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  • 1
    Digitale Medien
    Digitale Medien
    SDZ ENS 163 is a selective M1 agonist and induces release of acetylcholine (1992)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 345 (1992), S. 282-287 
    Details
    ISSN: 1432-1912
    Schlagwort(e): SDZ ENS 163 ; M1 receptor agonist selectivity ; M2 antagonism
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In the present study some pharmacological properties of the new muscarinic agonist SDZ ENS 163; (+)-(3S,cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl-2(3H)-thiophenonedihydrogenphosphate] have been investigated. In the rat superior cervical ganglion, a model for M1 muscarinic receptors, SDZ ENS 163 induced concentration-dependent depolarizations (pD2 = 6.5 ± 0.3; efficacy = 128 ± 4.2% compared to carbachol). SDZ ENS 163 was a very weak partial agonist with respect to M2 receptor-induced decrease in contractile force in rat left atria (efficacy = 14 ± 2.9%). In addition, SDZ ENS 163 competitively antagonized the effect of carbachol in rat left atria (pA2 = 5.8 ± 0.2). In the guinea-pig ileum SDZ ENS 163 was a partial agonist with respect to force of contraction mediated by M3 receptors (pD2 = 5.3 ± 0.1; efficacy = 72 ± 4.2%). The oxotremorine-induced inhibition of the electrically stimulated release of acetylcholine (ACh) in rat hippocampal slices was reversed by SDZ ENS 163 (pA2 = 5.5 ± 0.1). In addition after oral administration SDZ ENS 163 (3 – 10 μmol/kg) reduced brain ACh levels, which is indicative of increased ACh turnover. Finally, increases in energy of the low frequency band (2–5 Hz) were observed in rat hippocampal EEG after intraperitoneal administration of SDZ ENS 163 (0.3 – 30 μmol/kg). We conclude that SDZ ENS 163 is a selective M1 agonist in vitro with an additional M2 antagonistic effect. The in vivo effects of SDZ ENS 163 may result both from postsynaptic M1 agonistic as well as M2 receptor antagonistic activity. The unique pharmacological profile of SDZ ENS 163 may prove clinically favourable for treatment of cognitive deficits.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168688
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  • 2
    Digitale Medien
    Digitale Medien
    Serotonergic modulation of neurotransmission in the rat subicular cortex in vitro: a role for 5-HT1B receptors (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 553-557 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Serotonin ; 5-HT1B receptors ; Subiculum ; Glutamatergic transmission
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary We have studied the effect of serotonin on synaptic transmission in rat hippocampal subiculum slices. Electrical stimulation of the alveus induced a field potential in the subiculum. The non-NMDA glutamate receptor antagonist, NBQX (3 × 10−6 mol/l) suppressed the response by 78%, indicating that the signal involves glutamatergic neurons. Application of serotonin suppressed (EC50 = 3.6 × 10−6 mol/l) the amplitude of he evoked potentials in a reversible, concentration-dependent manner. The responses to 5-HT were not altered after pretreatment with the 5-HT uptake blocker, fluvoxamine (10−5 mol/l) or a combination of the MAO inhibitor pargyline (10−5 mol/l) and ascorbic acid (10−4 mol/l). The responses to 5-HT were also unaffected by pretreatment with the 5-HT1A selective antagonist NAN-190 (10−6 mol/l), the 5-HT2A antagonist ketanserin (10−6 mol/l) or the 5-HT3/5-HT4 antagonist ICS 205–930 (10−6 mol/l). The 5-HT1B selective agonist CP 93,129 mimicked the effects of serotonin, but was more potent (EC50 4.1 × 10−7 mol/l). The 5-HT1B receptor antagonist, (±)21-009 (3 × 10−7 mol/l), antagonized the response to 5-HT and CP 93,129 with a pKB value of 7.1 and 7.2, respectively. These results suggest that the effect of 5-HT in the rat subiculum is mediated by 5-HT1B receptors.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00167229
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  • 3
    Digitale Medien
    Digitale Medien
    Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats (1996)
    Springer
    Pflügers Archiv 431 (1996), S. 828-837 
    Details
    ISSN: 1432-2013
    Schlagwort(e): Capsaicin ; Sensory neurone ; Calcineurin ; Desensitization ; Ion channel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Capsaicin activates a non-specific cation conductance in mammalian sensory neurones. If capsaicin is applied continuously or repeatedly then there is a progressive decline in responsiveness. We have studied the mechanism of this desensitization using electrophysiological methods in cultured dorsal root ganglion neurones from adult rats. The rate of desensitization of capsaicin-induced responses is partly dependent on the extracellular calcium concentration and is slower when extracellular calcium is reduced. Desensitization is strongly inhibited by intracellular application of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N, N′,N′-tetraacetic acid (BAPTA). These data suggest that desensitization is due to a rapid rise in intracellular calcium levels which occurs when capsaicin-sensitive ion channels are activated. Desensitization is not reduced by the non-specific protein kinase inhibitors H7 or staurosporine or by okadaic acid, a selective inhibitor of protein phosphatases 1 and 2A. Desensitization is greatly reduced by cyclosporin A complexed to cyclophilin, which is a specific inhibitor of protein phoshatase 2B (calcineurin). A mechanism for desensitization of capsaicin responsiveness is proposed whereby the evoked rise in calcium activates calcineurin leading to dephosphorylation and desensitization of the capsaicin-sensitive ion channels.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF02332166
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  • 4
    Digitale Medien
    Digitale Medien
    Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats (1996)
    Springer
    Pflügers Archiv 431 (1996), S. 828-837 
    Details
    ISSN: 1432-2013
    Schlagwort(e): Key words Capsaicin ; Sensory neurone ; Calcineurin ; Desensitization ; Ion channel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract Capsaicin activates a non-specific cation conductance in mammalian sensory neurones. If capsaicin is applied continuously or repeatedly then there is a progressive decline in responsiveness. We have studied the mechanism of this desensitization using electrophysiological methods in cultured dorsal root ganglion neurones from adult rats. The rate of desensitization of capsaicin-induced responses is partly dependent on the extracellular calcium concentration and is slower when extracellular calcium is reduced. Desensitization is strongly inhibited by intracellular application of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N, N′,N′-tetraacetic acid (BAPTA). These data suggest that desensitization is due to a rapid rise in intracellular calcium levels which occurs when capsaicin-sensitive ion channels are activated. Desensitization is not reduced by the non-specific protein kinase inhibitors H7 or staurosporine or by okadaic acid, a selective inhibitor of protein phosphatases 1 and 2A. Desensitization is greatly reduced by cyclosporin A complexed to cyclophilin, which is a specific inhibitor of protein phoshatase 2B (calcineurin). A mechanism for desensitization of capsaicin responsiveness is proposed whereby the evoked rise in calcium activates calcineurin leading to dephosphorylation and desensitization of the capsaicin-sensitive ion channels.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/s004240050074
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  • 5
    Digitale Medien
    Digitale Medien
    Characterization of functional responses in A9 cells transfected with cloned rat 5-HT1C receptors (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 347 (1993), S. 119-124 
    Details
    ISSN: 1432-1912
    Schlagwort(e): 5-HT1C receptors ; A9 cells potassium conductance ; Calcium response ; Fura-2/Fluo-3
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Functional responses to stimulation of rat 5-HT1C receptors expressed in A9 cells were studied using whole cell voltage clamp and calcium recording techniques. Stimulation of 5-HT1C receptors evoked outward currents clamped at −50 mV. The outward currents were reduced when GTP was excluded from the intracellular recording solution or when GDR-β-S was added. 8-Bromo cyclic AMP (5 mmol/l) neither produced an effect per se nor affected the 5-HT-induced outward current in A9 cells, thus excluding CAMP as a second messenger involved in 5-HT1C receptor activation. Phorbol myristic acetate (PMA; 10 μmol/l) did not affect the electrical activity of the transfected A9 cells but reduced the 5-HT-induced current amplitude to 71±9% of the control value (n = 12). This indicates that activation of protein kinase C does not play a direct role in the 5-HT-induced response in these cells. The 5-HT induced currents mainly involved potassium ions, although a small contribution of chloride ions was also observed. The 5-HT-induced current was inhibited by the K+ channel blocking agents tetraethylammonium (1 mmol/l), apamin (0,5 μmol/l) and 4-aminopyridine (5 mmol/1). The 5-HT-induced currents recorded at −50 mV were unaffected by removal of extracellular calcium, but inclusion of the calcium chelator BAPTA (5 mmol/l) in the intracellular solutions abolished the current. Measurement with the calcium indicator Fluo-3 revealed a 5-HT-induced increase in intracellular calcium which was not affected by removal of extracellular calcium but declined after repeated stimulation. Determinated of pD2 and KB values of several 5-HT ligands using Fura-2 calcium measurements confirmed the pharmacology of the 5-HT1C receptor. The results show that cloned rat 5-HT1C C receptors expressed in A9 cells activate a calcium-dependent potassium conductance.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00169255
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  • 6
    Digitale Medien
    Digitale Medien
    Calcineurin inhibits desensitization of cloned rat 5-HT1C receptors (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 221-224 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Rat 5-HT1C receptors ; A9 cells ; Desensitization ; Calcineurin
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Functional responses to stimulation of rat 5-HT1C receptors expressed in A9 cells were studied using whole cell voltage clamp recording technique. Stimulation of 5-HT1C receptors with serotonin (5-HT) evoked calcium-dependent outward currents of 109 pA in cells clamped at — 50 mV. Pretreatment with the protein kinase C (PKC) activator phorbol myristic acetate (PMA) reduced the 5-HT-induced current amplitude by 46% of the control value. Inclusion of inositol triphosphate (IP3) in the pipette solution induced an outward current of 84 pA. The IP3-induced response was not affected by 60 min pretreatment with PMA. In the presence of the PKC antagonist calphostin C, 60 min treatment with PMA (10−6 mol/1) reduced the 5-HT response only by 8%. In cells preincubated with PMA, injection of the calcium/calmodulin dependent serine proteinphosphatase calcineurin gradually increased the 5-HT-induced responses by 34%. In A9 cells which were incubated 24 h with the 5-HT1C receptor agonist meta chlorophenylpiperazine hydrochloride (mCPP), 5-HT-induced responses were reduced by 23% of the vehicle pretreated control value. Injection of calcineurin in mCPP treated cells enhanced the 5-HT-induced response by 24%. The results suggest that in A9 cells rat 5-HT1C receptors are desensitized after phosphorylation by PKC. This desensitization can be counteracted by calcineurin-induced: dephosphorylation.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00169147
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  • 7
    Digitale Medien
    Digitale Medien
    M1 muscarinic receptors mediate intracellular calcium release in NB-OK1 human neuroblastoma cells (1992)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 346 (1992), S. 255-261 
    Details
    ISSN: 1432-1912
    Schlagwort(e): NB-OK1 cells ; M1 receptors ; Radioligand binding ; Calcium release ; PI turnover
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary Muscarine acetylcholine receptors were characterized in NB-OK1 cells using radioligand (3H-NMS) binding experiments and second messenger (calcium and phosphatidylinositol (PI) turnover) studies. In radioligand binding experiments the displacement curves of pirenzepine (KI = 1.3 × 10−8 M), AF-Dx 116 (KI = 8.2 × 10−7 M), methoctramine (KI = 8.4 × 10−8 M) and parafluorohexahydrosiladifenidol (pF-HHSiD) (K1 = 1.8 × 10−8 M) were monophasic and indicated the presence of M 1 muscarinic receptors. Schild analysis with the muscarinic antagonists pirenzepine, AF-Dx 116, methoctramine and pF-HHSiD yielded pA2 values of 8.40 +- 0.13, 6.48 =- 0.09, 7.61 +- 0.12 and 7.22 +- 0.08 in the calcium experiments and pA2 values of 8.13 +- 0.30 and 6.26 +- 0.26, 7.65 +- 0.16 and 7.46 +- 0.11, respectively, in the PI turnover experiments. These results indicate that both the carbachol-induced increase in intracellular calcium and the increase in PI turnover are mediated by M1 muscarinic receptors. In calcium free buffer, stimulation with carbachol induced similar responses to those seen under control conditions. From functional and radioligand binding experiments we conclude that the muscarinic receptor expressed in NB-OK1 cells is the M1 subtype. In addition, the M1 receptor-induced calcium response is related to PI turnover and is independent on extracellular calcium.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00173537
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  • 8
    Digitale Medien
    Digitale Medien
    Differences between negative inotropic and vasodilator effects of calcium antagonists acting on extra- and intracellular calcium movements in rat and guinea-pig cardiac preparations (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 567-575 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Calcium antagonists ; Negative inotropy ; Isolated rat heart ; Rat papillary muscle ; Guinea-pig papillary muscle
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In order to get more insight into the utilization of calcium in the mammalian heart and the influence of calcium antagonists on this process we have evaluated the negative inotropic and vasodilator effect of nifedipine, diltiazem, verapamil, bepridil and lidoflazine as well as of the intracellularly acting calcium antagonists ryanodine and TMB-8 in the presence of 0.9 and 1.8 mmol/l calcium in rat Langendorff hearts. The effect of ryanodine was also studied in guinea-pig Langendorff hearts. In addition, in rat and guinea-pig papillary muscles the effect of these drugs on the force of contraction was examined. With the exception of ryanodine and TMB-8 all calcium antagonists induced a pronounced coronary vasodilator effect. The rank order of potency for this effect was: nifedipine 〉 verapamil = diltiazem = bepridil = lidoflazine in the presence of 0.9 mmol/l calcium. At a calcium concentration of 1.8 mmol/l nifedipine and verapamil proved more potent, whereas diltiazem was less active. All calcium antagonists completely suppressed the development of the left ventricular pressure. At a calcium concentration of 0.9 mmol/l the potency order for this effect was: ryanodine 〉 nifedipine = verapamil 〉 diltiazem = bepridil = lidoflazine 〉 TMB-8. In the presence of 1.8 mmol/l calcium the concentration-response curves for reduction of the left ventricular pressure by nifedipine, verapamil and diltiazem slightly shifted to the right. In contrast to all calcium antagonists investigated, in guinea-pig Langendorff hearts ryanodine only partially decreased the left ventricular pressure. In rat papillary muscles ryanodine nearly completely reduced the force of contraction, whereas nifedipine only partially inhibited the force of contraction. Lidoflazine only slightly affected the force of contraction. In guinea-pig papillary muscles all drugs partially decreased the force of contraction. Lidoflazine, however, was more effective than in rat papillary muscles. In rat and guinea-pig papillary muscles the force of contraction was fully suppressed by a combination of nifedipine and ryanodine. The results of the present study suggest that in the rat heart extracellular calcium plays a major role in the maintenance of the coronary vascular tone. The development of contractile force relies on the release of activator calcium from the sarcoplasmic reticulum but also requires the influx of calcium through dihydropyridine-sensitive channels. In the guinea-pig heart activator calcium may also be released from a source complementary to the sarcoplasmic reticulum. Lidoflazine displays certain selectivity towards this particular calcium pool.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00260612
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  • 9
    Digitale Medien
    Digitale Medien
    A comparison of the cardioprotective effects of calcium antagonists from different classes upon ischaemic damage in the guinea-pig working heart (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 126-134 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Guinea-pig working heart ; Global ischaemia ; Calcium antagonists ; Dipyridamole ; Adenine nucleotides
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The cardioprotective effects of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and the coronary vasodilator dipyridamole were evaluated in the guinea-pig working heart with respect to cardiac function and high energy phosphate content after 45 min of global ischaemia and 25 min of reperfusion. All drugs, with the exception of dipyridamole, induced a negative inotropic effect, which resulted in a decrease of the aortic pressure (AoP), of its first derivative dAoP/dt and the cardiac output. To compare the anti-ischaemic effect of the calcium antagonists, concentrations were selected that reduced the dAoP/dt by 10% (EC10) and 30% (EC30), respectively. With the exception of nifedipine at the EC10 and bepridil and CERM 11956 at the EC30, perfusion with the calcium antagonists and dipyridamole (3 μmol/l) improved the recovery of contractile function after global ischaemia and reperfusion to a value between 60 and 80% of the controls in normoxic hearts. Pretreatment with nifedipine, verapamil, diltiazem, lidoflazine and mioflazine, but not with bepridil, CERM 11956 and dipyridamole led to slightly increased ATP levels in ischaemic hearts as compared to the control value in ischaemic hearts. After subsequent reperfusion for 25 min, for all drugs, ATP levels were further enhanced to 50% of the level in normoxic hearts; phosphocreatine levels reached normoxic values. In particular at the EC30, the effects of calcium antagonists on cardiac function varied in accordance with their known pharmacological and physiological profile. However, there appeared to exist no direct relationship between their beneficial effects on contractile activity and those on the levels of high energy phosphates after ischaemia and reperfusion.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00169218
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  • 10
    Digitale Medien
    Digitale Medien
    Abstracts of papers Pharmacological meeting (1989)
    Springer
    Pharmacy world & science 11 (1989), S. J3 
    Details
    ISSN: 1573-739X
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF02196046
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