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Sánchez ML, Rodríguez FD, Coveñas R. Neuropeptide Y Peptide Family and Cancer: Antitumor Therapeutic Strategies. Int J Mol Sci 2023; 24:9962. [PMID: 37373115 DOI: 10.3390/ijms24129962] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Currently available data on the involvement of neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) and their receptors (YRs) in cancer are updated. The structure and dynamics of YRs and their intracellular signaling pathways are also studied. The roles played by these peptides in 22 different cancer types are reviewed (e.g., breast cancer, colorectal cancer, Ewing sarcoma, liver cancer, melanoma, neuroblastoma, pancreatic cancer, pheochromocytoma, and prostate cancer). YRs could be used as cancer diagnostic markers and therapeutic targets. A high Y1R expression has been correlated with lymph node metastasis, advanced stages, and perineural invasion; an increased Y5R expression with survival and tumor growth; and a high serum NPY level with relapse, metastasis, and poor survival. YRs mediate tumor cell proliferation, migration, invasion, metastasis, and angiogenesis; YR antagonists block the previous actions and promote the death of cancer cells. NPY favors tumor cell growth, migration, and metastasis and promotes angiogenesis in some tumors (e.g., breast cancer, colorectal cancer, neuroblastoma, pancreatic cancer), whereas in others it exerts an antitumor effect (e.g., cholangiocarcinoma, Ewing sarcoma, liver cancer). PYY or its fragments block tumor cell growth, migration, and invasion in breast, colorectal, esophageal, liver, pancreatic, and prostate cancer. Current data show the peptidergic system's high potential for cancer diagnosis, treatment, and support using Y2R/Y5R antagonists and NPY or PYY agonists as promising antitumor therapeutic strategies. Some important research lines to be developed in the future will also be suggested.
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Affiliation(s)
- Manuel Lisardo Sánchez
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla and León (INCYL), University of Salamanca, 37008 Salamanca, Spain
| | - Francisco D Rodríguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemical Sciences, University of Salamanca, 37008 Salamanca, Spain
- Group GIR-USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37008 Salamanca, Spain
| | - Rafael Coveñas
- Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla and León (INCYL), University of Salamanca, 37008 Salamanca, Spain
- Group GIR-USAL: BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37008 Salamanca, Spain
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Fahrenkrug J, Hannibal J. Localisation of the neuropeptide PACAP and its receptors in the rat parathyroid and thyroid glands. Gen Comp Endocrinol 2011; 171:105-13. [PMID: 21176780 DOI: 10.1016/j.ygcen.2010.11.026] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 11/18/2010] [Accepted: 11/24/2010] [Indexed: 11/19/2022]
Abstract
PACAP (pituitary adenylate cyclase activating polypeptide) is widely distributed neuropeptide acting via three subtypes of receptors, PAC(1), VPAC(1) and VPAC(2). Here we examined the localisation and nature of PACAP-immunoreactive nerves in the rat thyroid and parathyroid glands and defined the distribution of PAC(1), VPAC(1) and VPAC(2) receptor mRNA's. In the parathyroid gland a large number of nerve fibres displaying PACAP-immunoreactivity were distributed beneath the capsule, around blood vessels and close to glandular cells. Most of the PACAP-nerves were sensory, since they co-stored CGRP (calcitonin-gene-related peptide) and were sensitive to capsaicin-treatment. mRNA's for PAC(1) and VPAC(2) receptors occurred in the parathyroid gland, mainly located in the glandular cells. In the thyroid gland PACAP-immunoreactive nerve fibres were associated with blood vessels, thyroid follicles and parafollicular C-cells. A high degree of co-existence between PACAP and VIP (vasoactive intestinal polypeptide) was observed in the intrathyroid nerve fibres and cell bodies of the thyroid ganglion indicating a common origin for the two peptides. A minor population of PACAP-immunoreactive nerve fibres with relation to blood vessels co-stored NPY (neuropeptide Y), whereas only a few fibres co-stored CGRP. PAC(1) and VPAC(1) receptor mRNA's occurred in follicular cells and blood vessels, whereas the expression of the VPAC(2) receptor was low. The findings suggest that PACAP plays a role in the regulation of parathyroid and thyroid blood flow and hormone secretion.
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Affiliation(s)
- Jan Fahrenkrug
- Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark.
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Miyato H, Kitayama J, Ishigami H, Kaisaki S, Nagawa H. Loss of sympathetic nerve fibers around intratumoral arterioles reflects malignant potential of gastric cancer. Ann Surg Oncol 2011; 18:2281-8. [PMID: 21290194 DOI: 10.1245/s10434-011-1562-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2010] [Indexed: 12/25/2022]
Abstract
BACKGROUND The role and clinical significance of the alteration of sympathetic nerve fibers (SNF) was assessed in gastric cancer. Loss of nerve fibers in malignant tumors has previously been described; however, how dysfunction of the nervous system is involved in cancer progression has not been clarified in clinical studies. MATERIALS AND METHODS The distribution of SNF was examined in 82 surgically resected gastric cancer specimens with immunohistochemical staining of tyrosine hydroxylase (TH), and the association with clinicopathological findings as well as the clinical outcome of the patients was retrospectively evaluated. RESULTS Arterioles in the normal gastric wall were totally covered with SNF, while the immunoreactivity to TH was markedly reduced around arterioles in cancer tissue. The degree of loss of SNF was significantly correlated with the depth of invasion (P < .0001) and lymph node metastasis (P < .0001) as well as microvessel density (MVD) (P = .0043). Moreover, patients who had tumors with marked loss of SNF showed a markedly worse clinical outcome, with an independent association by multivariate analysis. CONCLUSIONS Loss of periarteriolar SNF is associated with aggressive phenotype of gastric cancer possibly through enhanced angiogenesis and thus could be a useful marker to predict the clinical outcome.
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Affiliation(s)
- Hideyo Miyato
- Department of Surgery, Division of Surgical Oncology, University of Tokyo, Tokyo, Japan.
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Schmitt CP, Obry J, Feneberg R, Veldhuis JD, Mehls O, Ritz E, Schaefer F. β1-Adrenergic Blockade Augments Pulsatile PTH Secretion in Humans. J Am Soc Nephrol 2003; 14:3245-50. [PMID: 14638923 DOI: 10.1097/01.asn.0000101240.47747.7f] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
ABSTRACT. Pulsatile peptide hormone secretion provides efficient control of specific end organ functions. To test the hypothesis that sympathetic neuronal activity drives synchronous pulsatile PTH release from the parathyroid glands, we investigated the acute effects of β1-adrenergic receptor blockade on PTH secretion patterns in a single-blinded study in nine healthy adults. Plasma PTH levels were determined at 1-min intervals. After a 75-min baseline period, seven subjects received a continuous intravenous infusion of the short-acting β1-adrenergic receptor blocker esmolol for 105 min. After a 30-min washout period, esmolol was infused for another 30 min. Two additional subjects were randomized to receive solvent infusions. PTH secretion characteristics were analyzed by multiparameter deconvolution analysis, and the orderliness of plasma PTH fluctuations by Approximate Entropy statistics. BP slightly decreased during esmolol infusion, whereas heart rate, ionized calcium, phosphate, magnesium, and plasma and urine catecholamines remained unchanged. Esmolol increased mean plasma PTH by 33 ± 8% (P < 0.01), due to a preferential increase in the pulsatile PTH secretion component (+129 ± 44%, P < 0.02). The increased pulsatile PTH secretion was mediated by an augmented PTH burst mass (+117 ± 42%, P < 0.01), whereas burst frequency remained unchanged. The regularity of PTH fluctuations was not affected by the β-adrenergic blockade. The effects were reproducible during the second esmolol infusion. The authors conclude that the sympathetic nervous system has a modulating effect on pulsatile PTH secretion. Selective β-1 adrenergic blockade acutely increases plasma PTH by augmenting the mass of hormone secreted per burst, but it does not alter the rhythmicity of pulsatile PTH release.
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Affiliation(s)
- Claus P Schmitt
- Departments of Pediatrics and Internal Medicine, University of Heidelberg, Heidelberg, Germany
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Abstract
AIM: To investigate the distribution of neuropeptide-immunoreactive nerve fibers in esophageal and cardiac carcinoma as well as their relationship with tumor cells so as to explore if there is nerve innervation in esophageal and cardiac carcinoma.
METHODS: Esophageal and cardiac carcinoma specimens were collected from surgical operation. One part of them were fixed immediately with 4% paraformaldehyde and then cut with a cryostat into 40-µm-thick sections to perform immunohistochemical analysis. Antibodies of ten kinds of neuropeptide including calcitonin gene-related peptide (CGRP), galanin (GAL), substance P (SP), etc. were used for immunostaining of nerve fibers. The other part of the tumor specimens were cut into little blocks (1 mm3) and co-cultured with chick embryo dorsal root ganglia (DRG) to investigate if the tumor blocks could induce the neurons of DRG to extend processes, so as to probe into the possible reasons for the nerve fibers growing into tumors.
RESULTS: Substantial amounts of neuropeptide including GAL-, NPY-, SP-immunoreactive nerve bundles and scattered nerve fibers were distributed in esophageal and cardiac carcinomas. The scattered nerve fibers waved their way among tumor cells and contacted with tumor cells closely. Some of them even encircled tumor cells. There were many varicosities aligned on the nerve fibers like beads. They were also closely related to tumor cells. In the co-culture group, about 63% and 67% of DRG co-cultured with esophageal and cardiac tumor blocks respectively extended enormous processes, especially on the side adjacent to the tumor, whereas in the control group (without tumor blocks), no processes grew out.
CONCLUSION: Esophageal and cardiac carcinomas may be innervated by peptidergic nerve fibers, and they can induce neurons of DRG to extend processes in vitro.
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Affiliation(s)
- Shuang-Hong Lü
- Department of Neurobiology, Institute of Basic Medical Sciences, Academy of Military Medical Sciences, Beijing 100850, China
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Schmitt CP, Löcken S, Mehls O, Veldhuis JD, Lehnert T, Ritz E, Schaefer F. PTH pulsatility but not calcium sensitivity is restored after total parathyroidectomy with heterotopic autotransplantation. J Am Soc Nephrol 2003; 14:407-14. [PMID: 12538741 DOI: 10.1097/01.asn.0000043905.35268.86] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
In healthy humans, parathyroid hormone (PTH) is secreted via basal mode with superimposed oscillatory bursts every 8 to 12 min. Amplitude and frequency changes mediate the instantaneous response of the parathyroids to changes in ambient Ca(2+) concentrations. The parathyroid gland tetrad may be synchronized by autonomic innervation. This study investigated the effect of total parathyroidectomy and heterotopic autotransplantation of parathyroid tissue (PTX) on PTH secretion patterns in nine patients with end-stage renal disease. Intact-PTH versus time concentration profiles were obtained early (1 to 8 wk, n = 4) or late (15 to 33 mo, n = 5) after PTX. In four patients late after PTX, Ca(2+) responsiveness of PTH secretion was additionally investigated by citrate and calcium clamp studies. The nonrandomness of plasma PTH fluctuations was assessed by the approximate entropy (ApEn) statistic, and secretion characteristics by multiparametric deconvolution analysis. Results were compared with those of matched normal subjects and chronic renal failure (CRF) patients without PTX. PTH burst frequency was 2.9 +/- 0.1 h(-1) early and 7 +/- 0.4 h(-1) late after PTX as compared with 8.1 +/- 0.4 h(-1) in CRF and 7 +/- 0.3 h(-1) in healthy controls. Fractional pulsatile PTH secretion was diminished after PTX (18 +/- 2%) compared with healthy controls (32 +/- 5%, P < 0.05) and CRF patients (25 +/- 4%, P = 0.05). The orderliness of PTH release was significantly reduced after PTX (ApEn: 1.59 +/- 0.03 versus 1.41 +/- 0.09 in healthy and 1.46 +/- 0.03 in CRF controls, P < 0.01). Acute hypocalcemia elicited a lesser increase in pulsatile PTH secretion in PTX patients (147 +/- 134%) than in the CRF (500 +/- 92%, P = 0.05) and healthy controls (1410 +/- 290%, P < 0.05), mainly due to a diminished mass of PTH secreted per burst. Pulsatile PTH secretion was also resistant to hypercalcemia, wherein the suppression of burst mass was significantly reduced compared with that in healthy controls. In conclusion, pulsatile PTH secretion is partially restored within 2 yr of PTX. However, the capacity of the autotransplanted tissue to adapt to changes in ionized calcium remains profoundly disturbed.
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Affiliation(s)
- Claus P Schmitt
- Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
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Khan A, Tischler AS, Patwardhan NA, DeLellis RA. Calcitonin immunoreactivity in neoplastic and hyperplastic parathyroid glands: an immunohistochemical study. Endocr Pathol 2003; 14:249-55. [PMID: 14586070 DOI: 10.1007/s12022-003-0017-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Previous studies have established that calcitonin (CT) and the calcitonin generelated peptide (CGRP) are synthesized and stored in subsets of hyperplastic parathyroid cells that also contain chromogranin B (Schmid, KW, et al. Lab Invest 73:90, 1995). The purpose of the current study was to determine whether other generic but variably expressed neuroendocrine markers, i.e., synaptophysin (SYN) and CD57 (Leu7), are also present in normal, hyperplastic, and neoplastic parathyroid tissue and to assess their relationships to the presence of CT. DESIGN Immunoperoxidase stains for chromogranin A (CgA), chromogranin B (CgB), SYN, CD57, and CT were performed on 54 hyperplastic, 17 neoplastic (adenoma), and 16 normal parathyroid glands. Sequential sections were stained with antibodies to CgA, CgB, SYN, CD57, and CT using standard avidin-biotin-peroxidase techniques. RESULTS CgA was diffusely expressed in all normal, hyperplastic, and neoplastic glands. In hyperplasia, CgB was variably expressed in 6 cases (11%), SYN in 6 (11%), CD57 in 15 (28%), and CT in 8 (15%). In adenomas, CgB was variably expressed in 3 (17%), SYN in 3 (17%), CD57 in 4 (23%), and CT in 4 (23%). All normal glands were negative for CgB, SYN, and CT, while CD57 was variably expressed in 17%. Of the 12 glands that were CT positive, 8 were also positive for CgB, 2 for SYN, and 9 for CD57. Four glands that were strongly and diffusely positive for CT were CgB and SYN negative. CONCLUSIONS CgB, SYN, and CD57 are markers for subsets of hyperplastic and neoplastic parathyroid glands. CT is also expressed in a significant proportion of hyperplastic and neoplastic parathyroid glands, and may be independent of the presence of CgB, SYN, or DD57. The significance of these findings in relationship to the abnormal calcium metabolism in patients with parathyroid hyperplasia remains to be determined.
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Affiliation(s)
- Ashraf Khan
- Department of Pathology & Surgery, University of Massachusetts Medical School, Worcester, MA, USA.
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Sherwood NM, Krueckl SL, McRory JE. The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocr Rev 2000; 21:619-70. [PMID: 11133067 DOI: 10.1210/edrv.21.6.0414] [Citation(s) in RCA: 160] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The pituitary adenylate cyclase-activating polypeptide (PACAP)/ glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily began with a gene or exon duplication and then continued to diverge with some gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The diverse functions of PACAP include regulation of proliferation, differentiation, and apoptosis in some cell populations. In addition, PACAP regulates metabolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be identified.
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Affiliation(s)
- N M Sherwood
- Department of Biology, University of Victoria, British Columbia, Canada.
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Galvin RJ, Babbey LE, Hipskind PA, Lamar T, George CA, Baez M, Gitter BD. Substance P regulates PTH secretion through the neurokinin-1 receptor. Biochem Biophys Res Commun 2000; 270:230-4. [PMID: 10733932 DOI: 10.1006/bbrc.2000.2418] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The primary regulator of PTH secretion is serum ionized Ca(2+); however, neuropeptide-containing nerve fibers have been localized to the parathyroid gland. The purpose of this study was to determine whether or not substance P (SP) regulates PTH secretion. In dispersed porcine parathyroid cells, SP reversibly inhibited 0.5 mM CaCl(2)-induced PTH secretion (IC(50) = 0.29 nM) and had no effect at CaCl(2) concentrations of 1.5 mM and greater. At 0.5 mM CaCl(2), treatment with a NK-1 selective receptor agonist resulted in a concentration-dependent decrease in PTH secretion (IC(50) = 0.21 nM). In contrast, NK-2 and NK-3 receptor agonists were approximately 100-fold less active than SP or the NK-1 receptor selective agonist. An enantiospecific reversal of the effects of SP on PTH secretion was observed with LY306740, a potent selective NK-1 receptor antagonist (K(i) = 0.125 nM). In porcine parathyroid cells, expression of mRNA for the NK-1 receptor was observed using RT-PCR. In summary, a novel neuroendocrine pathway is described whereby the neuropeptide, SP, regulates PTH secretion through NK-1 receptors.
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Affiliation(s)
- R J Galvin
- Endocrine Division, Neurosciences Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
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Abstract
BACKGROUND Autotransplantation of parathyroid glands in man is performed to preserve parathyroid function after surgery. In a rat model, we performed autotransplantation into the renal subcapsular space to examine reinnervation and changes in cell activity in the transplanted glands. METHODS Parathyroids grafted for 1-20 weeks were examined immunocytochemically for general and specific neuroendocrine markers to visualize nerve fibers and glandular cells and for bromodeoxyuridine to determine cell proliferation. In situ hybridization was used to localize and quantitate chromogranin A and parathyroid hormone (PTH) mRNA expression. RESULTS Reinnervation was observed as early as 1 week after transplantation in that nerve fibers containing the general neuronal marker protein gene product 9.5 appeared along blood vessels. During the following 20 weeks, the nerve fiber density increased gradually. One week after transplantation, the immunoreaction intensity for PTH, chromogranin A, and pancreastatin was lower than in control glands. Bromodeoxyuridine-labeled cells were fewer than in control glands at 1 week and at 5-10 weeks after transplantation. The density of PTH mRNA labeling was lower than in control glands during the whole time period studied and reached a minimum after 10 weeks. The density of chromogranin A mRNA labeling was unaffected at 1 and 3 weeks after transplantation and then decreased to a minimum at 10 weeks after transplantation; at 20 weeks, the chromogranin A mRNA labeling had again reached the level in control glands. CONCLUSION The changes in PTH and chromogranin A immunoreaction intensity and mRNA density indicate reduced hormone production for several weeks after transplantation. Our results using transmitter-specific markers indicate a rapid ingrowth of mostly sympathetic nerve fibers, preferentially around blood vessels. Later on, parasympathetic and sensory nerve fibers reached the grafts. The parathyroid innervation may be of importance for parathyroid hormone regulation, and the finding of an early reinnervation could be of clinical importance.
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Affiliation(s)
- L Luts
- Department of Physiology and Neuroscience, University of Lund, Sweden
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Luts L, Bergenfelz A, Alumets J, Sundler F. Nitric Oxide Synthase in Human Parathyroid Glands and Parathyroid Adenomas. Endocr Pathol 1996; 7:207-213. [PMID: 12114733 DOI: 10.1007/bf02739923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Nitric oxide (NO) is a novel gaseous intercellular transmitter thought to play important physiological roles in the regulation of blood flow and hormone secretion in, for example, the pituitary, the thyroid, and the endocrine pancreas. Whether nitric oxide synthase (NOS) is present in the human parathyroid glands has not yet been demonstrated. In the present study, histologically normal, but functionally suppressed human parathyroid glands and parathyroid adenomas from patients with primary hyperparathyroidism were investigated by immunocytochemistry with antibodies against neuronal NOS and by reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry. We also used H&E to identify the NOS-immunoreactive cells. Immunocytochemistry demonstrated the presence of neuronal-type NOS in a subpopulation of glandular cells, identified as oxyphilic cells, in both normal parathyroid glands and adenomas. NADPH-diaphorase staining visualized NOS in the endothelium of blood vessels and in glandular cells, corresponding to those containing immunoreactive NOS. In addition, we found NADPIH-diaphorase staining in many chief cells. Our results indicate that both glandular cells and vascular endothelium in human parathyroid glands and adenomas express NOS. There is thus a morphological substrate for locally produced NO that may be involved in the regulation of parathyroid blood flow and hormone secretion.
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