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Biomedical subjects

L Björk

Publications and source records attributed to L Björk.

At least 19 recordsLinked to original sources
PubMed1992

Lipopolysaccharide induces human interleukin-1 receptor antagonist and interleukin-1 production in the same cell.

A new member of the interleukin-1 (IL-1) family has recently been described. Human IL-1 receptor antagonist (IL-1ra) is structurally related to IL-1 alpha and IL-1 beta but binds to IL-1 receptors on various target cells without demonstrable agonist activity. Understanding the mechanisms of regulation of IL-1ra production may clarify the biology of this unique cytokine as well as elucidate its possible role as a natural anti-inflammatory protein. The effects of lipopolysaccharide (LPS) on IL-1 alpha, IL-1 beta and IL-1ra production was studied at a single-cell level by use of cytokine-specific antibodies and indirect immunofluorescence technique. The peak synthesis of IL-1ra and IL-1 alpha/beta occurred in peripheral blood monocytes obtained from healthy blood donors within 4 and 6 h of cell stimulation, respectively. By double-staining procedure all IL-1ra-positive cells were also IL-1 alpha and/or beta positive. Thus, endotoxin induced simultaneous synthesis of the IL-1 gene family in the same cells. Only monocytes contributed to the production of IL-1 alpha, beta and IL-1ra during the 96 h of cell culture. The maximum number of IL-1ra-producing monocytes was 48 +/- 16% as compared to peak production of IL-1 alpha and beta which occurred in 75 +/- 9% and 80 +/- 12% (p < 0.001), respectively, of all peripheral blood monocytes. The incidence of IL-1 alpha- and beta-containing cells was not only significantly higher but also occurred for a longer time period, 72 h as compared to 24 h for IL-1ra localized in the Golgi organelle. However, IL-1ra-containing cells with a diffuse cytoplasmic appearance were also evident (20%-30%) at a later stage, 12 to 72 h after stimulation. Blocking IL-1 surface receptors by addition of exogenous recombinant IL-1 beta before stimulation could not inhibit the diffuse cytosolic localization. This indicates that the "late" staining pattern did not reflect IL-1ra being secreted and internalized after binding to extracellular receptors. Thus, perhaps IL-1ra modulates IL-1 effector mechanisms by receptor interactions both inside and outside the cell.

Adult↗
PubMed1992

Effects of (R)-8-OH-DPAT and the enantiomers of UH-301 on motor activities in the rat: antagonism of (R)-8-OH-DPAT-induced effects.

The effects of the enantiomers of 5-fluoro-8-hydroxy-2-(dipropylamino)tetralin, UH-301 and the potent 5-HT1A-receptor agonist (R)-8-hydroxy-2-(dipropylamino)tetralin, (R)-8-OH-DPAT, on locomotion, rearing and total activity were studied in rats. The experiments were performed as tests either of exploratory activity in non-habituated rats or of motor activity of rats habituated to the environment for 2 h before drug injection. (R)-8-OH-DPAT increased locomotion and total activity and decreased rearing in both conditions. (R)-UH-301 increased locomotion and slightly also total activity in habituated rats and decreased rearing in both conditions. (S)-UH-301 decreased locomotion and rearing in both conditions but only in doses of 10 mumol/kg and above. Lower doses of (S)-UH-301 (10 mumol/kg) antagonized (R)-8-OH-DPAT-induced increases of locomotion and total activity. As (S)-UH-301 decreased rearing, per se, it was not able to antagonize the (R)-8-OH-DPAT induced decrease. These results further support previous data that (S)-UH-301 is a 5-HT1A antagonist while (R)-UH-301 is a 5-HT1A agonist.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines.

The effects of Staphylococcus aureus enterotoxin A (SEA) and lipopolysaccharide (LPS) in cytokine production were assessed at the single cell level in cells obtained from healthy blood donors. Cytokine production was studied with UV-microscopy of fixed and permeabilized cells stained with cytokine specific monoclonal antibodies. The cytokines evaluated included tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, IL-8, IL-10, IL-2, IL-4, interferon (IFN)-gamma and TNF-beta. LPS exhibited marked production of IL-1 alpha, IL-1 beta, TNF-alpha, IL-6 and IL-8. After LPS stimulation IL-1 alpha, IL-1 beta, TNF-alpha and IL-8 were the dominating products, all peaking at or before 4 hours after cell stimulation. In addition, IL-10 production was evident after 12 hours of cell stimulation. The T-lymphocyte-derived cytokines TNF-beta, IL-2, IFN-gamma and IL-4 were never detected in the cultures. All cytokine production, except IL-8, was downregulated at 96 hours. In contrast, peak production of IL-1 alpha, IL-1 beta and IL-8, which were the dominant products, occurred after 12 hours in the SEA-stimulated cultures. Further, a significant T-lymphocyte production of TNF-beta, TNF-alpha, IFN-gamma and IL-2 was found with peak production 12-48 hours after initiation. Only low amounts of IL-6 were evident. The two types of cytokine pattern and kinetics found may correspond to the different clinical conditions after invasive Gram-negative Escherichia coli vs Gram-positive Staphylococcus aureus infections in humans, with a much more rapid onset of disease after E. coli infections.(ABSTRACT TRUNCATED AT 250 WORDS)

Cytokines↗
PubMed1991

(S)-UH-301 antagonizes (R)-8-OH-DPAT-induced cardiovascular effects in the rat.

The 5-HT1A-receptor antagonist (S)-UH-301 (S)-5-fluoro-8-hydroxy-2- (dipropylamino)tetralin) completely antagonized the hypotension and bradycardia induced by (R) = 8-OH DPAT [R)-8-hydroxy-2- (dipropylamino)tetralin) in conscious rats. (S)-UH-301 alone induced a weak hypertension, which might be due to its 5-HT1A-receptor antagonistic properties. (R)-UH-301 induced effects similar to those of (R)-8-OH DPAT, i.e., a short initial phase of hypertension followed by a long-lasting hypotension and bradycardia. Thus, (R)-UH-301 behaves as a 5-HT1A-receptor agonist and (S)-UH-301 as a 5-HT1A-receptor antagonist, abolishing the effects induced by (R)-8-OH DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Pharmacology of the novel 5-hydroxytryptamine1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin: inhibition of (R)-8-hydroxy-2-(dipropylamino)tetralin-induced effects.

The selective 5-hydroxytryptamine (5-HT1A) receptor agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) induces a large number of pharmacological effects. In the present study we demonstrate that a novel 8-OH-DPAT analog, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301], is able to antagonize completely the following (R)-8-OH-DPAT-induced effects in the rat: 1) reduction in brain 5-HT biosynthesis, measured as a decreased 5-hydroxytryptophan-accumulation after decarboxylase inhibition; 2) induction of the 5-HT1A behavior (flat body posture, forepaw treading and hindlimb abduction) in reserpine-pretreated animals; 3) reduction of body temperature; 4) inhibition of the cage-leaving response; and 5) reduction of 5-hydroxytryptophan- and quipazine-induced wet dog shakes. In addition, (S)-UH-301 reverses the 5-HT-induced inhibition of the forskolin stimulated cyclic AMP production in rat hippocampus without producing any effects per se in this assay. It is shown that high doses of (S)-UH-301 decrease rat brain biosynthesis of dopamine. These and previous data indicate that (S)-UH-301 also is a weakly potent dopamine-receptor agonist, but with a lower affinity for D2 as compared to 5-HT1A receptors. Thus, the data suggest that (S)-UH-301 is a 5-HT1A-receptor antagonist without intrinsic activity. Therefore, it is likely that (S)-UH-301 will become a valuable pharmacological tool in future 5-HT research.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

A 3-D model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogues of 8-hydroxy-2-(dipropylamino)tetralin.

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

Animals↗
PubMed1991

A radiologic method for the study of postoperative colonic motility in humans.

Propulsive colonic motility in the postoperative period was studied, in 49 patients undergoing cholecystectomy, by means of radiopaque markers, water-soluble contrast, and serial abdominal radiographs. The colon was divided into four segments, and the propagation of the markers and contrast to the segments was registered. Marker propagation correlated significantly with the propagation of the contrast to all segments of the colon (p less than 0.001). The first postoperative passage of gas did not correlate significantly with the propagation of the markers or the contrast to the various colonic segments. The first passage of faeces postoperatively did not correlate significantly with the return of propulsive motility in the right colon; however, there was a significant correlation with the propulsion of markers to the descending colon (p less than 0.05) and the rectosigmoid colon (p less than 0.05). The duration of postoperative paralytic ileus, as measured by the start of propagation of the markers from the caecum, correlated directly with the consumption of opiate analgesics in the postoperative period (p less than 0.01) but inversely with age (p less than 0.05). The duration of surgery did not correlate significantly with the duration of paralytic ileus in the colon. In conclusion, a limited number of radiopaque markers can be used to study the return of postoperative propulsive motility in the colon. The first postoperative passage of gas is not an indicator of the duration of postoperative paralytic ileus, whereas the first passage of faeces is primarily representative of the return of propagative motility in the left colon.

Adult↗
PubMed1991

Arterial phlebography of the leg.

On conventional ascending phlebography of the leg the deep femoral and pelvic veins are poorly visualized or not visualized at all. These veins are presumed to be the site of thrombosis and a source of pulmonary embolism in many instances. Diagnostic images of deep femoral and pelvic veins were obtained in 4 patients using injection of 30 ml of iopromide 300 mg I/ml into the iliac artery and DSA imaging of the venous phase of the angiogram.

Aged↗
PubMed1990

(R)- and (S)-5-hydroxy-2-(dipropylamino)tetralin (5-OH DPAT): assessment of optical purities and dopaminergic activities.

Racemic 5-hydroxy-2-(dipropylamino)tetralin (5-OH DPAT), a potent and selective dopamine (DA) D2-receptor agonist, was resolved into the enantiomers by a new method. The enantiomers of 5-OH DPAT were determined by chiral ion-pair chromatography using N-benzyloxycarbonylglycyl-L-proline as the counter ion. The enantiomeric purity of (R)-5-OH DPAT was found to be greater than 99.7%. The ability of the enantiomers to change the rat brain DOPA levels was evaluated in vivo. The results indicate that (R)-5-OH DPAT is a weakly potent DA D2-receptor antagonist.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Intra-arterial DSA and duplex-Doppler ultrasonography in detection of vascularized inguinal lymph node.

Twenty-three patients with ischemic disease of the legs referred for routine preoperative angiography were examined with intra-arterial DSA and high resolution ultrasonography with duplex-Doppler to detect inguinal lymph nodes. None of the patients had evidence of malignant or lymphomatous disease and only 3 had skin ulceration on the foot. DSA detected nodes in 9 patients (39%). In 3 cases the nodes were highly vascularized. Ultrasonography detected lymph nodes in 16 patients (70%). In all but 2 nodes a high velocity arterial flow was recorded. It is concluded that DSA and particularly duplex-Doppler ultrasonography are sensitive methods to detect vascularized lymph nodes and that such nodes are found in many patients with no evidence of malignancy or infection.

Adult↗
PubMed1989

Resolved N,N-dialkylated 2-amino-8-hydroxytetralins: stereoselective interactions with 5-HT1A receptors in the brain.

The enantiomers of the N,N-dimethylamino (1), N,N-diethylamino (2), and N,N-dibutylamino (4) derivatives of 8-hydroxy-2-(dipropylamino)tetralin (8-OH DPAT; 3) have been synthesized. The compounds have been tested for activity at central 5-hydroxytryptamine and dopamine receptors by use of biochemical and behavioral tests in rats. In addition, the ability of the enantiomers of 1-4 to displace [3H]-8-OH DPAT from 5-HT1A binding sites was evaluated. Rank order of potencies in the in vivo tests corresponded to that observed in the 5-HT1A binding assay. In all three tests, the enantiomeric potency ratio was about 10 for 1 and 2 and only around 2-4 for 3 and 4. The more potent enantiomer of 1-3 had the R configuration. In contrast, (S)-4 seemed to be slightly more potent than (R)-4.

5-Hydroxytryptophan↗
PubMed1989

(R)- and (S)-5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten- 8-ylamine. Stereoselective interactions with 5-HT1A receptors in the brain.

The enantiomers of 5,6,7,8-tetrahydro-1-hydroxy-N,N-dipropyl-9H-benzocyclohepten-8-++ +ylamine (3) have been synthesized and evaluated for central 5-hydroxytryptamine (5-HT) and dopamine (DA) receptor activity by use of behavioral and biochemical tests in rats. In addition, the ability of the compounds to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The absolute configuration of the enantiomers of 3 was determined indirectly by X-ray diffraction of (+)-(8R,alpha R)-5,6,7,8-tetrahydro-1-methoxy-N-(alpha-phenethyl)-9H- benzocyclohepten-8-ylamine hydrochloride (9.HCl), a resolved synthetic precursor. The stereoselectivity of the interaction of 3 with 5-HT1A receptors was more pronounced than that of 8-hydroxy-2-(dipropylamino)tetralin (1; 8-OH-DPAT); only (R)-3 displayed 5-HT activity. However, (R)-3 was of lower potency than any of the enantiomers of 1. The enantiomer (S)-3, which was found to be inactive as a 5-HT-receptor agonist, appeared to be a weakly potent DA-receptor agonist whereas (R)-3 seemed to be devoid of dopaminergic activity. The conformational preferences of 3 were studied by use of NMR spectroscopy and molecular mechanics calculations. Preferred conformations of (R)-3 are similar in shape to those of the stereoselective 5-HT1A-receptor agonist (2R,3S)-8-hydroxy-3-methyl-2-(dipropylamino)tetralin.

Animals↗
PubMed1988

Central dopaminergic and 5-hydroxytryptaminergic effects of C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin.

A number of stereochemically well defined C3-methylated derivatives of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been synthesized, and their stereochemical characteristics have been studies by use of NMR spectroscopy, X-ray crystallography, and molecular mechanics calculations. The compounds were tested for activity at central 5-HT and dopamine (DA) receptors, by use of biochemical and behavioral tests in rats. In addition, the ability of the cis- and trans-8-hydroxy-3-methyl-2-(di-n-propylamino)tetralins (15 and 11) to displace [3H]-8-OH-DPAT from 5-HT1A binding sites was evaluated. The stereoselectivity of the interaction of 11 and 15 with 5-HT receptors was much greater than that of 8-OH-DPAT. Observed rank order of potencies in the 5-HT1A binding assay corresponds to that in the in vivo biochemical assay.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Effects of the C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on central 5-hydroxytryptamine receptors.

The effects of the four possible C3-methylated stereoisomers of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) ((-)-CM-11, (+)-CM-11, (-)-CM-12, (+)-CM-12) on brain 5-hydroxytryptamine (5-HT) receptor functions were studied in rats. (-)-CM-11 and (+)-CM-12 inhibited dose dependently in all brain parts the accumulation of 5-hydroxytryptophan following decarboxylase inhibition. Their antipodes were inactive. The disappearance of 5-HT induced by alpha-propyldopacetamide was retarded by (-)-CM-11 and (+)-CM-12. The biochemically active isomers produced a flat body posture and forepaw treading. The results indicate that (-)-CM-11 and (+)-CM-12 stimulate 5-HT receptors directly although not as potently as 8-OH-DPAT. The concentration of dopamine was lowered and that of homovanillic acid was elevated by (+)-CM-11 and by both enantiomers of CM-12 in the corpus striatum and in the limbic system of rats. The accumulation of DOPA following decarboxylase inhibition was not markedly changed by any of the compounds. Locomotor activity was enhanced by (+)-CM-11 but not by any of the other compounds, and the effect was haloperidol-resistant. (+)-CM-11 induced no asymmetry in rats in which the corpus striatum was inactivated on one side. Thus, none of the isomers of CM-11 or CM-12 appears to have any effect on the dopamine receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗