The importance of an intact sympathetic innervation for the differentiation of the beta-adrenoceptor subtypes in the rat parotid gland.
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Adrenergic beta-Antagonists↗
Biomedical subjects
R Henriksson
Publications and source records attributed to R Henriksson.
beta 1- and beta 2-adrenoceptor agonists have different effects on rat parotid acinar cells.
To determine whether beta 1- and beta 2-adrenoceptors have similar functions in salivary glands, Sprague-Dawley rats were chronically treated with either the beta 1-selective (prenalterol), beta 2-selective (terbutaline), or the nonselective beta-agonist isoproterenol. All three agonists increased parotid and submandibular gland weight and acinar cell size. Isoproterenol and prenalterol caused marked quantitative and qualitative alterations in the granule population, whereas terbutaline had no effect. A single injection of isoproterenol caused a significant amylase release and accumulation of cAMP. Prenalterol was as potent as isoproterenol with regard to amylase release but was without effect on the cAMP content. In contrast, terbutaline had a minimal effect on amylase release but had the same effect as isoproterenol on cAMP accumulation. The in vitro perifusion experiments confirmed these in vivo results with respect to the effects of the selective beta-agonists. Thus, the present investigation using both morphological and biochemical methods suggests that beta 1- and beta 2-adrenoceptors may have different functions in rat parotid acinar cells. In addition, the stimulus-growth coupling seems to be unrelated to stimulus-secretion coupling.
Adrenergic beta-Agonists↗
Trophic effect of the sympathetic nervous system on the early development of the rat parotid gland: a quantitative ultrastructural study.
Rats were sympathetically denervated on one side by avulsion of the superior cervical ganglion either immediately after birth (within 4 hr) or when the salivary glands were fully developed. Nine weeks after ganglionectomy the parotid glands were subjects to microscopical studies. As shown by the lack of specific fluorescence, sympathetic denervation caused an almost total depletion of catecholamines in the acini. This was further substantiated at the electron microscopic level using KMnO4 as fixative. No alterations in either gland weight or in acinar cell size were noticeable after adult sympathectomy. On the other hand, neonatal denervation caused a decrease in gland weight as well as ascinar cell hypotrophy. The mean volume of individual acinar cells was reduced by roughly 25% and the granule volume density by about 50%. Also the mean volume of individual granules was decreased. These findings indicate an important role for the sympathetic nerve system in the maturation of the rat parotid gland.
Age Factors↗
Characterization of the rat parotid beta-adrenoceptor.
1 The effects of various beta-adrenoceptor agonists on amylase secretion from the rat parotid gland were studied by means of two different in vitro techniques. 2 The dose-response relation for each agonist was established, as also were the ED50 values. 3 All drugs appeared to act directly on the acinar cells, as reserpine-treatment did not abolish their secretagogic effects. 4 Two groups of agonists could be distinguished: one group consisting of adrenaline, noradrenaline and the B1-selective agonist prenalterol (H133/22) with a high enzyme discharge potency and a second group consisting of the beta 2-agonists, terbutaline and salbutamol, with a markedly lower effect. 5 The present data further support the theory that rat parotid acinar cells are supplied mainly with beta-adrenoceptors of the beta 1-subtype, similar to those present in heart and adipose tissue.
Adrenergic beta-Agonists↗
Anomalous effects of disodium cromoglycate. A study on two secretory systems.
The effects of disodium cromoglycate (DSCG) on in vitro histamine release from peritoneal and pleural mast cells, and a possible interference with adrenergic mechanisms was studied. Parallel to this study, the effects of DSCG on the well-established adrenoceptor-mediated amylase release from parotid glands were investigated. It was found that DSCG in low concentrations potentiates histamine release from peritoneal mast cells. Further more, this potentiation is enhanced by alpha-adrenoceptor blockade and diminished by beta-adrenoceptor antagonists. Histamine release from pleural mast cells is affected inversely to peritoneal cells, that is, the secretion is inhibited by DSCG at a high concentration but not at a low one. The inhibition is unaffected by alpha-blockers but totally abolished by the beta-antagonist propranolol. The amylase release induced by norepinephrine, mediated via beta1-adrenoceptor, is depressed by DSCG. The beta-antagonist-sensitive amylase release induced by phentolamine is also inhibited by DSCG. Finally, DSCG alone induces amylase release from the parotid gland. These results would seem to indicate that DSCG exerts some alpha-adrenoceptor activity. However, it is not possible, at present, to state whether this activity is of agonistic nature. DSCG has effects which with respect to pattern, correspond well to the action of beta-adrenoceptor agonists.
Adrenergic alpha-Antagonists↗
Dynamics of beta adrenoceptor induced amylase release and cyclic AMP accumulation in the guinea pig submandibular gland.
The dynamics of amylase release from the guinea pig submandibular gland were studied in vitro by applying a multi-channel microperfusion set. This technique makes it possible to measure time related enzyme release more accurately and to take samples of perifused tissue at short intervals. Stimulation of the beta-adrenoceptor with norepinephrine gives rise to a rapid initial enzyme discharge, detectable within 15 s. Administration of propranolol inhibits enzyme release, which is not restored after removal of the agent. Simultaneous measurements of tissue cyclic AMP during norepinephrine stimulation at various time intervals display a significant increase of cAMP as early as 15 s after stimulation of secretion. This increase of cAMP thus coincides with the discharge of amylase. In addition, cAMP continuously accumulates during 30 min of norepinephrine perifusion of the slices. The present study describes a valuable tool with high sensitivity for visualizing the relations between enzyme secretion from the salivary gland and the intracellular biochemical processes. The data obtained further indicate a close correlation between amylase and cAMP during the initial phase of enzyme discharge.
Amylases↗
Quantitative structural analysis and the secretory behaviour of the rat parotid gland after long and short term isoprenaline treatment.
Isoprenaline (IPR) was administered as daily subcutaneous injections into newborn rats for a period of 9 weeks (long-term treatment) and into 8 week-old rats for 10 days (short-term treatment). Both the parotid and the submandibular glands increased five- to six-fold in weight in the two groups due to hypoertrophy as well as to hyperplasia. The parotid glands were subjected to electron microscopic stereological analyses and to in vitro secretory studies. The results were compared with non-treated controls. Whereas mean total cell volume in the latter was 807 microns 3 it amounted to 5804 microns 3 in glands from long-term IPR-treated rats. A striking increase in size and number of cytoplasmic granules was noted after IPR treatment; there was also a marked decrease in granule electron density as compared with control cells. Granule volume density was 31.2 +/- 1.8% in controls and 58.0 +/- 1.5% in long-term IPR-treated rats. The increase in volume density, however, was accompanied by a relative decrease in amylase and cyclic AMP contents. On a percentage basis, the basal secretion of amylase from incubated IPR-treated parotid glands was markedly higher (roughly twice) than that of control glands; the absolute release of amylase into the medium, however, was only slightly increased. Basal secretion was not energy requiring, which would suggest a passive diffusion. Stimulation by beta-adrenoceptor agonists, including beta 1 and beta 2 selective agents, had no or only a small stimulatory effect in vitro on IPR-treated glands. Dibutyryl cyclic AMP was effective in controls but not in treated glands. Cholinergic stimulation caused a considerable amylase release from glands of IPR-treated rats; this release was comparable to that obtained in controls. The results suggest that superstimulation of the beta-adrenoceptor leads to a decreased sensitivity for adrenergic agonists. This may be due to membrane changes (e.g. modified receptor sites) and/or to an altered intracellular metabolism (e.g. a modified turnover of cyclic nucleotides).
Adrenergic beta-Agonists↗
Secretory behavior and ultrastructural changes in mouse gallbladder principal cells after stimulation with cholinergic and adrenergic drugs. A morphometric study.
Principal cells of mouse gallbladder epithelium were subjected to a quantitative electron microscope study after in vivo and in vitro exposure to pilocarpine, noradrenaline, atropine, and phenoxybenzamine. Stereologic measurements were performed on randomly selected principal cells, and special interest was paid to changes in the size of the secretory granule population of the cells. Thirty minutes after in vivo and in vitro stimulation with pilocarpine, there was a significant decrease of the volume density of the glycoprotein-containing granules in the principal cells. Thirty minutes after in vivo administration of the cholinergic antagonist atropine, a significant increase of this parameter was observed. In vitro incubation for 30 min with a combination of pilocarpine and atropine extinguished the pilocarpine-induced effect on the secretory granules. Noradrenaline and phenoxybenzamine (an alpha-adrenergic blocking agent) in vivo and in vitro (30 min) had no effect on the volume density of the secretory granules. The authors' findings suggest that principal cells of the mouse gallbladder epithelium exhibit an increased rate of secretion of glycoprotein granules after stimulation in vivo and in vitro with cholinergic agents, whereas adrenergic agents are without effect.
Animals↗
Effects of a new selective beta1-adrenoceptor agonist on amylase secretion from the rat parotid gland.
The effects of a new selective beta1-adrenoceptor agonist, (--)-1-(4-hydroxyphenoxy)-3-isopropyl-amino-propanol-2-hydrochloride (H 133/22), on amylase secretion from the rat parotid gland were investigated in an in vitro system. The results were compared to the secretory responses obtained with noradrenaline, adrenaline, methoxyamine and terbutaline. H 133/22 was found to be a potent enzyme secretagogue and appeared even more effective than noradrenaline and adrenaline, particularly at low concentrations. The beta1-adrenoceptor agonist, terbutaline, also stimulated amylase discharge from the parotid gland but was much less potent than H 133/22. Methoxyamine had no effect on enzyme secretion. We suggest that the adrenergic stimulation of amylase secretion from the rat parotid gland is mainly mediated by beta1-receptors.
Adrenergic beta-Agonists↗
Distribution of mucosubstances in adenoid cystic carcinoma.
The distribution of mucosubstances in adenoid cystic carcinoma was investigated, and an attempt was made to characterize histochemically the various mucosubstances present. For these purposes the high iron diamine technique (HID), as well as the Astra blue, aldehyde fuchsin and Alcian blue staining methods were employed. Alcian blue was further combined with the periodic acid-Schiff (PAS) technique, the Alcian blue being applied at pH levels between 0.5 and 2.5. In addition the effect of neuraminidase and hyaluronidase treatment as well as methylation and acid hydrolysis procedures on the staining qualities were studied. Acidic mucosubstances with varying histochemical properties were present in different structures of the neoplasm. The characteristic pseudocyst, a major structural component of the neoplasm, stained strongly with HID, Astra blue, aldehyde fuchsin and Alcian blue at low pH. These staining reactions were markedly suppressed by hyaluronidase treatment, and are apparently attributable to the presence of chondroitin 4- and/or 6-sulfate. Employing the Alcian blue-critical electrolyte concentration technique, the basophilia of the pseudocysts was suppressed at a concentration of 0.5-0.6 M MgCl2, which might indicate polysaccharides of relatively low degree of sulfation. An additional, non-sulfated acid mucin could also be demonstrated in these structures. In certain duct and gland like structures of the tumours, a change in staining pattern from blue or blue-red to red could be observed after exposure of the sections to neuraminidase and subsequent staining with the Alcian blue (pH 2.5)-PAS sequence. Similar observations were also made when the pH of the Alcian blue was lowered to 1.5-1.0, as well as after acid hydrolysis. These findings afford evidence for the presence of a neuraminidase susceptive sialomucin in certain epithelial secretions of the tumor. At the ultrastructural level the replicated basement lamina of the pseudocysts displayed a strong positive reaction with the PA-CrA-silver staining technique. Furthermore, amorphous material within the lumina of small duct like structures also displayed a positive reaction. The amorphous material of the cystic compartments was less reactive.
Carcinoma, Adenoid Cystic↗
Some ultrastructural features of acinic cell carcinoma.
The ultrastructure of an acinic cell carcinoma, occurring in the left parotid gland of a 52-year-old woman and causing a total facial nerve paralysis, is described. Histologically the tumour consisted of numerous granulated cells arranged around lumen-like openings and resembling a secretory system. Furthermore, areas with agranulated cells growing in a solid pattern were also encountered. In the electron microscope the cytoplasmic granules of the tumour cells displayed a varied appearance. Granules of a dense homogeneous type, as well as granules with a more electron lucid appearance were observed. Furthermore, numerous cytoplasmic granules displayed a bipartite structure with a dense central and a more electron lucid outer zone. In specimens primarily fixed in OSO4 or KMnO4 the granules displayed a 'leached out' appearance. The membrane-bounded of the tumour cells also showed a strong positive staining with the periodic acid-chromic silver technique of Rambourg et al. (1969). Other characteristic ultrastructural features of the tumour cells studied were: Smooth cell surfaces, the presence of subplasmalemmal bands of electron dense material, desmosome-like attachment areas between cells and grossly altered mitochondria.
Carcinoma↗
[Grating floors in Sweden--trends and experiences].
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Animals↗
Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression.
Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, the ventricular ependyma, meninges, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal brain tissue. Our finding may suggest a functional co-operation of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.
Animals↗
The effect of long-term variation in sympathetic activity on testicular morphology in immature rats.
In order to investigate the effect of increased and decreased sympathetic activity on testicular development, immature male rats were injected with isoproterenol or 6-hydroxydopamine from birth up to 49 days of age. Isoproterenol treatment resulted in a marked Leydig cell hypertrophy but the development of the spermatogenic epithelium was unaffected compared to that in saline treated controls. 6-hydroxydopamine treatment in a dose inhibiting the development of the parotid gland did not influence testicular development.
Animals↗
Role of ondansetron plus dexamethasone in fractionated chemotherapy.
This randomised, double-blind, parallel-group study was carried out to compare the efficacy and safety profile of ondansetron plus dexamethasone and metoclopramide plus dexamethasone in patients receiving fractionated cisplatin (20-25 mg/m2/day) chemotherapy for the treatment of testicular cancer. An interim analysis of 95 patients showed that the ondansetron regimen was significantly superior compared to the metoclopramide regimen (p < 0.001). According to the study protocol the study was terminated at this stage. At the time the decision to stop the study was taken, a total of 113 patients had been enrolled and were evaluable on an 'intention to treat' basis. Fifty-six of these had received ondansetron (32 mg i.v. single dose/day) plus dexamethasone (20 mg i.v. single dose/day) and 57 were given metoclopramide (2 mg/kg or 1 mg/kg i.v. twice a day) plus dexamethasone (20 mg i.v. single dose/day). The ondansetron regimen was significantly superior in the control of emesis and nausea. Seventy-one percent of patients experienced 2 or fewer emetic episodes over the entire 5-day study period compared with 26% of patients given metoclopramide (p < 0.001). Seventy-nine percent of patients in the ondansetron group experienced 'none' or only 'mild' nausea compared with 39% of patients in the metoclopramide group (p < 0.001). The dose of metoclopramide had to be reduced during the study from 2 mg/kg i.v. twice daily to 1 mg/kg i.v. twice daily because 4 of the first 8 patients randomised to this treatment experienced extrapyramidal reactions. Ondansetron was well tolerated and it did not induce any extrapyramidal reactions. The results of this study show that ondansetron plus dexamethasone represents a very effective treatment option for patients receiving fractionated cisplatin chemotherapy for testicular cancer.
Adolescent↗
Alterations of tumour cells, stroma and apoptosis in rat prostatic adenocarcinoma following treatment with histamine, interleukin-2 and irradiation.
The present study was designed to determine whether IL-2 and histamine alone, or in combination could modulate the effects of irradiation on Dunning (R3327) rat adenocarcinomas at the cellular level. Copenhagen x Fisher rats carrying bilateral tumours in the flank were used. When the tumours had a median volume of 150 mm3, one group of rats was treated with histamine alone (4 mgkg-1 subcutaneously on week days), another group with interleukin-2 (IL-2) alone (425 IU kg-1 continuous infusion) and a third group with both histamine and IL-2 during 6 weeks. Irradiation was given one week after the onset of treatment with histamine and/or IL-2, with a linear accelerator 6 MV, in a dose of 6 Gy/day for 3 days to the tumour of one side, while the other side served as control. Morphometric analyses of the amount of cystic structures, volume density for tumour epithelium, stroma and acinar lumina, the number of activated macrophages and natural killer cells (NK-cells) and in situ detection of apoptotic cells was carried out 5 weeks after the irradiation, when the experiment was ceased. The combination of IL-2 with histamine and irradiation significantly augmented the reduction of tumour cells (p < 0.002) and increased the number of apoptotic cells (p < 0.007) compared to irradiation alone. The number of cystic structures within tumour tissue increased in all tumours that received histamine, but was most pronounced in the three combination group. A strong negative correlation between the epithelial cells and the apoptotic index (rs = -0.61, p < 0.0001) and a strong positive correlation between the stroma and the apoptotic index (rs = 0.59, p < 0.001) was found. A prominent infiltration of activated macrophages was observed in the irradiated group. This infiltration was impaired by the drugs. The results suggested that the used three modality treatment could be of value in increasing the efficacy of local radiotherapy concomitantly with a most plausible effect on micrometastatic spread. The results also propose that volume measurements alone are not an optimal parameter when evaluating effects of new treatment modalities.
Adenocarcinoma↗
Hypothermic modulation of doxorubicin, cisplatin and radiation cytotoxicity in vitro.
BACKGROUND: The influence of hypothermia on doxorubicin, cisplatin and radiation cytotoxicity was investigated in vitro. MATERIALS AND METHODS: A human glioma cell line (251MG) in early exponential growth was exposed to doxorubicin or cisplatin at various concentrations for 4 hours, or X-irradiation at 28 degrees C or 37 degrees C. The cells continued growing in multi-well plates at 37 degrees C and were counted every third day until the end of the logarithmic phase, on day 13. RESULTS: Exposure to doxorubicin 0.05-0.5 microg/ml or cisplatin 1-10 microg/ml caused a dose-dependent inhibition of cell growth with a significantly reduced toxicity when exposed at 28 degrees C as compared to 37 degrees C. Irradiation with 4 Gy also resulted in less toxicity during hypothermia. Chlorpromazine 0.01-10 microg/ml, used to induce hypothermia in vivo (1), neither influenced, cellular growth itself nor interacted with doxorubicin, cisplatin or irradiation. CONCLUSION: Moderate hypothermia (28 degrees C) appears to protect against the cellular insult of doxorubicin, cisplatin and ionising irradiation and their consequences.
Antineoplastic Agents↗
Heterogeneity in the expression of markers for drug resistance in brain tumors.
Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.
ATP Binding Cassette Transporter, Subfamily B, Mem↗