Acute changes in dopamine levels in rat adrenal glands after administration of dopamine receptor agonists and antagonists

The study was aimed at in vivo pharmacological identification of the possible dopamine (DA) receptor(s) involved in changes of the DA level in rat adrenal glands. Previous work in this laboratory has shown that the DA level is largely controlled by the rate of catecholamine synthesis. The rats were killed by decapitation after various periods of drug administration and the catecholamine content of adrenal glands and forebrain was measured by high-performance liquid chromatography with electrochemical detection. Administration of the DA D-1 + D-2 receptor agonist, apomorphine, induced a statistically significant increase in DA levels in the adrenal glands. The same effect was noted after administration of the DA D-2 receptor agonist, quinpirole. The DA D-2 receptor antagonist, raclopride, blocked the apomorphine-induced increase in adrenal DA levels but had no effect per se on these levels. The DA D-1 receptor agonist, SKF 38393, and the DA D-1 receptor antagonist, SCH 23390, did not have any effect on apomorphine-induced changes in DA content in the adrenals. The DA elevating effect of the DA D-2 receptor agonist, quinpirole, in the adrenals was completely blocked by the DA D-2 receptor antagonist, domperidone. This compound does not cross the blood-brain barrier readily and is thus supposed to act mainly on peripheral tissues. In support of this, the dose of domperidone used did not affect brain DOPAC levels. Our data, together with observations reported in the literature, indicate that the adrenal medulla contains DA receptors of the D-2 subtype, which are capable of controlling the DA level in rat adrenal glands.     

Dopamine receptors,controlling dopamine levels in rat adrenal glands — comparison with central dopaminergic autoreceptors

Summary Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case /(–)-HW165/. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.     

Different molecular forms of cholecystokinin and CCKB receptor binding in the rat brain after chronic antidepressant treatment

Cholecystokinin (CCK) is a neuropeptide recently implicated in affective disorders. This study aimed at measuring the levels of different molecular forms of CCK and the binding characteristics of CCK_B receptors in the rat brain after three weeks of treatment with four different antidepressants, imipramine, amitriptyline, desipramine, and citalopram (all at the dose of 10 mg/kg once per day i.p.). Chronic treatment with imipramine and desipramine had a significant immobility-reducing effect in the Porsolt‘s swim test. The effect of amitriptyline, albeit in the same direction, was not significant, and citalopram had no effect in this test. In the elevated plus-maze test of anxiety, all drugs tended to increase the number of open arm entries and the ratio open/total arm entries, but only the effects of imipramine were statistically significant. None of the treatments affected the total levels of CCK or the levels of CCK-8-sulphated, CCK-8-nonsulphated, CCK-5, or CCK-4 in the frontal cortex. There was no effect of the treatments on CCK_B receptor binding in the frontal cortex, hippocampus, or striatum. Imipramine and amitriptyline, however, increased the affinity of CCK_B receptor binding in the hypothalamus. Thus, no consistent effect of chronic antidepressant treatment on the CCK-ergic neurotransmission in the rats was found. Received: 4 June 1996 / Accepted: 26 August 1996     

The prevalence and clinical significance of alpha 1-antitrypsin deficiency (PiZ) and ANCA specificities (proteinase 3, BPI) in patients with ulcerative colitis

Our aim was to determine the prevalence of the PiZ allele for alpha 1-antitrypsin (AAT) deficiency and some relevant antineutrophil cytoplasmic antibody (ANCA) specificities in patients with ulcerative colitis (UC), and explore a possible association between these markers. In addition, we studied the relation to disease extension and activity. Sera from 141 patients with UC (72 women) were analyzed while 50 blood donors and 54 patients with acute myocardial infarction served as controls. Serum samples were screened for PiZ with ELISA and phenotyped by isoelectric focusing. BPI-ANCA and PR3-ANCA were detected by ELISA. Results were that 8.5% (12/141) of the patients with UC were PiZ carriers, higher than expected in the general Swedish population (4.7%) (p = 0.03). There was a significant difference between PiZ-carriers and non-PiZ-carriers in the extension and severity of colitis (odds ratio = 4.1, confidence interval = 1.1, 14.9; p = 0.028, and odds ratio = 9.0, confidence interval = 1.1, 73.3; p = 0.015; respectively). BPI-ANCA and PR3-ANCA were detected in 20.5% (29/141) and 12% (17/141) (p < 0.05 compared with controls for all parameters). Occurrence of BPI-ANCA and PR3-ANCA was not related to extension or severity of colitis (p > 0.05 for both variables). We observed no association between PiZ-carrier status and occurrence of BPI-ANCA or PR3-ANCA. The increased frequency of heterozygosity for the PiZ variant of AAT deficiency among patients with UC might imply a role played by protease inhibitors for regulation of inflammation and immunologic response in UC.     

Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity

BACKGROUND AND AIMS: The hydrolysis of sphingomyelin (SM) generates key molecules regulating cell growth. Animal cancer studies support an inhibitory role for this pathway in the malignant transformation of the colonic mucosa. The activity of a specific intestinal alkaline sphingomyelinase (SMase), which hydrolyzes SM, is reduced in colorectal tumors. In this study we measured alkaline SMase activity in patients with longstanding colitis and assessed if a reduction can be used as a marker in surveillance of high risk patients. METHODS: Alkaline SMase activity was measured in 139 colonic biopsies from 34 patients with longstanding, extensive colitis and from 11 controls. Fifteen patients had earlier diagnosis of dysplasia or DNA aneuploidy. Alkaline SMase activity was related to histologic dysplasia and DNA aneuploidy assessed by flow cytometry, patient age, and duration of disease. RESULTS: Alkaline SMase activity was significantly lower in the patient group with and without dysplasia compared with controls (p = 0.006). In biopsies, an association was not found between alkaline SMase activity, dysplasia, or DNA ploidy. However, alkaline SMase activity decreased with age both in patients and controls (p = 0.008). CONCLUSIONS: Reduction of alkaline SMase activity seen in colorectal cancer and adenomas is also present in patients with chronic colitis. It is not complementary to dysplasia or DNA-aneuploidy in the identification of high risk patients. The age-associated decrease of alkaline SMase activity seems to be a general phenomenon indicating premature senescence of the mucosa in longstanding colitis.     

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response?

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are na?ve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.     

Serum concentrations of collagen degrading enzymes and their inhibitors after downhill running

In the present study the release of proteins degrading extracellular matrix compounds to circulation was measured after damaging exercise in humans. Muscle damage was induced by downhill running; furthermore, the exercise was performed at both cold temperature (5 degrees C) and room temperature (22 degrees C) to study also the possible effect of environmental temperature on serum concentrations of matrix metalloproteinases MMP-2 and MMP-9, tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2, and MMP-2/TIMP-2 complex, and muscle damage monitored by serum creatine kinase measurements. Results were compared with those obtained from patients having rhabdomyolysis, myositis and Becker muscular dystrophy. The present study demonstrates an acute increase in serum concentrations of MMP-9, TIMP-1, and MMP-2/TIMP-2 complex, but no changes in serum MMP-2 concentrations in response to eccentric exercise. Serum creatine kinase activity data suggest greater muscle damage after downhill running in a cold environment than at room temperature. The present observations about at most slight changes in serum MMP and TIMP concentrations and lack of their correlation to increased serum creatine kinase after exercise indicate that serum measurements of MMPs and TIMPs do not sensitively respond to exercise induced skeletal muscle damage and extracellular matrix regeneration. On the other hand, severe skeletal muscle damage, such as rhabdomyolysis, myositis and Becker muscular dystrophy, seemed to have an effect on serum MMP and TIMP concentrations.     

Ribosome and free amino acid content in muscle during hemodialysis

Patients (N = 8) with chronic renal failure and uremia treated with hospital hemodialysis were in a pilot study investigated before and after a single hemodialysis session. The extracorporeal dialysis circuit was flushed regularly with saline to avoid clotting and the use of heparin. Percutaneous skeletal muscle biopsies were taken before and after the dialysis to determine the content of free amino acids together with the concentration and size distribution of ribosomes before and after dialysis. After dialysis the alanine concentration in muscle decreased by 20% (P less than 0.05), while all other amino acids were unaffected. The total ribosome concentration per mg of DNA decreased by 31% (P less than 0.01) and the relative proportion of polyribosomes by 7% (P less than 0.05) after the dialysis compared to predialytic values. All individual plasma amino acids decreased during the dialysis procedure except for threonine and arginine, which were unaltered, and leucine and isoleucine, which increased. The decline in ribosome and polyribosome content together with the changes in amino acid levels indicate a low capacity for protein synthesis and increased catabolism in muscle of hemodialyzed patients.