only L-dopa induced a rise in plasma glucagon, glucose, and insulin levels. The failure of apomorphine to affect glucagon secretion, despite a substantial effect on growth hormone and prolactin, was also observed in insulin-dependent diabetics known to exhibit A-cell hyperresponsiveness to various stimuli. In view of the highly dissimilar molecular and pharmacologic characteristics of L-dopa and apomorphine, these data do not exclude a local dopaminergic effect of L-dopa at the pancreatic level, but strongly militate against a central dopaminergic pathway for glucagon stimulation.     

Dynamic evaluation of prolactin secretion during the early hours of life in human newborns.

PRL secretion was evaluated in 30 human newborns during the early hours of life. Both levodopa and pyridoxine administration failed to suppress PRL release in all subjects. Synthetic TRH elicited a constant, prompt increase in PRL levels. No significant changes were observed after somatostatin injections. These results demonstrate normal pituitary PRL reserve in newborns. The failure to respond to levodopa and pyridoxine administration might reflect partial immaturity of the pituitary dopaminergic receptors.     

Humoral markers of endothelial dysfunction in essential hypertension

AIM: To elucidate potential markers of endothelial dysfunction and relationships between humoral and vasoregulatory responses of the endothelium in patients with essential hypertension. MATERIAL: Thirty four male patients (mean age 54.4+/-9.2) with I-II degree hypertension and left ventricular hypertrophy. METHODS: Endothelial function was assessed non-invasively by registration of flow-mediated brachial artery dilatation. Serum level of vascular adhesive molecule 1S (VCAM-1S) was measured by enzyme immunoassay, levels of aldosterone and insulin-like growth factor-1 (IGF-1) - by radioimmunoassay. RESULTS: Brachial artery flow mediated dilatation was 2.0+/-7.46%. Patients with hypertension compared with healthy subjects had significantly higher mean levels of VCAM-1S (713.9+/-123.2 and 590.8+/-51.8 pg/ml, respectively, p<0.001), aldosterone (105.41+/-50.17 and 42.7+/-13.16 ng/ml, respectively, p<0.001), and IGF (209.7+/-49.1 and 137+/-21 pg/ml, respectively, p<0.001). Direct significant correlations were found between humoral and functional markers of endothelial dysfunction in the group of patients with essential hypertension. CONCLUSION: These results can be interpreted as indicative of pathogenetic role of IGF-1 and aldosterone in the development of the endothelial dysfunction and myocardial remodeling in essential hypertension     

Histaminergic regulation of prolactin secretion: dose-response relationship and possible involvement of the dopaminergic system

Histamine (HA) may participate in the neuroendocrine regulation of pituitary hormone secretion. HA diphosphate infused iv for 120 min in a dose of 9, 18, 30, or 50 micrograms/kg BW.h to six normal men stimulated PRL secretion in a dose-dependent manner [absolute change in PRL (delta PRL) area = 52 X (HA dose) - 618; r = 0.9926; P less than 0.001]. The stimulatory effect of HA was modest and occurred during the second hour of infusion. This increase might be due to the opposing effects of HA on PRL secretion, specifically stimulation via H1 receptors and inhibition via H2 receptors. The PRL-releasing effect of 11 micrograms HA dihydrochloride was not significantly different from that of an equimolar dose of HA diphosphate (18 micrograms). Selective activation of H2 receptors by combined infusion of HA and the H1 receptor antagonist mepyramine inhibited PRL secretion compared to the effect of NaCl [delta PRL, -55 +/- 23 (+/- SEM) vs. -20 +/- 17 microIU/ml; P less than 0.01; n = 6). Mepyramine infused alone had no effect (delta PRL, -43 +/- 22 vs. -33 +/- 30 microIU/ml; n = 6). Selective activation of H1 receptors by combined infusion of HA and the H2 receptor antagonist cimetidine stimulated PRL secretion (delta PRL, 193 +/- 40 vs. -20 +/- 17 microIU/ml; P less than 0.0005; n = 6). When infused alone, cimetidine had only a modest and late stimulatory effect (delta PRL, 35 +/- 22 vs. -27 +/- 15; P less than 0.025; n = 6). Dopamine receptor blockade with metoclopramide (MET; 10 mg, three times daily, orally) did not prevent the PRL-inhibiting action of H2 receptor activation (delta PRL, -374 +/- 70 vs. -184 +/- 107 microIU/ml; P less than 0.01; n = 6), whereas the PRL-stimulating effect of H1 receptor activation was abolished by the drug (delta PRL, -249 +/- 64 vs. -174 +/- 54 microIU/ml; n = 6). The latter effect of MET was not due to exhaustion of the lactotrophs, since 200 micrograms TRH stimulated PRL secretion during MET treatment. These findings suggest that the H1 receptor-mediated PRL-stimulating effect of HA occurs through an inhibition of the dopaminergic system, whereas the H2 receptor-mediated PRL-inhibiting effect of HA does not involve dopaminergic neurons.     

Pharmacologic evidence that a D2 receptor subtype mediates dopaminergic stimulation of prolactin secretion from the anterior pituitary gland.

The ability of low concentrations of dopamine (DA) to stimulate the secretion of prolactin (PRL) was examined in perifused or monolayer cultures of anterior pituitary cells. In cultures perifused with media containing 100 nM DA, changing the DA concentration to either 1 or 100 pM caused a significant dose-dependent stimulatory PRL secretory response within 6 min when compared to the PRL secretory response to removal of DA altogether. Picomolar concentrations of DA caused a biphasic PRL secretory response. This response is characterized by an immediate increase in the rate of PRL secretion similar to that seen when the cells were treated with 100 nM thyrotropin-releasing hormone followed by a decrease in the rate of PRL secretion to levels comparable to cells receiving media alone. In a monolayer culture system DA, at concentrations between 10 nM and 1.0 pM, caused significant stimulation of PRL secretion relative to media alone. Maximal stimulation occurred at nanomolar concentrations of DA (approximately 60% greater than control). Although the D2 agonists, bromocriptine and 2-(N-phenethyl-N-propyl)-amino-5-hydroxytetralin hydrochloride (PPHT) caused significant (p less than 0.05) inhibition of PRL secretion at nanomolar concentrations and above, neither had stimulatory activity. The D1 agonists, SKF 38393 and SKF 82958, had no effect on PRL secretion when tested at 0.1 pM to 1 microM. These data suggest that DA not only inhibits PRL secretion in vitro, but also stimulates PRL secretion at relatively low concentrations. Stimulation is mediated by a DA receptor which is neither recognized by D2 nor D1 agonists, suggesting a possible third DA receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dopaminergic blockade on the secretion of growth hormone and prolactin in man

Serum growth hormone (GH) response to insulin and glucagon administration was studied in 12 male and 12 female volunteers under control conditions, and under treatment with pimozide and metoclopramide. In addition, serum prolactin levels were measured during the treatment period. Pimozide and metoclopramide administration had no effect on the GH response to insulin and glucagon. In contrast, serum prolactin levels increased markedly during the treatment period. Dopaminergic blockade is unable to affect GH secretion in response to insulin and glucagon administration in man.     

Effect of captopril on plasma prolactin in patients with essential hypertension

The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5 +/- 1.4 ng/mL to 9.1 +/- 1.0 ng/mL (p less than 0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (delta plasma prolactin) vs delta plasma renin activity (r = -0.688, p less than 0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.     

Salt sensitivity and central dopaminergic activity in patients with essential hypertension

The pathophysiological role of the central dopaminergic mechanism in human essential hypertension (EH) is still unknown. We studied on the relationship between the dopaminergic activity and the salt-sensitivity. Twenty three hospitalized patients with EH were divided into the salt-sensitive group (SS, n = 12) or non salt-sensitive group (NSS, n = 11) by their responses whether they caused more than 8% increase in mean blood pressure (MBP) when the dietary salt was increased from 2g/day to 20g/day for 7 days of each. The change of central dopaminergic activity by the salt load was evaluated by the decrement of plasma prolactin (PRL) response to small dosage (25 micrograms) of thyrotropin releasing hormone. The mean percent change of PRL response by the salt load in the SS group was -6.5 +/- 8.3% (mean +/- SEM), which was significantly lower than 26.8 +/- 5.5% in the NSS group (p less than 0.01). There was a significant negative correlation between the percent changes of PRL response and the percent changes of MBP by the salt load (r = -0.448, p less than 0.05). These results suggested that the rise in blood pressure by salt load in SS patients with EH might be due to a reduced activity of the central dopaminergic mechanism.     

The pathophysiological role of renal dopaminergic activity in patients with essential hypertension

To evaluate the role of the renal dopaminergic system on renal water-sodium metabolism patients with essential hypertension (EHT), urinary excretion of dopamine, urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) were all investigated before and after the administration of dopamine (3 micrograms/kg/min, intravenous infusion for 60 minutes), dopamine antagonist, metoclopramide (8 mg/m2 BSA, intravenous injection) or mild sodium loading in both normotensive subjects and benign EHT. In the basal values, no significant difference in urinary excretion of free (u-fDA), conjugated (u-cDA) or total dopamine (u-tDA) was found between normotensives and hypertensives. However, low renin EHT showed a pronounced reduction in u-fDA compared with normotensis subject and (NT) normal renin EHT. In this study, a significant reduction of u-cDA and of u-tDA was also found in those patients with low renin essential hypertension. In the normotensive and essential hypertensive groups UNaV or FENa showed a positive correlation with u-fDA (measured simultaneously), but not with u-tDA or u-cDA. The regression line between u-fDA and UNaV or FENa in EHT was shifted towards a lower u-fDA level than in NT. UNaV and FENa were increased by dopamine infusion and were decreased by metoclopramide injection in both NT and EHT. Changes of UNaV and FENa following dopamine or metoclopramide, showed a negative correlation with u-fDA measured immediately before the administration of these drugs. The enhanced natriuretic response to infused dopamine and the attenuated antinatriuretic response to injected metoclopramide were significant in low renin EHT, when compared with NT or normal renin EHT patients.(ABSTRACT TRUNCATED AT 250 WORDS)