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Biomedical subjects

B Fredholm

Publications and source records attributed to B Fredholm.

At least 19 recordsLinked to original sources
PubMed2001

Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice.

The hypothesis that adenosine acting on adenosine A1 receptors (A1R) regulates several renal functions and mediates tubuloglomerular feedback (TGF) was examined using A1R knockout mice. We anesthetized knockout, wild-type, and heterozygous mice and measured glomerular filtration rate, TGF response using the stop-flow pressure (P(sf)) technique, and plasma renin concentration. The A1R knockout mice had an increased blood pressure compared with wild-type and heterozygote mice. Glomerular filtration rate was similar in all genotypes. Proximal tubular P(sf) was decreased from 36.7 +/- 1.2 to 25.3 +/- 1.6 mmHg in the A1R+/+ mice and from 38.1 +/- 1.0 to 27.4 +/- 1.1 mmHg in A1R+/- mice in response to an increase in tubular flow rate from 0 to 35 nl/min. This response was abolished in the homozygous A1R-/- mice (from 39.1 +/- 4.1 to 39.2 +/- 4.5 mmHg). Plasma renin activity was significantly greater in the A1R knockout mice [74.2 +/- 14.3 milli-Goldblatt units (mGU)/ml] mice compared with the wild-type and A1R+/- mice (36.3 +/- 8.5 and 34.1 +/- 9.6 mGU/ml), respectively. The results demonstrate that adenosine acting on A1R is required for TGF and modulates renin release.

Adenosine↗
PubMed1999

Mu- and delta-opioid receptor agonists inhibit DARPP-32 phosphorylation in distinct populations of striatal projection neurons.

In the striatum, DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa) is highly expressed by virtually all projection medium-sized spiny neurons. cAMP-dependent phosphorylation of DARPP-32 is stimulated via activation of dopamine D1 receptors in striatonigral neurons, and via activation of adenosine A2A receptors in striatopallidal neurons. In this study, we have examined the contribution of mu-, delta- and kappa-opioid receptors to the regulation of DARPP-32 phosphorylation, in rat striatal slices. The results show that, at low concentrations (100 pm-1 nm), the mu-opioid agonist, Tyr-D-Ala-Gly-N-Me-Phe-glycinol (DAMGO), inhibits the increase in DARPP-32 phosphorylation induced by activation of D1, but not by activation of A2A receptors. Conversely, the delta-receptor agonist, Tyr-D-Pen-Gly-Phe-D-Pen (DPDPE), inhibits DARPP-32 phosphorylation induced by activation of A2A, but not by activation of D1 receptors. The kappa-receptor agonist, U50488, does not affect DARPP-32 phosphorylation induced by either D1 or A2A agonists. Thus, mu-opioid receptors interact with dopamine D1 receptors on striatonigral neurons, whereas delta-opioid receptors interact with adenosine A2A receptors on striatopallidal neurons. These results suggest that regulation of DARPP-32 phosphorylation is involved in mediating some of the effects exerted by enkephalin on striatal medium-sized spiny neurons.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

Oscillations in KATP channel activity promote oscillations in cytoplasmic free Ca2+ concentration in the pancreatic beta cell.

Pancreatic beta cells exhibit oscillations in electrical activity, cytoplasmic free Ca2+ concentration ([Ca2+](i)), and insulin release upon glucose stimulation. The mechanism by which these oscillations are generated is not known. Here we demonstrate fluctuations in the activity of the ATP-dependent K+ channels (K(ATP) channels) in single beta cells subject to glucose stimulation or to stimulation with low concentrations of tolbutamide. During stimulation with glucose or low concentrations of tolbutamide, K(ATP) channel activity decreased and action potentials ensued. After 2-3 min, despite continuous stimulation, action potentials subsided and openings of K(ATP) channels could again be observed. Transient suppression of metabolism by azide in glucose-stimulated beta cells caused reversible termination of electrical activity, mimicking the spontaneous changes observed with continuous glucose stimulation. Thus, oscillations in K(ATP) channel activity during continuous glucose stimulation result in oscillations in electrical activity and [Ca2+](i).

Adenosine Triphosphate↗
PubMed1994

[Clarification of mechanism of acetylsalicylic acid].

Acetylsalicylic acid is probably the most widely used of all drugs. Recent data has provided new insights into its mechanism of action and documented its usefulness in cardiovascular prevention. At the same time we now understand better why plants benefit from new production of the mother compound-salicylic acid. Thus very old drugs can be quite newsworthy.

Aspirin↗
PubMed1993

Intramembrane receptor-receptor interactions: integration of signal transduction pathways in the nervous system.

During recent years a large number of observations have been made indicating that neuropeptides and other transmitters in various brain areas can regulate the affinity of monoamine receptors via the activation of their own receptors. These "receptor--receptor interactions" can either take place at the plasma membrane level or use intracytoplasmatic loops. This review is mainly focused on the evidence for hetero-regulation of dopamine (DA) D2 receptors in the basal ganglia. The existence of such receptor--receptor interactions increases the plasticity of transmission and opens up the possibility of developing new drugs which indirectly modulate receptor recognition and decoding processes. This would avoid the use of direct receptor agonists or antagonists which induce major side effects such as tolerance and abstinence. Disturbances in the receptor--receptor interactions, including DA D2 receptors, may be involved in the development of neurological and mental diseases such as schizophrenia.

Animals↗
PubMed1993

Stimulation of the KATP channel by ADP and diazoxide requires nucleotide hydrolysis in mouse pancreatic beta-cells.

1. The mechanisms by which ADP and the hyperglycaemic compound diazoxide stimulate the activity of the ATP-regulated K+ channel (KATP channel) were studied using inside-out patches isolated from mouse pancreatic beta-cells maintained in tissue culture. 2. The ability of diazoxide and ADP to increase KATP channel activity declined with time following patch excision and no stimulation was observed after 15-40 min. 3. Activation of KATP channels by ADP required the presence of intracellular Mg2+. The stimulatory effect of ADP was mimicked by AMP but only in the presence of ATP. Replacement of ATP with the non-hydrolysable analogue beta, gamma-methylene ATP did not interfere with the ability of ADP to stimulate KATP channel activity. By contrast, enhancement of KATP channel activity was critically dependent on hydrolysable ADP and no stimulation was observed after substitution of alpha,beta-methylene ADP for standard ADP. 4. The ability of diazoxide to enhance KATP channel activity was dependent on the presence of both internal Mg2+ and ATP. Diazoxide stimulation of KATP channel activity was not observed after substitution of beta,gamma-methylene ATP for ATP. However, in the presence of ADP, at a concentration which in itself had no stimulatory action (10 microM), diazoxide was stimulatory also in the presence of the stable ATP analogue. 5. The stimulatory action of diazoxide on KATP channel activity in the presence of ATP was markedly enhanced by intracellular ADP. This potentiating effect of ADP was not reproduced by the stable analogue alpha,beta-methylene ADP and was conditional on the presence of intracellular Mg2+. A similar enhancement of channel activity was also observed with AMP (0.1 mM). In the absence of ATP, diazoxide was still capable of stimulating channel activity provided ADP was present. This effect was not reproduced by AMP. 6. In both nucleotide-free solution and in the presence of 0.1 mM ATP, the distribution of the KATP channel open times were described by a single exponential with a time constant of approximately 20 ms. Addition of ADP or diazoxide resulted in the appearance of a second component with a time constant of > 100 ms which comprised 40-70% of the total number of events. Under the latter experimental conditions, the open probability of the channel increased more than fivefold relative to that observed in the presence of ATP alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Diphosphate↗
PubMed1990

Evidence that protein kinase C activation is essential for killing by IL-2-activated lymphocytes.

Previous pharmacological evidence has suggested that activation of protein kinase C (PKC) is necessary for T and natural killer (NK) killing of different target cells. In the present study we find, using interleukin 2 (IL-2)-activated lymphocytes (LAK cells), that phosphorylation of a well-characterized 80-kDa PKC substrate increases during conjugation to target cells. Furthermore, down-regulation of PKC by pretreatment with the active phorbol esters PDB (24 h) or PMA (2 h), but not with the inactive phorbolester PDD, simultaneously inhibits killing by LAK cells. H-7, an inhibitor of PKC, also inhibited LAK-cell killing without affecting the target-effector cell conjugate formation. We also demonstrate that pretreatment of target cells with phorbol ester (PMA) decreases killing, suggesting that PKC activation in the target cell population may also influence killing although the effect may vary depending on the particular target cell used. We conclude that PKC activation is essential for triggering of lysis in LAK cells.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1989

Reciprocal interactions between alpha 2-adrenoceptor agonist and neuropeptide Y binding sites in the nucleus tractus solitarius of the rat. A biochemic and autoradiographic analysis.

Interactions between a alpha 2-adrenoceptor agonist and neuropeptide Y (NPY) binding sites have been studied in the rat medulla oblongata (MO) using biochemical binding techniques as well as quantitative autoradiography. Tritiated para-amino clonidine (3H-PAC; alpha 2-adrenoceptor agonist), idazoxan (3H-IDA; alpha 2-adrenoceptor antagonist) and iodinated neuropeptide Y (125I-NPY) were used as radioligands. (1) Neuropeptide Y (NPY; 10(-8) M) but not bovine pancreatic polypeptide (BPP) nor peptide YY (PYY 10 nM) increased the KD value of 3H-PAC binding sites. However, intraventricular administration of a high dose of NPY (1.25 nmol) did not change the 3H-PAC binding characteristics in MO membrane preparations of these animals. (2) GTP 10(-4) lowered the affinity of 3H-PAC binding. NPY (10 nM) had no additional effect, nor did NPY influence the GTP induced shift in potency of clonidine to displace 3H-IDA from its binding sites. (3) In the autoradiographical experiments NPY (10 nM) significantly reduced 3H-PAC binding (2 nM) in the nucleus tractus solitarius (NTS) area by 35%. (4) When clonidine, either given centrally in vivo (3.75 nmol) or in vitro (10 nM) the binding of 125I-NPY was reduced (34 and 24%, respectively) in the NTS. When the monoamine receptors were irreversibly blocked in vivo by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 10 micrograms i.c. 24 h) 125I-NPY (0.5 nM) binding was increased by 137% in the NTS. This effect of EEDQ was prevented by pretreatment with the alpha 2-adrenoceptor antagonist idazoxan. These results provide support for a direct intramembrane interaction between the alpha 2-receptor and the NPY receptor within the NTS and may be of importance in central cardiovascular regulation.

Animals↗
PubMed1987

Inhibitory effects of neuropeptide Y on cyclic AMP accumulation in slices of the nucleus tractus solitarius region of the rat.

The effects of neuropeptide Y (NPY) on cyclic AMP (cAMP) accumulation in slices of the dorsal midline area of the caudal part of the medulla oblongata containing the nucleus tractus solitarius (nTS) have been studied. Neuropeptide Y (30 and 300 nM) significantly reduced the [3H]cAMP accumulation induced by forskolin and phorboldibutyrate. Similar results were obtained after incubation with the alpha-adrenoceptor agonist clonidine (1 microM). These results indicate that stimulation of the NPY receptors and alpha-adrenoceptors in the nTS region may cause inhibition of the adenylate cyclase. Such a mechanism may at least partly underlie the centrally mediated hypotensive effects of the costored transmitters adrenaline and NPY.

Adenylyl Cyclases↗
PubMed1987

Characterization of PHA and anti-T3 induced transduction mechanisms in a human T-cell leukaemia line.

Stimulation of the T-cell line JURKAT with PHA or anti-T3 antibody leads to a rapid and sustained rise of cytosolic free Ca2+, as determined by quin2 fluorescence measurements. Pertussis toxin and N-ethylmaleimide, substances known to inactivate a regulatory N-protein, caused partial to complete inhibition of the cytosolic free Ca2+ response induced both by anti-T3 or PHA. The high cytosolic free Ca2+ level induced by anti-T3 or PHA declined more rapidly after addition of phorbol ester, phorbol myristate acetate (PMA). PMA did not affect cytosolic free Ca2+ changes induced by ionomycin indicating that the effect of PMA is due to a direct inhibitory effect on a transduction mechanism and not to activation of Ca2+ extrusion. Our data suggest that a regulatory N-protein is involved in the transduction of the PHA and anti-T3 response into a rapid and sustained elevation of cytosolic free Ca2+. Activation of protein kinase C by PMA modulates the calcium response in JURKAT cells, suggesting that protein kinase C may be involved in feedback regulation of the transduction mechanism.

Calcium↗
PubMed1987

Central catecholamine-neuropeptide Y interactions at the pre- and postsynaptic level in cardiovascular centers.

Central catecholamine (CA)-neuropeptide Y (NPY) interactions and their regulation by glucocorticoids have been analyzed in vivo and in vitro, especially in the dorsal cardiovascular center of the medulla oblongata, including the nucleus tractus solitarius (nTS), using immunocytochemical, receptor autoradiographical, biochemical, and physiological techniques. Intraventricular (i.v.t.) injections of NPY in a low (7.5 pmol) or a high (1.25 nmol) dose increased adrenaline levels 4 h later in the caudal part of the dorsomedial medulla. Furthermore, NPY immunoreactivity (IR) tended to decrease in the rostral part of the dorsomedial medulla 5 min after injection of clonidine (1 microgram) in the alpha-chloralose anaesthetized rat. Thus, presynaptic interaction between NPY and adrenaline (A) mechanisms may exist in the dorsal cardiovascular center taking place at the network local circuit level or the membrane level of the NPY/A costoring synapses of the dorsomedial medulla. In vitro NPY (10 nM) reduced the affinity of the alpha 2-adrenergic agonist binding sites in the nTS, and clonidine (10 nM) reduced the 125I-NPY binding in the dorsomedial medulla. These results indicate the existence of postsynaptic receptor-receptor interactions between alpha 2-adrenergic and NPY receptors in the dorsal cardiovascular center. This interaction may in part take place at the level of the Ni protein, since NPY (300 nM) inhibited cyclic AMP (cAMP) accumulation in slices of the dorsomedial medulla. However, the interactions also probably take place at the proteins carrying the recognition sites, since NPY and adrenaline together given i.v.t. significantly antagonized the hypotensive effects of one another. Thus, the reduced affinity of the alpha 2-adrenergic receptor induced by NPY may reflect a reduced efficiency of this receptor and not an increased coupling of Ni protein to the adenylate cyclase. Thus, the postsynaptic interaction between the two receptors represents inter alia a sensitivity regulation of the two receptors. Evidence is also presented for the existence of a glucocorticoid regulation of NPY IR neurons, especially of those innervating the locus coeruleus, since after 2 weeks adrenalectomy reduced NPY IR in this area. Furthermore, glucocorticoid receptor IR was demonstrated in the nuclei of NPY nerve cell bodies of the nTS. Thus, glucocorticoids exert direct actions on cardiovascular NPY/CA costoring neurons, actions that may contribute to their hypertensive effects in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗