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Biomedical subjects

K Brodin

Publications and source records attributed to K Brodin.

At least 19 recordsLinked to original sources
PubMed1994

Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions.

Recent reports suggest that a cholecystokinin (CCK)-related dysfunction may be a target by which drugs can modulate anxiety and panic disorders. In the present study, effects of subchronic (14 days) treatment with the monoamine uptake inhibitors nortriptyline (30 mumol/kg per day), amitriptyline (29 mumol/kg per day), clomipramine (32 mumol/kg per day) and alaproclate (39 mumol/kg per day), as well as with the benzodiazepine clonazepam (0.25 mumol/kg per day), on rat brain levels of CCK- and substance P-like immunoreactivity, were compared. The drugs were administered by continuous s.c. infusion using implanted osmotic pumps. The plasma concentrations of the monoamine uptake inhibitors were similar after 1 and 2 weeks of treatment, indicating that steady-state plasma levels had been reached during the first week. Treatment with clomipramine or clonazepam increased the CCK-like immunoreactivity level in the ventral tegmental area (by 64.4 +/- 28.8% and 105.1 +/- 28.8%, respectively) and in the cingulate cortex (by 30.3 +/- 10.1% and 36.0 +/- 11.8%, respectively) (P < 0.05 or P < 0.01). Clomipramine also significantly increased the CCK-like immunoreactivity level in the periaqueductal grey by 85.1 +/- 29.7%. Neither nortriptyline nor amitriptyline or alaproclate produced any significant alterations in the CCK- or substance P-like immunoreactivity levels in the areas examined. The present results may suggest that an altered utilization of CCK in limbic circuits could be of importance for the well documented clinical effect of clomipramine and clonazepam in panic disorders.

Amitriptyline↗
PubMed1994

Multiple molecular forms of tachykinins in rat spinal cord: a study comparing different extraction methods.

Various procedures for extraction at acid, neutral and alkaline pH were compared with regard to the yield of different tachykinins and tachykinin-like substances from rat spinal cord. Reverse phase high performance liquid chromatography (RP-HPLC) and radioimmunoassay with various C-terminally directed tachykinin antisera and a newly developed N-terminally directed substance P (SP)-antiserum (SPN 1) were used. Antiserum SPN 1 fully reacts with SP-analogues modified at the C-terminal end (SP free acid and SP-Gly-Lys) and also (77%) with SP(1-9) but not with C-terminal SP-fragments lacking 2 or more N-terminal amino acids. The highest levels of SP-like immunoreactivity (LI) and neurokinin A (NKA)-LI were measured after combined water and acetic acid extraction procedures. Also when measuring cholecystokinin-like immunoreactivity the highest level was obtained following this extraction procedure. RP-HPLC revealed a major component of SP-LI at the position of synthetic SP irrespectively of the extraction method and if the C- or N-terminally directed antiserum was used. Neutral water extracts contained a late eluting component detected with the C-terminally, but not with the N-terminally, directed antiserum. Acid and alkaline extracts, in contrast, contained components which could be detected with the N-terminally, but not with the C-terminally, directed SP-antiserum. Immunoreactive components eluting at the position of NKA and NKB were found in all types of extracts with NKA-, kassinin- and eledoisin-antisera. The NKB- and neuropeptide K (NPK)-components were more prominent in acid than in neutral and alkaline extracts. In conclusion, the present results indicate that rat spinal cord may contain molecular forms of tachykinin-like immunoreactivity in addition to those previously described and illustrate the importance of the choice of extraction method in immunochemical studies. Combined extraction in water and acetic acid appears to be a suitable method when the content of peptides with different chemical properties are to be measured in a tissue sample.

Animals↗
PubMed1994

Effects of sequential removal of rats from a group cage, and of individual housing of rats, on substance P, cholecystokinin and somatostatin levels in the periaqueductal grey and limbic regions.

The effect of specific stressful stimuli on neuropeptide levels was studied in rat brain regions known to be involved in the mediation of stress responses and anxiety. Rats were sequentially removed, one by one with 20-min intervals from group cages and immediately decapitated. A selective increase of the somatostatin level was observed in the amygdala in the rats taken for sacrifice second last and last, compared to the rats taken earlier from the respective group cage (increases by 40 to 69%, p < 0.05 or p < 0.01). Isolation of rats in single cages for 24 h or 1 week before sacrifice, increased the substance P level in the dorsal periaqueductal grey by 26 and 27% (p < 0.05 in both cases), respectively, compared to group housed rats. In group housed rats treated with diazepam (5 mg/kg, s.c.) 140 min before sacrifice, the level of substance P in the rostral hippocampus and dorsal periaqueductal grey was reduced by 40% (p < 0.001) and 28% (p < 0.05), respectively, compared to saline treated controls. In conclusion, handling, as well as a single dose of the anxiolytic drug diazepam, appears to induce rapid, selective and region-specific changes of regional brain peptide levels in the rat. The effects of handling are likely to be related to the acute stress response and are probably not secondary to increased plasma glucocorticoid levels.

Amygdala↗
PubMed1992

Short-term restraint stress and s.c. saline injection alter the tissue levels of substance P and cholecystokinin in the peri-aqueductal grey and limbic regions of rat brain.

Rats were exposed to short-term restraint (held by the tail for 1 min), injected s.c. with saline or subjected to the combination of these treatments. Fifteen and 30 min after these treatments the means serum corticosterone level was significantly increased by more than four times, compared to rats taken directly from their home cages, indicating a stress response. In the peri-aqueductal grey, the level of substance P-like immunoreactivity was increased by 45% (P < 0.01) and 65% (P < 0.01) 30 and 60 min after the combined treatment, respectively. Significant increases of the level of substance P-like immunoreactivity in the peri-aqueductal grey were also found after restraint only and after a s.c. saline injection. Similar, but less marked, changes in the level of cholecystokinin-like immunoreactivity in the PAG were also seen. In the accumbens a significantly decreased level of substance P-like immunoreactivity was encountered at 15 and 30 min after treatment, while the levels of cholecystokinin- and neuropeptide Y-like immunoreactivity were not significantly changed. In other regions studied, no effects on peptide levels were seen. The changes in peptide levels had a time course similar to that of the increase in serum corticosterone. Also the successive removal of rats from a common cage was found to increase significantly the serum corticosterone and the substance P-like immunoreactivity in the peri-aqueductal grey in the animals that were taken late in sequence from the cage.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Repeated electroconvulsive shock increases tachykinin and cholecystokinin mRNA expression in ventral periaqueductal gray.

The effect of repeated electroconvulsive shock (five shocks during 10 days) on preprocholecystokinin and preprotachykinin-A messenger RNA expression was studied in the mesencephalic periaqueductal gray and adjacent areas of rat using in situ hybridization histochemistry with specific oligonucleotide probes. An increased number of preprocholecystokinin and preprotachykinin-A messenger RNA hybridization positive neurons (+30% and +47%, respectively) in the Edinger-Westphal nucleus was observed following repeated electroconvulsive shock. In addition, both preprocholecystokinin and preprotachykinin-A messenger RNA expression, measured as grain density over single neurons, was significantly increased (+37% and +45%, respectively). The results indicate that cholecystokinin- and substance P-containing neurons in the Edinger-Westphal nucleus are activated by repeated electroconvulsive shock, which may be related to the antidepressant and analgesic effects of electroconvulsive shock treatment.

Animals↗
PubMed1991

Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3H-imipramine binding and serotonin uptake and concentration in major depressive disorder.

In an open study of 12 inpatients who met the DSM-III criteria for a major depressive episode, the effects of clomipramine (CI) on the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured simultaneously with the effects on 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentration in platelets after 3 and 6 weeks of treatment. Drug (CI and desmethylclomipramine) plasma concentrations were determined. The concentrations of 5-HIAA and HMPG decreased substantially, and the concentration of HVA remained unchanged. There was also a large and significant reduction of the number of imipramine binding sites (Bmax) and of the platelet 5-HT concentration. The 5-HT uptake was not measurable after 3 weeks of treatment. None of the parameters changed significantly between weeks 3 and 6. There were no significant correlations between antidepressant effect (measured by the Montgomery-Asberg Depression Rating Scale) and plasma drug concentrations, although a tendency to a significant correlation between antidepressant effect and CI was observed at 3 weeks. There were no significant intercorrelations between the different 5-HT parameters and no other significant correlations between the biochemical measures and clinical outcome.

Adult↗
PubMed1987

A long lasting gastrin response to apomorphine revealed by inhibitors of gastric acid secretion.

Gastrin levels, in the peripheral venous blood of conscious dogs treated with apomorphine (0.05 mg/kg IV), were analysed with a radioimmunoassay. Pretreatment (30 min) with the gastric acid inhibitors cimetidine, ranitidine (H2 receptor antagonists, 4 mg/kg and 1 mg/kg respectively) or omeprazole (H+-K+ ATPase inhibitor, 1.6 mg/kg) prolonged the elevation of gastrin levels occurring in response to an administration of apomorphine. Haloperidol (0.1 mg/kg), but not the peripheral dopamine receptor antagonist domperidone (0.2 mg/kg), abolished the enhanced gastrin response to apomorphine occurring after pretreatment with cimetidine. Cimetidine did not increase the gastrin response to apomorphine in vagotomized dogs. The results are interpreted in terms of an additive gastrin response to apomorphine (different from the short lasting initial peak previously described) which is vagally mediated and inhibited by the gastric acid.

Animals↗
PubMed1983

Molecular forms of gastrin in canine duodenum after antrectomy.

Extracts of the proximal third of the duodenum from 8 antrectomized dogs with the gastrointestinal continuity restored by gastroduodenostomy (n = 4) or gastrojejunostomy (n = 4) as well as from 4 unoperated controls were subjected to gel chromatography. The eluates were all assayed using two different gastrin antisera, one directed against the COOH-terminal end of gastrin and the other directed against the NH2-terminal end of gastrin-17. The gastrin component pattern was very similar in all antrectomized dogs regardless if they had a gastroduodenostomy or a gastrojejunostomy. Gastrin-17 was found to dominate while the amount of gastrin-34 was at most one tenth of that of gastrin-17. Using the COOH-terminal directed antiserum approximately 15% (mean value) of the total gastrin-like immunoreactivity eluted in a peak appearing in the same region as the COOH-terminal octapeptide of cholecystokinin. In unoperated control dogs the corresponding peak constituted approximately 70% (mean value) of the total gastrin-like immunoreactivity. In two of the control dogs small amounts of gastrin-like immunoreactivity appeared at the elution volumes of gastrin-34 and gastrin-17. In the duodenal extracts of all dogs gastrin-like immunoreactivity was found between the elution sites of gastrin-34 and gastrin-17. This material probably represents cholecystokinin-33. The present results show that the increase in duodenal gastrin found after antrectomy, which we have reported previously, is due mainly to an increase in gastrin-17.

Animals↗
PubMed1982

Increase in duodenal tissue gastrin in dogs following antrectomy with gastroduodenostomy and after total gastrectomy with oesophagoduodenostomy.

The gastrin concentration in plasma and duodenal tissue was determined in dogs following antrectomy and total gastrectomy as well as in unoperated control animals. The first week after both types of operations, during which time the dogs were parenterally fed the basal plasma gastrin concentration was markedly reduced, and then it slightly increased. The increase in plasma gastrin concentration from the second postoperative week until sacrifice was found to be statistically significant in one of six antrectomized dogs and in two of three dogs in which the whole stomach had been resected. In unoperated controls the gastrin concentration in the proximal third of the duodenum was found to be 6.8 +/- 0.8 pmol/g tissue wet weight (mean value +/- SE, n = 11). Following antrectomy a time dependent increase was seen, the corresponding values being 11.0 +/- 2.5 (n = 4), 36.4 +/- 15.7 (n = 6) and 136.1 +/- 44.2 (n = 6) pmol/g at 3, 9-10 and 14-16 weeks after operation, respectively. A similar increase was seen following total gastrectomy. 8 weeks after this type of operation the concentration was 22.2 +/- 12.5 (n = 3) pmol/g. The gastrin concentration of the middle and distal thirds of the duodenum was not changed by the operations. The results show that removal of the main source of gastrin, i.e. the pyloric antrum, induces an increase in the tissue level of gastrin in the upper portion of the duodenum.

Animals↗
PubMed1982

The effect of antrectomy on the number of gastrin-immunoreactive cells in the canine duodenum.

The number of gastrin-immunoreactive cells in the duodenum was assessed by immunohistochemistry in 10 dogs that had been subjected to antrectomy with gastroduodenostomy (Billroth I), in 4 dogs in which an antrectomy with gastrojejunostomy (Billroth II) had been performed and in 4 unoperated controls. Gastrin-immunoreactive cells were found only in dogs that had been subjected to antrectomy ad modum Billroth I and then only within the first 30 mm of the duodenum, i.e. in the duodenal bulb. The gastrin cells occurred scattered on the villi, in the crypts and within the glands of Brunner. In 3 of the dogs patches of antral-type mucosa occurred within the first 10 mm of the duodenum. All dogs in which gastrin-immunoreactive cells were found have in a previous study been shown to have a markedly increased tissue concentration of gastrin in the proximal third of the duodenum compared to unoperated controls. In the dogs subjected to antrectomy ad modum Billroth II in which no cells were observed the level of gastrin in duodenal tissue has been found to be moderately elevated compared to that of control dogs. The results indicate that the increased gastrin concentration in the proximal third of the duodenum following antrectomy ad modum Billroth I corresponds to an increase in the number of gastrin-immunoreactive cells in the duodenal bulb.

Animals↗
PubMed1979

On the mechanism of relaxation of tracheal muscle by theophylline and other cyclic nucleotide phosphodiesterase inhibitors.

The mechamism of action of theophylline was studied by investigating the relationship between relaxant effect and inhibition of cyclic nucleotide phosphodiesterase (PDE) and by studying interactions with adenosine actions. Guinea pig tracheal smooth muscle cyclic AMP PDE had two apparent KmS': 0.4 and 70 microM for cyclic AMP. Theophylline and papaverine competetively inhibited the low Km form. Hydrolysis of 2.0 microM cyclic AMP and cyclic GMP was inhibited by several drugs. Some agents (e.g. ZK 62 711, ICI 63,197, Ro 20--1724, dipyridamol) were considerably more potent as inhibitors of cyclic AMP than of cyclic GMP hydrolysis, while other agents (M & B 22.948 and dilazep) selectively inhibited cyclic GMP breakdown, and some (theophylline, papaverine, IBMX and SQ 20,006) showed little selectivity. There was a weak but significant correlation between inhibition of cyclic AMP phosphodiesterase and relaxation of tracheal smooth muscle in vitro. There was also a correlation between the ratio of IC25 cyclic AMP/IC25 cyclic GMP and the smooth muscle relaxation, indicating that inhibition of cyclic AMP rather than cyclic GMP hydrolysis determined relaxation. However, there was a marked tachyphylaxis to the relaxant effect of the cyclic AMP selective PDE-inhibitors, while the nonselective methylxanthines did not show tachyphylaxis. The effect of theophylline was antagonized by low concentrations of adenosine, which by itself caused a weak tracheal contraction. The effect of PDI-inhibitors can be partly explained by decreased cyclic AMP breakdown but other mechanisms, such as antagonism of endogenous adenosine, may contribute to the observed relaxant action.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Studies on duodenal gastrin concentrations in dogs following antrectomy and total gastrectomy.

In extracts of the normal duodenum from dog minute amounts (2%) of gastrin are present compared to those extracted from the pyloric antrum (4). Despite that, basal levels of gastrin in plasma are not lowered when the antrum is surgically removed and test meal stimulation still significantly elevates the concentrations of plasma gastrin. When also the duodenal bulb is surgically removed basal gastrin levels decrease considerably and stimulation by a meal no longer raises the gastrin concentration in plasma (5). The related results suggest that extra-antral release of gastrin may take place under basal and stimulated conditions in dogs and that this release essentially occurs from the proximal portion of the duodenum, i.e. the duodenal bulb. Considering the low amounts of gastrin normally present in the duodenum of dog we found that levels of gastrin in plasma under basal and stimulated conditions after antrectomy surprisingly high and have therefore put forward the hypothesis that a compensatory increase in duodenal gastrin content takes place when the antrum is surgically removed (3). In the present study the relation between time following antrectomy and duodenal concentration of gastrin has been studied. In addition we also investigated how total gastrectomy influences the gastrin content of duodenum in dogs.

Animals↗
PubMedDate not supplied

The online screening technique for urinary benzodiazepines: comparison with EMIT, FPIA, and GC-MS.

Three commercial immunoassay systems (EMIT, EPIA, Online) for the screening of benzodiazepines in urine were evaluated using authentic patient samples with gas chromatography-mass spectrometry (GC-MS) as the reference method. The Online system (kinetic interaction of microparticles in solution) gained in performance by applying a 100-ng/mL cutoff limit and by incorporating beta-glucuronidase treatment, which could be automated on the Cobas Mira Plus instrument. When using enzymatic hydrolysis, all three immunoassay systems had high levels of sensitivity, including samples containing only flunitrazepam and nitrazepam metabolites. A high degree of concordance was observed between the Online and FPIA (fluorescence polarization immunoassay) systems when analyzing 138 randomly selected patient samples. The EMIT II and EMIT d.a.u. (enzyme multiplied immuno technique) systems gave a higher number of positive results, but the presence of benzodiazepines could not be verified by GC-MS in a substantial number of these cases. The rate of unconfirmed positive results was increased when enzyme hydrolysis was incorporated in the EMIT II assay. Although differences in the performances of the investigated assay systems were observed, they all seem appropriate for clinical use in detecting benzodiazepine intake in drug abusers when enzymatic hydrolysis is included.

Benzodiazepines↗