Sulpiride‐induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats
Elva Adán‐CastroLourdes Siqueiros‐MárquezGabriela Ramírez‐HernándezNundehui Díaz‐LezamaXarubet Ruíz‐HerreraFrancisco Freinet NúñezCarlos D. Núñez‐AmaroLudivina Robles‐OsorioThomas BertschJakob TriebelGonzalo Martı́nez de la EscaleraCarmen Clapp
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Abstract:
Excessive vasopermeability and angiogenesis compromise vision in diabetic macular oedema (DME) and diabetic retinopathy (DR). Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits diabetes-induced retinal hypervasopermeability and ischaemia-induced retinal angiogenesis in rodents. Hyperprolactinaemia generated by the dopamine D2 receptor antagonist, levosulpiride, is associated with higher levels of vasoinhibin in the vitreous of patients with DR, implying a beneficial outcome due to vasoinhibin-mediated inhibition of retinal vascular alterations. Here, we tested whether hyperprolactinaemia induced by racemic sulpiride increases intraocular vasoinhibin levels and inhibits retinal hypervasopermeability in diabetic rats. Diabetes was generated with streptozotocin and, 4 weeks later, rats were treated for 2 weeks with sulpiride or osmotic minipumps delivering PRL. ELISA, Western blot, and Evans blue assay were used to evaluate serum PRL, retinal vasoinhibin, and retinal vasopermeability, respectively. Hyperprolactinaemia in response to sulpiride or exogenous PRL was associated with increased levels of vasoinhibin in the retina and reduced retinal hypervasopermeability. Furthermore, sulpiride decreased retinal haemorrhages in response to the intravitreal administration of vascular endothelial growth factor (VEGF). Neither sulpiride nor exogenous PRL modified blood glucose levels or bodyweight. We conclude that sulpiride-induced hyperprolactinaemia inhibits the diabetes- and VEGF-mediated increase in retinal vasopermeability by promoting the intraocular conversion of endogenous PRL to vasoinhibin. These findings support the therapeutic potential of sulpiride and its levorotatory enantiomer, levosulpiride, against DME and DR.Keywords:
Sulpiride
Hyperprolactinaemia
This experiment was designed to determine 1) the efficacy of daily s.c. injections of a dopamine antagonist, sulpiride, for increasing prolactin secretion in geldings in winter and 2) whether increasing prolactin concentrations would hasten the onset of hair shedding or enhance gonadotropin secretion. Five geldings each received vehicle (vegetable oil) or sulpiride (100 mg in vehicle) daily from February 8 through March 29. On February 8 and every 7 d thereafter through March 29, blood samples were drawn around treatment injections and hair samples were collected. On March 30, all geldings received an injection of GnRH and thyrotropin-releasing hormone. Over the 8-wk sampling period, prolactin response to sulpiride varied in a quadratic manner (P < .002). Average area under the 2-h response curve for sulpiride-treated geldings was 24.9 h.ng.mL−1 on February 8, declined to 4.3 after 4 wk, and then increased to 14.8 by the 8th wk of treatment (pooled SE = 4.1 h.ng.mL−1). Prolactin concentrations in control geldings did not vary (P > .1) after injection or over the 8-wk period. Weight of hair pulled from sulpiride-treated geldings did not peak as sharply or as high as that from control gelding (P < .05) and continued to be high through the 11th wk. Sulpiride treatment reduced (P = .071) the LH response to GnRH on March 30; the FSH and prolactin responses to secretagogue were not altered (P > .25). In conclusion, even though prolactin concentrations were increased by sulpiride, the effects on gonadotropin secretion and hair shedding were minor and opposite of those expected.
Sulpiride
Dopamine antagonist
Gonadotropin
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The effect of the acute or chronic administration of sulpiride on serum prolactin and gonadotropin levels was studied in castrated male rats. Sulpiride administered in acute intravenous injections induced a quick increase in serum prolactin levels and no significant changes in serum gonadotropins. The peak in serum prolactin was observed 30 min after the injection of sulpiride, with a decrease of serum prolactin levels at 60 and 120 min. The subcutaneous administration of sulpiride for 13 days induced a significant increase in serum prolactin levels at the end of the treatment, and no significant changes in serum FSH and LH levels.
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Gonadotropin
Serum concentration
Subcutaneous injection
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SUMMARY Thirty‐five samples of serum with levels of immunoreactive prolactin greater than 500 mu/l have been fractionated by gel filtration. In samples from seven normal subjects with elevated prolactin levels following TRH or insulin stimulation and samples from twelve patients with prolactin levels greater than 1500 mu/l, over 80% of the immunoreactive material eluted in the position of native or ‘little’ prolactin. In eleven out of sixteen samples containing 500 to 1500 mu/l the proportion of ‘little’ prolactin was less than 80% and more than 20% eluted as ‘big‐big’ prolactin. It appears therefore that patients with moderately elevated levels of immunoreactive prolactin may not have genuine hyperprolactinaemia.
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The effect of sulpiride, a neuroleptic agent, on the secretion of prolactin by the anterior pituitary gland of the rat was studied. A significant increase in serum prolactin was observed after subcutaneous administration of the drug. Although sulpiride (0-10 micronmol/1 or 0-14 mmol/1) had no effect on the secretion of newly synthesized or radioimmunoassayable prolactin in vitro, the drug significantly overcame the inhibitory action that dopamine (0-50 micronmol/1) exerted on prolactin secretion. Rats implanted with a prolactin-secreting pituitary tumour MtTW15 showed an inhibition of prolactin biosynthesis and release. Injection of these rats with sulpiride restored prolactin biosynthesis and release of the hormone toward normal levels. These results demonstrate that sulpiride has a direct effect on the pituitary antagonizing the inhibitory effects exerted by dopaminergic mechanisms, although the drug itself does not stimulate the secretion of prolactin in vitro. Sulpiride may have a direct action on the pituitary lactotrophs in vivo, but effects at higher centres have not been excluded.
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Prolactin cell
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The effect of chronic administration of sulpiride on serum human growth hormone (hGH), prolactin and thyroid stimulating hormone (TSH) was examined in 6 normal subjects. Sulpiride was given orally at a dose of 300 mg (t.i.d.) for 30 days. Sulpiride raised serum prolactin levels in all subjects examined. In addition, sulpiride suppressed hGH release induced by L-dopa, although the basal hGH level was not changed. Sulpiride treatment appeared to antagonize partially the inhibitory effect of L-dopa on prolactin release. Following thyrotropin-releasing hormone (TRH) injection, the percent increment in prolactin levels from the baseline in sulpiride-treated subjects was less than in controls without sulpiride. In contrast, both the basal and TRH-stimulated TSH levels were not influenced by sulpiride. These observations suggest that sulpiride suppresses L-dopa-induced hGH release and stimulates prolactin release, presumably by acting against the dopaminergic mechanism either on the hypothalamus or on the pituitary. The decreased prolactin response to TRH after sulpiride treatment may indicate a diminished reserve capacity in pituitary prolactin release.
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Abstract. The effect of 100 mg im sulpiride on plasma Prl levels was studied in 10 normal females, 21 patients with galactorrhoea and normal plasma Prl, 10 women with puerperal hyperprolactinaemia and 27 patients with amenorrhoea-galactorrhoea and high plasma Prl levels. The response to sulpiride in patients with galactorrhoea but normal Prl was slightly higher ( P < 0.05) than that observed in normal women, but only if expressed in per cent. Women with puerperal hyperprolactinaemia respond to the drug with a marked increase in Prl (mean ± sem : 563.0 ± 142.8%), even though their baseline values are already very high (mean ± sem : 133.6 ± 23.8 ng/ml). By contrast, there is a lower or no response to sulpiride in 13 women with pituitary tumour. The same was true in 11 patients with hyperprolactinaemia of uncertain aetiology but also 10 of these subjects presented signs suggestive of a tumour. In the last 3 patients with pathological hyperprolactinaemia in whom a consistent Prl increase after sulpiride was observed, hyperprolactinaemia was probably not of tumourous origin. On the basis of these results, the sulpiride test appears promising for discriminating between organic and 'functional' cases of enhanced Prl secretion.
Hyperprolactinaemia
Sulpiride
Etiology
Prolactinoma
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We have studied the response of prolactin (PRL) secretion to the test combining i.m. sulpiride in the dose 1 mg/kg followed by 200 micrograms i.v. of TRH, in 12 normal women and 37 patients with hyperprolactinaemia. The response was expressed as a percentage rise in plasma PRL concentration (delta %) 20 minutes after the administration of sulpiride or TRH. In the controls the response in PRL secretion to sulpiride worked out at between 639 and 2,760%. When there was a pituitary adenoma or supra-sellar lesion the PRL response to sulpiride was always less than 481%. On the other hand the PRL response with TRH after sulpiride was not significantly different as between the controls (less than 175%) and the patients (less than 91%). We conclude: 1) the combined sulpiride and TRH test is useless for assessing hyperprolactinaemia; 2) the sulpiride test on the other hand makes it possible to show that hyperprolactinaemia cannot be stimulated and to suspect the presence in this case of a prolactin producing adenoma or a supra-sellar tumour.
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Hyperprolactinaemia
TRH stimulation test
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Since the establishment of a sensitive and specific radioimmunoassay for serum prolactin levels, very rapid progress has been made in the understanding of the physiology of prolactin and its role in human disease. Hyperprolactinaemia is now known to be a common finding in many conditions. Up to 20% of women with unexplained functional secondary amenorrhoea have an elevated serum prolactin level. Reduction of serum prolactin levels to normal, by removal of a prolactinsecreting tumour or by treatment with bromoergocryptine, results in a restoration of normal menstrual cycles and fertility. This paper outlines the control of prolactin secretion and discusses the mechanisms which result in secondary amenorrhoea. A new method of investigation of hyperprolactinaemia is proposed which localizes the site of abnormality which results in an elevation of serum prolactin levels.
Hyperprolactinaemia
Menstruation
Abnormality
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Normal men and normally menstruating women received i.m. injections of 0.1 to 4.0 mg/kg sulpiride. This psychotropic drug induced a very rapid (already significant after 5 minutes) and sustained (still significant after 7 hours) elevation of prolactin (PRL) concentrations in all subjects with no consistent modification of LH and FSH. After injection of 4.0 mg/kg, there was similarly no modification of mean TSH concentrations in the women tested in the luteal phase, as well as of mean GH levels in men. Sulpiride prevented the inhibitory effect on PRL levels of 500 mg levodopa, administered orally simultaneously; levodopa administered 2 hours prior to sulpiride failed to counteract the PRL-stimulatory effect of sulpiride. Under chronic sulpiride-induced hyperprolactinaemia, levodopa exhibited however a very slight inhibitory effect on PRL concentrations. These data are in agreement with the hypothesis that sulpiride acts mainly at the pituitary level by blocking dopamine receptors of the lactotropes and support the concept that the menstrual cycle perturbations observed under chronic sulpiride administration result from hyperprolactinaemia itself or from a mechanism quite similar to that by which sulpiride induces hyperprolactinaemia.
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Hyperprolactinaemia
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