摘要:

Bromocriptine or other dopamine agonists are usually effective for the treatment of prolactin-secreting adenomas. Five to 18% of prolactinomas, however, do not respond to such therapy. We have shown previously that such resistance to bromocriptine correlates with reduced binding to the D2 receptor subtype of dopamine, the major PRL inhibiting factor. In the present work, we demonstrated that reduced binding actually corresponds to decreased expression of the gene coding for the D2 receptor in the pituitary from bromocriptine-resistant patients, as shown by 4-fold lower levels of the corresponding mRNAs compared to those coding for actin. The existence of two D2 receptor isoforms, D2S and D2L generated by alternative splicing, has been described in several tissues, including the pituitary. Both are negatively coupled to adenylyl cyclase and inhibit prolactin secretion, but, in addition, the shortest one (D2S) is more efficiently coupled to phospholipase C. Consequently, we also investigated whether expression of a particular D2 receptor isoform was preferentially affected in resistant adenomas. The proportion of messengers corresponding to the short receptor isoform (D2S) was lower in resistant compared to responsive adenomas: D2S/D2L = 0.74 ± 0.08 and 1.00 ± 0.07, respectively. In parallel, much lower levels of D2 receptor mRNAs were found in growth hormone-secreting adenomas, with a D2S/D2L ratio comparable to those of both normal human pituitary and bromocriptine-sensitive prolactinomas (1.05 ± 0.11). Thus, resistance to bromocriptine therapy seems to involve defects in D2 dopamine receptor expression and possibly in posttranscriptional splici

ISSN:0028-3835    

DOI:10.1159/000126764

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

Pyroglutamyl peptidase II (PPII) is a thyrotropin-releasing hormone (TRH) hydrolyzing ectoenzyme with a narrow specificity. In the adenohypophysis, it is present on lactotropes. This study was undertaken in order to determine whether TRH itself regulates PPII activity in the adenohypophysis. After 5 days in culture, dispersed cells from female pituitaries expressed detectable levels of PPII activity when 10–8M 3,3’,5’-triiodo-L-thyronine was present throughout the culture. 10–6M TRH decreased PPII activity with a maximal effect (down to 46% of initial values) at 16 h and an ED50 of 10–9M. [3Me-His2]TRH, a potent agonist of the TRH receptor was effective at lower concentrations (ED50: 1.6 × 10–10M). Phorbol- 12-myristate-13-acetate (PMA; 10–6M), a protein kinase C (PKC) activator, diminished PPII activity to 61 % or initial values with an ED50 of 2.2 × 10–8M. Maximal effects of PMA and TRH were not additive. Neither PMA nor TRH effects were reversed by inhibitors of protein kinases (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine or sphingosine or staurosporine); TRH-induced downregulation of the enzyme was not modified by PMA pretreatment. TRH had no effect on two other ectopeptidases, endopeptidase 24.11 and dipeptidyl aminopeptidase IV. These data demonstrate that TRH specifically downregulates PPII activity in adenohypophyseal cells through TRH receptor activation and suggest that the activation of a presumably calcium-independent PKC mimics the TRH effect. TRH regulation of PPII activity may contribute to adjust lactotrope resp

ISSN:0028-3835    

DOI:10.1159/000126765

出版商:S. Karger AG    

年代:1994

数据来源: Karger

摘要:

In situ hybridization and specific radioimmunoassays were used to study the influence of ethanol on proopiomelanocortin (POMC) and prodynorphin (PDYN) biosynthesis in the rat pituitary. Repeated intragastric ethanol administration (starting with a total daily dose of 5 g/kg every 2nd day, until a dose of 10 g/kg was attained on the 10th day and that dose was maintained by the 19th day) resulted in a reduction in the POMC mRNA level (about 20%) in the intermediate lobe of the pituitary (3 h after the last dose), whereas the level of β-endorphin in the neurointermediate lobe was attenuated (by about 32%) only during the withdrawal (48 h after the last dose). Additionally, the plasma level of β-endorphin after repeated ethanol and during withdrawal was significantly reduced (by about 44 and 66%, respectively). No changes in the POMC mRNA or the β-endorphin levels were detected in the anterior lobe. In contrast, the PDYN mRNA level was found to be decreased in the anterior lobe during the withdrawal (by about 43%). This decrease was in conjunction with an increase in the α-neoendorphin level (by about 57%) in that lobe. The PDYN mRNA level in the intermediate lobe and the α-neoendorphin level in the neurointermediate lobe were unchanged after ethanol, as well as during the withdrawal period. Acute ethanol (5 g/kg) decreased the level of β-endorphin in the anterior lobe; this effect being associated with an elevation in the peptide level in plasma. On the other hand, acute ethanol had no effect on the POMC and PDYN mRNA levels, nor did it affect the α-neoendorphin concentration in the pituitary. The results of our study indicate that acute and repeated ethanol differentially affects the biosynthesis of opioid peptides in the specific lobes of the pituitary. In the light of an opioidergic local regulation of endocrine secretion, these effects may participate in hormonal disturbances which are common in chronic alco

ISSN:0028-3835    

DOI:10.1159/000126766

出版商:S. Karger AG    

年代:1994

数据来源: Karger