Naunyn-Schmiedeberg's archives of pharmacology
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Naunyn Schmiedebergs Arch. Pharmacol. · Feb 1998
Comparative StudyComparison of human alpha1-adrenoceptor subtype coupling to protein kinase C activation and related signalling pathways.
The coupling of human alpha1-adrenoceptor subtypes to protein kinase C (PKC) and PKC-related signalling events were investigated in rat-1 fibroblasts stably expressing alpha1A-, alpha1B- or alpha1D-adrenoceptors at densities of 1328+/-200, 5030+/-703 and 150+/-14 fmol/mg protein respectively. In functional assays the alpha1-adrenoceptor agonist phenylephrine significantly stimulated PKC (assessed as increased activity in the membrane fraction) in cells expressing alpha1A- or alpha1B- but not alpha1D-adrenoceptors. In immunoblot assays phorbol ester treatment enhanced membrane-associated immunoreactivity of PKCalpha, PKCdelta and PKCepsilon to a similar extent in all three cell lines. ⋯ We conclude that human alpha1A- and alpha1B-adrenoceptors expressed in rat-1 cells couple to activation of PKCalpha, PKCdelta and PKCepsilon but not PKCzeta; this may involve stimulation of phospholipases C and D and intracellular Ca2+ elevations. Activation of these pathways by alpha1D-adrenoceptors appears to be much weaker and was not detected consistently; this was not fully explained by weak partial agonism of phenylephrine at this subtype or by lower receptor densities. Overall the alpha1A-adrenoceptor may have the highest efficiency of stimulus-response coupling among human alpha1-adrenoceptor subtypes.
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Naunyn Schmiedebergs Arch. Pharmacol. · Nov 1997
Comparative StudyPresynaptic snake beta-neurotoxins produce tetanic fade and endplate potential run-down during neuromuscular blockade in mouse diaphragm.
The present study investigated the ability of a number of presynaptic snake neurotoxins (snake beta-neurotoxins) to produce nerve-evoked train-of-four fade, tetanic fade and endplate potential run-down during the development of neuromuscular blockade in the isolated mouse phrenic-hemidiaphragm nerve-muscle preparation. All the snake beta-neurotoxins tested, with the exception of notexin, produced train-of-four and tetanic fade of nerve-evoked isometric muscle contractions. Train-of-four fade was not present during the initial depressant or facilitatory phases of muscle tension produced by the snake beta-neurotoxins but developed progressively during the final depressant phase that precedes complete neuromuscular blockade. ⋯ However when EPP amplitude fell to near uniquantal levels (< 3 mV) the extent of toxin induced-fade was reduced. Unlike postjunctional snake alpha-neurotoxins, prejunctional snake beta-neurotoxins interfere with acetylcholine release at the neuromuscular junction during the development of neuromuscular blockade. This study provides further support for the hypothesis that fade in twitch and tetanic muscle tension is due to an underlying rundown in EPP amplitude resulting from a prejunctional alteration of transmitter release rather than a use-dependent block of postjunctional nicotinic receptors.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jul 1997
Effects of gastroprokinetic agents on gastroparesis in streptozotocin-induced diabetic rats.
The influence of diabetic hyperglycemia on solid gastric emptying in rats was examined. Diabetes was produced by streptozotocin (STZ, 40 mg/kg i.v.), and diabetic hyperglycemia was observed from 1 day after the STZ injection. The gastric emptying of glass beads in the diabetic rats was significantly delayed compared with that in age-matched control rats at 1, 3 and 7 days after diabetes induction. ⋯ Ramosetron and the substituted benzamides cisapride and zacopride partially reversed the gastroparesis in the vagotomized rats. These results suggest that acute hyperglycemia is important mechanism for the delay of solid gastric emptying in diabetic rats. It is also suggested that selective 5-HT3 receptor antagonists and substituted benzamides enhance gastric emptying not only in normal rats but also in diabetic and vagotomized rats.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jul 1997
Differential desensitization of ionotropic non-NMDA receptors having distinct neuronal location and function.
The release of tritium from rat hippocampal synaptosomes prelabeled with [3H]noradrenaline ([3H]NA) or [3H]5-hydroxytryptamine ([3H]5-HT) and from rat neocortex synaptosomes prelabeled with [3H]choline and the release of endogenous GABA and glutamate from rat neocortex synaptosomes were monitored during superfusion with media containing varying concentrations of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid. Concentration-dependent release potentiations were elicited by both excitatory amino acids (EAAs) in all the transmitter systems investigated. The releases evoked by 100 microM AMPA were, in all cases, almost totally dependent on external Ca2+ and sensitive to 6.7-dinitroquinoxaline-2,3-dione (DNQX), indicating involvement of non-NMDA receptors. ⋯ Finally, the effect of AMPA on the release of [3H]ACh did not respond to cyclothiazide also during three subsequent stimuli with 100 microM AMPA. To conclude: a) ionotropic non-NMDA receptors mediating enhancement of NA, 5-HT, ACh, GABA and glutamate release exist on the corresponding nerve terminals; b) the receptors present on noradrenergic and serotonergic neurons are AMPA-preferring receptors, whereas the glutamate autoreceptors resemble most the kainate-preferring subtype; the receptors mediating ACh and GABA release can not be subclassified at present; c) desensitization may not be a property of all non-NMDA ionotropic receptors. The receptors here characterized represent five models of native non-NMDA receptors suitable for pharmacological and molecular studies.
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Naunyn Schmiedebergs Arch. Pharmacol. · Jul 1997
Effects of adenosine and adenosine analogues on mean circulatory filling pressure and cardiac output in anesthetized rats.
The effects of adenosine and adenosine analogues, 2-[p-(2-[carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) and N6-2-(4-aminophenyl)-ethyladenosine (APNEA), on mean arterial pressure, cardiac output, mean circulatory filling pressure, arterial resistance, venous resistance and heart rate in untreated or treated (with ganglion-blockers mecamylamine and atropine) pentobarbital-anesthetized rats were examined. Infusion of adenosine (100, 300 and 900 microg/kg/min), CGS 21680 (0.1, 0.3 and 0.9 microg/kg/min) or APNEA (1.0, 3.0 and 9.0 microg/kg/min) reduced mean arterial pressure and arterial resistance in all groups. Adenosine and APNEA also reduced mean circulatory filling pressure, venous resistance and heart rate in untreated animals. ⋯ In addition, APNEA and adenosine reduced arterial resistance but were unable to alter venous resistance while CGS 21680 reduced mean circulatory filling pressure and arterial resistance but did not further affect cardiac output, heart rate and venous resistance in ganglion-blocked animals. The results of the present study suggest that adenosine and APNEA dilate arterioles and vein, whereas CGS 21680 causes arterial dilatation but not venodilatation in untreated animals due to hypotension-induced sympathetic activation. A possible explanation for the present observations could be differences in the distribution of vascular A2 versus A3 adenosine receptors in the venous circulation.