piperidines and Adrenal-Cortex-Neoplasms

The use of remifentanil has been recommended because of its ability to minimise the hypertensive response to tracheal intubation and surgical stimulation in various types of surgery. We describe the use of remifentanil in the anaesthetic management of three cases of open adrenalectomy, two for removal of a phaeochromocytoma and one for removal of an adrenal cortical tumour. Although the use of remifentanil was associated with no adverse events in the patient undergoing resection of the adrenal cortical tumour, its administration was associated with significant hypotension and bradycardia in the two phaeochromocytoma patients, who had both been given alpha- and beta-adrenergic receptor blocking drugs before surgery. It did not prevent the increases in blood pressure or plasma catecholamine levels associated with tumour manipulation in these patients. Remifentanil should therefore be used with caution in patients receiving alpha- and beta-adrenergic receptor blocking drugs. The use of potent vasodilators may still be necessary during tumour manipulation even if remifentanil is being infused.

Topics: Adrenal Cortex Neoplasms; Adrenalectomy; Anesthetics, Intravenous; Epinephrine; Female; Hemodynamics; Humans; Male; Middle Aged; Norepinephrine; Pheochromocytoma; Piperidines; Remifentanil

Evidence has accumulated showing that vasoactive peptides, such as endothelin-1, adrenomedullin and urotensin-II, are expressed in various kinds of tumour cells. In the present study, the expression of endothelin-1 and endothelin receptors was studied in eight human tumour cell lines: T98G (glioblastoma), IMR-32 and NB69 (neuroblastoma), BeWo (choriocarcinoma), SW-13 (adrenocortical carcinoma), DLD-1 (colonic carcinoma), HeLa (cervical carcinoma) and VMRC-RCW (renal carcinoma). Reverse transcriptase-PCR showed expression of endothelin-1 mRNA in seven out of the eight cell lines, the exception being BeWo cells. ET(A) receptor mRNA was expressed in T98G, IMR-32 and NB69 cells, but weakly in the other cells. ET(B) receptor mRNA was expressed in IMR-32, NB69 and BeWo cells, but only weakly in T98G and HeLa cells. Immunoreactive endothelin was detected in the culture media of six out of the eight cell lines, but not in that of IMR-32 or BeWo cells. Treatment of T98G cells with an anti-endothelin-1 antibody or an anti-adrenomedullin antibody for 24 h decreased cell numbers to approx. 84% and 90% of control respectively. Treatment with the ET(A) receptor antagonist BQ-610 (1 microM) significantly decreased cell number to about 90% of control, whereas the ET(B) receptor antagonist BQ-788 had no significant effect. On the other hand, exogenously added endothelin-1, adrenomedullin or urotensin-II (0.1 microM) had no significant effects on cell number. These results suggest that endothelin-1 acts as a paracrine or autocrine growth stimulator in tumours. The effect of endothelin-1 on tumour growth appears to be mediated by the ET(A) receptor.

Topics: Adrenal Cortex Neoplasms; Adrenomedullin; Antibodies, Monoclonal; Cell Division; Choriocarcinoma; Colonic Neoplasms; Endothelin Receptor Antagonists; Endothelin-1; Glioblastoma; Growth Substances; HeLa Cells; Humans; Kidney Neoplasms; Neuroblastoma; Oligopeptides; Peptides; Piperidines; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Tumor Cells, Cultured; Urotensins; Vasodilator Agents

The mechanisms and factors leading to enhanced aldosterone secretion and ultimately to neoplastic transformation of the adrenal cortex are poorly defined. Angiotensin-II (Ang-II) and endothelin-1 (ET-1) have emerged as likely candidates among potential aldosterone secretagogues and adrenocortical growth-promoting factors. We therefore compared the effects of Ang-II and ET-1 on steroid hormone secretion of Conn's adenomas.. Ten Conn's adenomas that showed responsiveness to Ang-II blockade in vivo were recruited. Fragments of the tumors were collected immediately after surgical excision, and dispersed cells were obtained by collagenase digestion and mechanical disaggregation. Steroid hormones secreted by dispersed Conn's adenoma cells were assayed by quantitative high-performance liquid chromatography or radioimmunoassay.. Both Ang-II and ET-1 (10(-9) mol/L) similarly enhanced the overall steroid hormone production. ET-1 raised the release of pregnenolone (as evaluated by blocking its further metabolism by cyanoketone), corticosterone, 18-hydroxycorticosterone, and aldosterone, without affecting that of 11-deoxycortisol, cortisol, and 11-deoxycorticosterone. The hormonal responses to ET-1 were partially reversed by 10(-7) mol/L of either the ETA-receptor antagonist BQ-123 or the ETB-receptor antagonist BQ-788 and were abolished when both antagonists were used together. The aldosterone response to the selective activation of ETA and ETB receptors was studied in three Conn's adenomas by exposing dispersed cells to ET-1 (10(-9) mol/L) plus BQ-788 (10(-7) mol/L) and to the ETB-receptor agonist BQ-3020 (10(-8) mol/L). Both treatments raised aldosterone output by about 2-fold. ETA receptor-mediated aldosterone response was abolished by the protein kinase (PK) C inhibitor calphostin C (10(-5) mol/L). ETB receptor-mediated secretory response was lowered by either calphostin C and the cyclooxygenase (COX) inhibitor indomethacin (10(-5) or 10(-4) mol/L) and was completely suppressed when these two were combined. The PKA inhibitor H-89 and the lipoxygenase inhibitor phenidone were ineffective.. Collectively, our findings indicate that Ang-II and ET-1 equipotently stimulate both early and late steps of aldosterone synthesis in Conn's adenoma cells. The secretagogue effect of ET-1 occurs via the activation of ETA and ETB receptors, which are coupled with the PKC-dependent and the PKC- and COX-dependent signaling pathways, respectively.

Topics: Adrenal Cortex Hormones; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Adult; Aged; Aldosterone; Angiotensin II; Endothelin-1; Endothelins; Female; Humans; Indomethacin; Isoquinolines; Male; Middle Aged; Naphthalenes; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Prostaglandin-Endoperoxide Synthases; Protein Kinase C; Pyrazoles; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Sulfonamides; Tumor Cells, Cultured

The role played by endothelin (ET-1) and its receptor subtypes A and B (ET(A) and ET(B)) in the functional regulation of human NCI-H295 adrenocortical carcinoma cells has been investigated. Reverse transcription-PCR with primers specific for prepro-ET-1, human ET-1 converting enzyme-1, ET(A), and ET(B) complementary DNAs consistently demonstrated the expression of all genes in NCI-H295 cells. The presence of mature ET-1 and both its receptor subtypes was confirmed by immunocytochemistry and autoradiography, respectively. Aldosterone synthase (AS) messenger RNA was also detected in NCI-H295 cells, and AS gene expression was enhanced by both ET-1 and the specific ET(B) agonist IRL-1620; this effect was not inhibited by either the ET(A) antagonist BQ-123 or the ET(B) antagonist BQ-788. A clear-cut increase in the intracellular Ca2+ concentration in NCI-H295 cells in response to ET(B), but not ET(A), activation was observed. In light of these findings, the following conclusions can be drawn: 1) NCI-H295 cells possess an active ET-1 biosynthetic pathway and are provided with ET(A) and ET(B) receptors; 2) ET-1 regulates in an autocrine/paracrine fashion the secretion of aldosterone by NCI-H295 cells by enhancing both AS transcription and raising the intracellular Ca2+ concentration; and 3) the former effect of ET-1 probably involves the activation of both receptor subtypes, whereas calcium response is exclusively mediated by the ET(B) receptor.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Aspartic Acid Endopeptidases; Autoradiography; Base Sequence; Calcium; Cytochrome P-450 CYP11B2; DNA, Complementary; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Gene Expression Regulation, Enzymologic; Humans; Immunohistochemistry; Metalloendopeptidases; Oligopeptides; Piperidines; Polymerase Chain Reaction; Protein Precursors; Receptors, Endothelin; Tumor Cells, Cultured