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The changes in aldosterone levels produced by different concentrations (10 5 –10 8 M) of clozapine (Cloz; u) or raclopride (Raclo; p) in the presence of 1 M A-II and DA (). The aldosterone increments were calculated using the levels stimulated by 1 M A-II alone as the baseline. f, Increments when raclopride (10 5 –10 8 M) and 1 M clozapine were added simultaneously. Data are the mean and SEM from five independent experiments. *, P 0.01; †, P 0.05 (vs. A-II alone).
Source publication
Aldosterone secretion is evidently regulated by a dopaminergic inhibitory mechanism. Pharmacological characterization and autoradiographic studies revealed D2-like receptors in the adrenal cortex, especially in the zona glomerulosa. However, the subtype of the dopamine receptors involving this regulation has not been elucidated. To investigate whic...
Contexts in source publication
Context 1
... -30% when 10 4 -10 7 m DA was added (Fig. 5B). The elevation of aldosterone secretion by DA was not different among these concentrations. This augmen- tation of aldosterone secretion by DA was abolished by clo- zapine. In the presence of 1 m A-II and DA, clozapine (10 5 -10 7 m) decreased aldosterone levels by 40 -55% com- pared with A-II alone (Fig. 6). The reduction tended to be dose dependent, although no significant difference in the reduction was observed among these concentrations of clo- zapine. The inhibition was absent when the concentration of clozapine was 10 8 ...
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... of 10 5 m raclopride in the presence of 1 m A-II and DA resulted in a 20% lower aldosterone level than that stimulated by 1 m A-II alone (P 0.05; n 5; Fig. 6). At higher concentrations of raclopride (10 6 -10 8 m), aldoste- rone levels were greater than that stimulated by A-II alone, by 6%, 19%, and 29%, respectively (Fig. 6). However, the increased magnitude was only significant at the concentra- tion of 10 8 m, but was not different from that induced by 1 m A-II and DA. The increments in ...
Context 3
... of 10 5 m raclopride in the presence of 1 m A-II and DA resulted in a 20% lower aldosterone level than that stimulated by 1 m A-II alone (P 0.05; n 5; Fig. 6). At higher concentrations of raclopride (10 6 -10 8 m), aldoste- rone levels were greater than that stimulated by A-II alone, by 6%, 19%, and 29%, respectively (Fig. 6). However, the increased magnitude was only significant at the concentra- tion of 10 8 m, but was not different from that induced by 1 m A-II and DA. The increments in aldosterone secretion produced by raclopride were significantly augmented when 1 m clozapine was added simultaneously. The increments were 15%, 55%, 77%, and 90%, ...
Context 4
... only significant at the concentra- tion of 10 8 m, but was not different from that induced by 1 m A-II and DA. The increments in aldosterone secretion produced by raclopride were significantly augmented when 1 m clozapine was added simultaneously. The increments were 15%, 55%, 77%, and 90%, respectively, in the presence of 10 5 -10 8 m raclopride (Fig. 6). Neither clozapine nor raclopride alone had an effect on aldosterone ...
Citations
... D1-like and D2-like receptors are expressed in the normal adrenal gland. In particular, D2 and D4 receptor are localized in the three areas of the adrenal cortex and in the adrenal medulla where DRs mediate the dopamine regulation of aldosterone, cortisol, sex hormones, and catecholamines secretion, respectively [18,[68][69][70][71][72]. Nevertheless, D2 receptor is mainly expressed in the zona glomerulosa and reticularis of the adrenal cortex [18,70], suggesting a pivotal role in the control of aldosterone and sex hormone secretion. ...
... In particular, D2 and D4 receptor are localized in the three areas of the adrenal cortex and in the adrenal medulla where DRs mediate the dopamine regulation of aldosterone, cortisol, sex hormones, and catecholamines secretion, respectively [18,[68][69][70][71][72]. Nevertheless, D2 receptor is mainly expressed in the zona glomerulosa and reticularis of the adrenal cortex [18,70], suggesting a pivotal role in the control of aldosterone and sex hormone secretion. ...
... Similarly, both BRC and CAB inhibited ACTH secretion in at least 50% of human corticotroph pituitary tumour primary cultures [19,23]; importantly, a significant dosedependent inhibition of ACTH secretion was found after both BRC and CAB administration only in primary cultures expressing D2 receptor, with ACTH response to DAs correlated with D2 receptor expression [23]. In NCI-H295R, a human adrenocortical carcinoma cell line producing aldosterone and cortisol, and representing a preclinical model of adrenal CS, D2 and D4 receptors were found to mediate the dopamine regulation of aldosterone, and not cortisol, production [70]. Moreover, in human adrenal hyperplasia cell primary cultures, a potentially more feasible model of adrenal CS, CAB, but not BRC, significantly inhibited both baseline and ACTHstimulated aldosterone, but not cortisol production [18], suggesting that the expression of DRs in adrenal cortex might be mainly involved in the regulation of aldosterone rather than cortisol secretion. ...
Cushing’s Syndrome (CS), or chronic endogenous hypercortisolism, is a rare and serious disease due to corticotroph pituitary (Cushing’s disease, CD) and extra-pituitary (ectopic CS) tumours overproducing ACTH, or cortisol-secreting adrenal tumours or lesions (adrenal CS). The first-line treatment for CS is represented by the surgical removal of the responsible tumour, but surgery might be unfeasible or ineffective and medical treatment can be required in a relevant percentage of patients with CS, especially CD and ectopic CS. Corticotroph pituitary and extra-pituitary tumours, as well as adrenal tumours and lesions responsible for CS express dopamine receptors (DRs), which have been found to mediate inhibition of hormone secretion and/or cell proliferation in experimental setting, suggesting that dopaminergic system, particularly DRs, might represent a target for the treatment of CS. Dopamine agonists (DAs), particularly cabergoline (CAB), are currently used as off-label treatment for CD, the most common form of CS, demonstrating efficacy in controlling hormone secretion and tumour growth in a relevant number of cases, with the improvement of clinical picture, and displaying good safety profile. Therefore, CAB may be considered a reasonable alternative treatment for persistent or recurrent CD after pituitary surgery failure, but occasionally also before pituitary surgery, as adjuvant treatment, or even instead of pituitary surgery as first-line treatment in case of surgery contraindications or refusal. A certain beneficial effect of CAB has been also reported in ectopic CS. However, the role of DAs in the clinical management of the different types of CS requires further evaluations.
... Administration of the D2 antagonist metoclopramide resulted in a rise in plasma aldosterone in humans [18,19] but failed to modify aldosterone concentrations in rats [20,21]. Wu et al. [22] demonstrated that activation of D4 receptors can increase aldosterone secretion, whereas an inhibitory effect is mediated via D2 receptors. ...
There is no doubt that chronic stress accompanied by adrenocortical stress hormone release affects the development and treatment outcome of several mental disorders. Less attention has been paid to the effects of psychotropic drugs on adrenocortical steroids, particularly in clinical studies. This review focuses on the knowledge related to the possible modulation of cortisol and aldosterone secretion under non-stress and stress conditions by antipsychotic drugs, which are being used in the treatment of several psychotic and affective disorders. The molecular mechanisms by which antipsychotic drugs may influence steroid stress hormones include the modulation of central and/or adrenocortical dopamine and serotonin receptors, modulation of inflammatory cytokines, influence on regulatory mechanisms in the central part of the hypothalamic-pituitary axis, inhibition of corticotropin-releasing hormone gene promoters, influencing glucocorticoid receptor-mediated gene transcription, indirect effects via prolactin release, alteration of signaling pathways of glucocorticoid and mineralocorticoid actions. Clinical studies performed in healthy subjects, patients with psychosis, and patients with bipolar disorder suggest that single and repeated antipsychotic treatments either reduce cortisol concentrations or do not affect its secretion. A single and potentially long-term treatment with dopamine receptor antagonists, including antipsychotics, has a stimulatory action on aldosterone release.
... Conversely, D 1 receptors are reportedly expressed in normal adrenal gland (presumably in the zona fasciculata) and some cortisol-secreting adenomas, but not in aldosterone-secreting adenomas. While several reports have suggested D 2 receptors negatively regulate aldosterone production, the effects of dopamine and dopamine agonists on adrenocortical steroidogenesis remains controversial [28][29][30][31][32] . Pivonello et al. demonstrated biphasic effects of cabergoline on steroid production by human adrenal hyperplasia-derived cells. ...
Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, we tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal steroidogenesis. Although cabergoline is a potent dopamine D2 receptor agonist, additional experiments showed that cabergoline exerted effects as a low-affinity agonist of D1 receptors by increasing intracellular cyclic AMP. Further analysis of OSR1⁺ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.
... dopaminergic aldosterone suppression 13 : indeed, antagonists such as metoclopramide, but not agonists, increase plasma aldosterone concentration in normal subjects and in patients with APA. However, the response to metoclopramide is inversely proportional to the percentage of ZF-like cells in the APA, attributed to downregulation of D2R in these cells. ...
... However, the response to metoclopramide is inversely proportional to the percentage of ZF-like cells in the APA, attributed to downregulation of D2R in these cells. [13][14][15] Expression of the D1R subtype is well documented in the ZG of nonhuman species, as demonstrated by in situ hybridization, immunohistochemistry, and binding studies. 16,17 In normal human adrenal, D1R expression has been demonstrated by reverse transcription polymerase chain reaction, 18 but an autoradiographic study found only D2R (and D4R)specific binding. ...
... 8 D2R was subsequently reported to be downregulated in APAs with high ZF-like cell composition. 13,14 This report was before recognition of KCNJ5 mutations in ZF-like APAs. Our results offer further insight to dopaminergic responses in this subtype: not only is D2R downregulated but also the dominant effect of dopamine is likely to be on their D1R, consequent on reduced NEFM expression. ...
Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D, ATP1A1, ATP2B3, and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM, encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin.
... dopaminergic aldosterone suppression 13 : indeed, antagonists such as metoclopramide, but not agonists, increase plasma aldosterone concentration in normal subjects and in patients with APA. However, the response to metoclopramide is inversely proportional to the percentage of ZF-like cells in the APA, attributed to downregulation of D2R in these cells. ...
... However, the response to metoclopramide is inversely proportional to the percentage of ZF-like cells in the APA, attributed to downregulation of D2R in these cells. [13][14][15] Expression of the D1R subtype is well documented in the ZG of nonhuman species, as demonstrated by in situ hybridization, immunohistochemistry, and binding studies. 16,17 In normal human adrenal, D1R expression has been demonstrated by reverse transcription polymerase chain reaction, 18 but an autoradiographic study found only D2R (and D4R)specific binding. ...
... 8 D2R was subsequently reported to be downregulated in APAs with high ZF-like cell composition. 13,14 This report was before recognition of KCNJ5 mutations in ZF-like APAs. Our results offer further insight to dopaminergic responses in this subtype: not only is D2R downregulated but also the dominant effect of dopamine is likely to be on their D1R, consequent on reduced NEFM expression. ...
Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D, ATP1A1, ATP2B3, and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM, encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin.
... Dopamine exerts a tonic inhibitory action on aldosterone secretion via type 2 dopamine (DA2) receptors (4,73,323,329,375) which are present in ZG cells (410,577). The fact that DA2 receptor antagonists (most commonly metoclopramide) induce a brisk rise in plasma aldosterone, but administration of dopamine or specific DA2 agonists (such as bromocriptine) usually fail to suppress aldosterone under basal, sodium replete conditions, suggests that this tonic inhibition is virtually complete in the basal, unstimulated state (70,72,375). ...
In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extraadrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.
... In recent years, several peptide receptors, including dopamine subtype 2 receptor (D2DR), were found to be overexpressed in PHEOs (2)(3)(4)(5). Because nuclear medicine, using radiolabeled peptides, enables the localization and characterization of tumors and may potentially treat patients, new radiopharmaceutical targets are of particular interest in this clinical setting. ...
... Previous studies have shown the presence of D2DR in normal adrenal medulla and PHEOs at the mRNA and protein level (2)(3)(4). Recently we have shown that D2DR mRNA levels of expression in PHEOs are similar to that observed in nonfunctioning pituitary adenomas (5). ...
... However, 123 I-IBZM-SPECT, which targets both D2DR and D3DR, was unable to visualize PHEOs in our patients. Even if D3DR is not expressed in PHEOs (2,4), high expression of D2DR should allow PHEO visualization. The absence of positivity of D2DR imaging with 123 I-IBZM is currently an unexplained finding. ...
ContextDopamine subtype 2 receptors (D2DR) are overexpressed in pheochromocytomas (PHEOs). D2DR-expressing tumors can be visualized by iodine-123 labeled iodobenzamide ((123)I-IBZM) single photon emission computed tomography (SPECT).Objective
The hypothesis was that D2DR high expression in PHEOs would allow in vivo visualization through (123)I-IBZM SPECT. The present prospective pilot study (NCT 00875407) aims to evaluate the performance of (123)I-IBZM SPECT in PHEOs, and to correlate the tumor uptake with D2DR expression in tumor samples after surgery.Setting, Materials and Methods
Ten unrelated patients with PHEOs were evaluated, prior to adrenalectomy, with (123)I-IBZM SPECT (whole body scan at 4h and 24h post-injection; and SPECT centered on the abdomen at 24h). D2DR mRNA and protein expression were evaluated in all tumors by quantitative real-time RT-PCR and immunohistochemistry, respectively.Main Outcome Measure:Intensity of tumoral uptake of (123)I-IBZM.ResultsAll PHEOs express D2DR mRNA (ranging from 2.1 to 14.7 copy/copy ß-Gus) and protein (immunostaining score: moderate or strong in 9/10 cases). However, none of the patients (0 %) showed increased tumor uptake of (123)I-IBZM.Conclusions
These results suggest that (123)I-IBZM is not a useful radiopharmaceutical in the detection and characterization of PHEOs despite D2DR expression. Our findings and data from the related literature may support different hypotheses to explain failure of D2DR targeting by (123)I-IBZM.
... It has been extensively demonstrated, with various techniques, that DR are expressed in the large majority of pituitary adenomas, including GH-secreting, prolactin (PRL)-secreting, ACTH-secreting, and clinically non-functioning tumors (Panetta & Patel 1995, Stefaneanu et al. 2001, Pivonello et al. 2004b, Zatelli et al. 2005, Ferone et al. 2008, Saveanu et al. 2008). Furthermore, DR expression has been well characterized in other NET, such as pheochromocytomas (Pupilli et al. 1994, Pivonello et al. 2004a) and paragangliomas (Wu et al. 2001). Beyond the above-mentioned NET, the presence of DR – mainly D 2 – has been demonstrated in a small group of well-differentiated endocrine tumors (including lung and thymic carcinoids), associated with ectopic ACTH secretion and Cushing's syndrome (Pivonello et al. 2007a). ...
Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D(2) receptor (D(2)) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D(2) as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D(2) pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.
... In situ hybridization was performed using a mRNAlocator TM kit (Ambion, Inc., Austin, TX, USA) following the manufacturer's instructions with a minor modification. 23 In brief, tissue sections were deparaffinized, rehydrated, and permeabilized with proteinase K for 10 min. After permeabilization, the slides were incubated with 1AE32% triethanolamine for 3 min, and then acetylated with 1AE32% triethanolamine containing 0AE24% acetic anhydride for another 10 min. ...
Objectives:
Most patients with Cushing's disease (CD) respond to corticotrophin-releasing hormone (CRH) or desmopressin with increased corticotrophin (ACTH) and cortisol levels. Although the vasopressin receptor subtype located on normal corticotrophs is the V3 receptor (V3R), desmopressin is a selective V2 receptor (V2R) agonist and it is unclear whether corticotrophinomas exhibit aberrant V2R expression. Furthermore, no studies have determined the relationship between the in vivo response of CD patients to desmopressin and vasopressin receptor expression, or between the response to CRH and CRH receptor (CRHR) expression. Therefore, the aim of this study was to investigate the expression of vasopressin receptors (V1R, V2R, and V3R) and CRHR on corticotroph tumours and its possible relation to the in vivo response.
Designs:
A prospective study of 29 patients with CD.
Methods:
Patients underwent desmopressin and CRH stimulation tests before surgery. The expression of vasopressin receptors and CRHR on corticotrophinomas was determined by immunocytochemistry.
Results:
Most of the corticotrophinomas exhibited abundant expression of V1R, V3R, and CRHR, whereas the expression of V2R varied greatly and was lower in macroadenomas than in microadenomas. Both the percentage increment of ACTH and net area under the curve (AUC) of ACTH in the desmopressin stimulation test were found to be correlated with tumour volume. After adjustment for tumour volume, a positive correlation was found between the percentage increment of ACTH and the degree of V2R expression, but not between that of V1R or V3R. No relationship between the level of expression of CRHR on tumour tissues and the percentage increment or netAUC of ACTH to CRH was observed in CD patients.
Conclusions:
We concluded that V2R was expressed on corticotrophinomas and that the level of its expression correlated well with the ACTH response to desmopressin in CD patients, although abundant expression of V1R and V3R was also found in almost all corticotroph tumours. Further studies are needed to elucidate the role of these receptors in the pathogenesis of CD.
... The D 2 affinity of dopastatin contributes strongly to the effect of this molecule in pituitary tumors (Pupilli et al. 1994, Saveanu et al. 2002, Jaquet et al. 2005). DR and in particular D 2 have been identified in PCC at mRNA and protein level (Pupilli et al. 1994, Wu et al. 2001, Pivonello et al. 2004). D 2 antagonists modify catecholamine adrenal secretion (Mannelli et al. 1988), whereas the D 2 agonists were not yet directly tested on PCC secretion to our knowledge. ...
... The mean D 2 mRNA level was similar to that found in pituitary GH and gonadotroph tumors (Saveanu et al. 2006, Florio et al. 2008) but was clearly higher than that of the GEP-NETs. Previous studies have shown the presence of D 2 in normal adrenal medulla and PCC by northern blot (Pupilli et al. 1994, Wu et al. 2001), by RT-PCR (Wu et al. 2001 ), or by RT-PCR, immunohistochemistry , and ligand binding studies (Pivonello et al. 2004). However, these studies concerned a limited number of nine PCC and no PGL. ...
... The mean D 2 mRNA level was similar to that found in pituitary GH and gonadotroph tumors (Saveanu et al. 2006, Florio et al. 2008) but was clearly higher than that of the GEP-NETs. Previous studies have shown the presence of D 2 in normal adrenal medulla and PCC by northern blot (Pupilli et al. 1994, Wu et al. 2001), by RT-PCR (Wu et al. 2001 ), or by RT-PCR, immunohistochemistry , and ligand binding studies (Pivonello et al. 2004). However, these studies concerned a limited number of nine PCC and no PGL. ...
While somatostatin receptors (sst), through somatostatin-radiolabeled analogs, are used, mainly in second line, in the diagnosis and treatment of pheochromocytomas (PCC) and paragangliomas (PGL), the clinical significance of dopamine receptor subtype 2 (D₂) in PCC/PGL is unknown. Indeed, radiolabeled dopamine (DA) analogs such as fluorine 18 ((18)F)-DA, used for positron emission tomography in PCC localization, are mainly correlated to the presence of noradrenaline transporter (NAT) and vesicular monoamine transporters (VMAT) but not to D₂. The aim of this study was to quantitate D₂ and sst expression in 52 PCC/PGL and to compare it with that of 35 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Quantitative RT-PCR of sst(1-3) and sst₅, D₂, NAT, VMAT1/2 was performed in all tumors, while immunohistochemistry analysis of sst₂ and D₂ was performed in seven tumors. D₂ mRNA was expressed in all PCC/PGL. Mean expression was significantly higher in PCC/PGL than in GEP-NETs (4.8 vs 0.5 copy/copy β-glucuronidase (Gus)). sst₂ and sst(1) were expressed in most PCC/PGL, with sst(2)-dominant expression (mean mRNA: 1.6 vs 0.4 copy/copy β-Gus). sst₂ expression level was similar to that of GEP-NETs, whereas sst₅ expression level was significantly lower (0.12 vs 0.78 copy/copy β-Gus). Our study evidenced strong D₂ mRNA expression in PCC and for the first time in PGL. PCC/PGL express sst₂ mRNA at levels similar to those of GEP-NETs. New drugs can target ssts and D₂ more efficiently than current somatostatin analogs. Moreover, transporters like NAT and VMAT1/2, could be co-targeted with sst, as a basis of new radionuclide compounds in the imaging and treatment of these tumors.
