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E Adler-Graschinsky

Publications and source records attributed to E Adler-Graschinsky.

At least 37 records · Page 2Linked to original sources
PubMed1992

Relaxant effects of beta-carbolines on rat aortic rings.

The effects of two beta-carbolines, methyl 6,7-dimethoxy-4-ethyl-beta- carboline-3-carboxylate (DMCM) and ethyl beta-carboline-3-carboxylate (beta CCE) were assayed on rat aortic rings precontracted with different agonists. The beta-carbolines tested induced a concentration-dependent (2-200 microM) relaxation of aortic rings precontracted with 30 mM KCl. This relaxation was not modified by the removal of the rat aortic endothelium. Contractions elicited by the activation of either voltage-gated calcium channels (0.05 microM BAY K 8644) or receptor-operated calcium channels (0.1 microM norepinephrine), as well as contractions produced by the entry of calcium as a lipid-soluble complex (10 microM A23187), were also reduced by DMCM and by beta CCE. In addition, whereas DMCM did not modify calmodulin activity, both beta-carbolines inhibited in a concentration-dependent manner (0.6-200 microM) the rat aortic cyclic nucleotide phosphodiesterase activity. Moreover, DMCM as well as beta CCE potentiated the relaxation of K(+)-contracted aortic rings induced by the stimulation of either adenylyl cyclase with forskolin (0.1-1 microM) or guanylyl cyclase with sodium nitroprusside (0.1-100 nM). The intracellular rat aortic levels of cyclic AMP measured in the presence of 0.1 microM forskolin were increased by 100% in the presence of DMCM. On the other hand, 6 microM DMCM potentiated the relaxation induced by nifedipine in K(+)-contracted aortic rings, whereas the K+ channel blocker 10 mM tetraethylammonium did not modify the relaxation elicited by DMCM in the norepinephrine-contracted preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Benzodiazepines decrease the release of [3H]noradrenaline and of [3H]acetylcholine in the cat superior cervical ganglion.

The effects of two benzodiazepines, diazepam and clonazepam, were studied on the release of [3H]noradrenaline and of [3H]acetylcholine elicited by preganglionic stimulation of the cat isolated superior cervical ganglion and on the contractile responses evoked by either nerve stimulation or exogenous noradrenaline in the cat isolated nictitating membrane. Both 10 microM diazepam and 10 microM clonazepam reduced by approximately 50% the release of [3H]noradrenaline and of [3H]acetylcholine in the cat ganglion whereas they did not modify the contractile responses in the nictitating membrane. It is concluded that benzodiazepines are also peripheral neuroactive agents and that they exhibit a tissue-selective action within the same animal species.

Acetylcholine↗
PubMed1989

Diminution by benzodiazepines of the chronotropic responses to noradrenaline in rat isolated atria.

The effects of various benzodiazepines on chronotropic responses were assayed in spontaneously beating rat isolated atria. The increases in atrial rate obtained from concentration-response curves to noradrenaline were reduced dose dependently by both the peripheral agonist, Ro 5-4864 5 and 10 microM, and the mixed agonist, diazepam 5, 10 and 50 microM, but not by the central benzodiazepine agonist, clonazepam 10 and 30 microM. The inhibitory effects of the benzodiazepines on the atrial responses to noradrenaline were not counteracted by either the peripheral benzodiazepine antagonist, PK 11195 10 microM, or the central benzodiazepine antagonist, Ro 15-1788 10 and 100 microM. Both 10 microM Ro 5-4864 and 10 microM diazepam also reduced the increases in atrial rate produced by either the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, or the adenylate cyclase activator, forskolin. On the contrary, diazepam and Ro 5-4864 did not modify the chronotropic responses of the atria either to direct exposure to CaCl2 or to the calcium agonist, BAY K 8644. The increases in the intracellular levels of cAMP induced by noradrenaline were not modified by Ro 5-4864 and were even increased by 50% in the presence of diazepam. It is concluded that benzodiazepines probably reduce the chronotropic responses to noradrenaline in rat isolated atria through the interaction with the cAMP-linked chain of events that follows the activation of beta-adrenoceptors.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Different receptor subtypes mediate the dual presynaptic effects of 5-hydroxytryptamine on peripheral sympathetic neurones.

1. The aim of the present work was to characterize the presynaptic 5-HT receptors that mediate either the facilitation of the responses to nerve stimulation in the nictitating membrane of the cat or the inhibition of the responses to nerve stimulation in the guinea-pig atria. 2. In the nictitating membrane of the cat, the shift to the left in the frequency-response curves produced by 5-HT (0.1 microM) was prevented by the 5-HT3 receptor antagonists, metoclopramide (1 microM) and MDL 72222 (0.01 microM). 3. The facilitatory effect of 5-HT is also prevented by the 5-HT2 receptor antagonist, 0.01 microM ketanserin. Nevertheless, this drug reduced by itself the responses to both nerve stimulation and exogenous NA in the nictitating membrane. 4. In the guinea-pig isolated atria, the inhibitory effect of 5-HT on the chronotropic responses to cardioaccelerans nerve stimulation was mimicked by the mixed 5-HT1A + 5-HT1B + 5-HT1D receptor agonist 5-carboxamidotryptamine (5-CT 0.1 and 1 microM). The 5-HT1A receptor agonist 8-OH-DPAT (0.1 and 1 microM) did not modify the responses of the atria to the nerve stimulation. 5. The 5-HT2 receptor antagonists, ketanserin (0.01 and 0.1 microM) and cyproheptadine (1 microM), did not prevent the inhibitory effect of 5-HT in the guinea-pig atria. 6. The present results suggest that the facilitatory effects of 5-HT in the nictitating membrane of the cat are linked to the activation of 5-HT3 receptors whereas the inhibitory effects observed in the guinea-pig atria are mediated by 5-HT1-like receptors.

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

Presynaptic effects of l-alanine on peripheral sympathetic neurotransmission.

Concentrations ranging from 0.1 nM to 30 microM of the aminoacids l-alanine (l-ALA), taurine, hypotaurine and beta-ALA were assayed on the chronotropic responses of rat isolated atria stimulated through their cardioaccelerans nerves. The increases in atrial rate obtained in frequency-response curves to nerve stimulation (0.1-12.8 Hz) were not modified by taurine, hypotaurine and beta-ALA but were reduced by l-ALA (0.01 and 0.1 microM). L-ALA did not modify the chronotropic responses to exogenous norepinephrine (NE). In the atria labeled in vitro with [3H]NE, the release of radioactivity evoked by postganglionic nerve stimulation at 2 Hz (6 V, 0.5 msec duration for 2 min) was reduced to 70% of control values by 0.1 microM l-ALA. The release of [3H]NE evoked by 60 and 100 mM KCl was also reduced by 0.1 microM l-ALA to 40 and to 70% of control values, respectively. L-ALA (0.1 microM) did not affect the outflow of tritium provoked by a 1-min incubation with 1 microM tyramine. The chronotropic responses to nerve stimulation were not modified by the l-ALA metabolites pyruvate and glutamate but were reduced by an analog of l-ALA, alpha-(methylamino)-isobutyric acid, which also diminished the release of [3H]NE elicited by nerve stimulation at 2 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed1986

Serotonin uptake inhibitors and the prejunctional effects of serotonin on peripheral sympathetic nerves.

The experiments were designed to study whether the inhibitors of the uptake of serotonin (5-HT) potentiated the prejunctional effects of 5-HT on peripheral sympathetic nerves. The effect of two selective 5-HT uptake inhibitors, citalopram and fluoxetine, were studied on the presynaptic actions of 5-HT in the cat isolated nictitating membrane and in the guinea-pig isolated atria. Frequency-effect curves to nerve stimulation and concentration-response curves to noradrenaline (NA) were performed in both preparations. The facilitation that 0.1 microM 5-HT causes on the contractile responses to nerve stimulation of the nictitating membrane of the cat was not potentiated but entirely prevented by both 0.01 microM citalopram and 1.0 microM fluoxetine. On the other hand the diminution that 1.0 microM 5-HT evokes on the chronotropic responses to nerve stimulation of guinea-pig isolated atria was not modified at all by 0.1 and 1.0 microM fluoxetine and only partially prevented by 10.0 microM fluoxetine and by 0.001 microM, 0.01 microM and 0.1 microM citalopram. This latter effect of citalopram was unrelated to the concentration employed. The 5-HT uptake inhibitors did not modify per se either the responses to nerve stimulation or the sensitivity to exogenous NA in both tissues studied. In addition, the 5-HT uptake inhibitors did not interfere with the contractile responses caused by 5-HT in the cat isolated nictitating membrane. Taken together, these observations might indicate a pharmacological rather than a physiological role for the effects of 5-HT in guinea-pig isolated atria and cat nictitating membranes. It is concluded that the 5-HT uptake inhibitors do not potentiate but even antagonize the presynaptic effects of 5-HT. Our results also show that 5-HT uptake inhibitors are more effective to interfere with the facilitation rather than with the inhibition that 5-HT causes on sympathetic responses.

Animals↗
PubMed1985

Morphine decreases 3H-norepinephrine release and increases endogenous norepinephrine levels in the isolated cat superior cervical ganglion.

The isolated cat superior cervical ganglion (SCG) was labeled in vitro with either 3H-norepinephrine (3H-NE) or 3H-choline and stimulated through its preganglionic trunk. The release of 3H-NE and 3H-acetylcholine (3H-ACh) elicited by the stimulation was measured under control conditions and in the presence of drugs. The incubation during 30 min with 10 microM morphine lead to a 70% decrease in the amount of 3H-NE released in response to the preganglionic stimulation (10 Hz, 80 V, during 5 min). No further decrease in 3H-NE release was produced by a 10 times higher concentration of morphine. The reduction in 3H-NE release caused by morphine was coincident with a 60% increase in the endogenous content of NE. Both effects of morphine were entirely prevented by an antagonist of opioid receptors, 1.0 microM naltrexone. The opioid antagonist did not modify by itself either the stimulation-induced release of 3H-NE or the endogenous content of NE. The basal efflux of 3H-NE was not altered by morphine. In ganglia labeled with 3H-choline, morphine (10 and 100 microM) did not modify either the basal efflux of 3H-ACh or the release of 3H-ACh evoked by stimulation of the preganglionic trunk (5 Hz, 40 V, during 5 min). These observations suggest that in the cat SCG morphine has a direct action on the dendrites of the postganglionic neuron which store and release NE. The effects of morphine in vitro on 3H-NE release and on the tissue levels of NE may be mediated through the interaction with dendritic opioid receptors.

Acetylcholine↗
PubMed1984

Ionic mechanisms involved in the release of 3H-norepinephrine from the cat superior cervical ganglion.

It has previously been reported that in the isolated cat superior cervical ganglion (SCG) labeled with tritiated norepinephrine (3H-NE), the stimulation of the preganglionic trunk at 10 Hz as well as the exposure to 100 microM exogenous acetylcholine (ACh), produced a Ca++-dependent release of 3H-NE. The present results show that a Ca++-dependent release of 3H-NE was produced also by exposure to either 50 microM veratridine or 60 mM KCl. Tetrodotoxin (0.5 microM) abolished the release of 3H-NE induced by preganglionic stimulation, ACh and veratridine but did not modify the release evoked by KCl. The metabolic distribution of the radioactivity released by the different depolarizing stimuli showed that the 3H-NE was collected mainly unmetabolized. In the cat SCG neither the release of 3H-NE evoked by KCl nor the endogenous content of NE was modified by pretreatment with 6-OH-dopamine (6-OH-DA). On the other hand, this chemical sympathectomy depleted the endogenous content of NE in the cat nictitating membrane, whose nerve terminals arise from the SCG. The data presented suggest that the depolarization-coupled release of NE from the cat SCG involves structures that are different to nerve terminals and that contain Na+ channels as well as Ca++ channels.

Acetylcholine↗
PubMed1984

Metoclopramide increases the release of catecholamines from isolated human phaeochromocytomas.

Metoclopramide increased the release of catecholamines from isolated human phaeochromocytomas but not from isolated rat adrenal glands employed as control tissue. This selective effect of metoclopramide may have resulted from the high endogenous levels of catecholamines found in the tumours. It is suggested that the administration of drugs which can potentially produce the release of catecholamines should be very carefully controlled in patients with phaeochromocytoma.

Adrenal Glands↗
PubMed1983

Dual presynaptic effects of 5-hydroxytryptamine on peripheral noradrenergic synapses.

The aim of the present experiments was to study the effects of 5-hydroxytryptamine (5-HT) on the responses to postganglionic stimulation of two models of the peripheral sympathetic nervous system: the isolated nictitating membrane of the cat and the guinea-pig isolated atria. In the nictitating membrane of the cat, 5-HT (0.1 microM) shifted to the left the frequency-response curve to nerve stimulation. This potentiating effect was prevented by 5-HT receptor antagonists (0.1 microM methysergide, 0.1 microM pizotifen and 0.1 microM morphine) and also by the beta-adrenoreceptor blocker propranolol (0.1 microM). The alpha 2-adrenoreceptor antagonist yohimbine (0.1 microM) had no effect on the 5-HT-induced potentiation. In the guinea-pig isolated atria the responses to cardioaccelerans nerve stimulation were diminished by 5-HT (0.1 to 1.0 microM). The shift to the right in the frequency-response curve induced by 5-HT (1.0 microM) was additive to the antagonism caused in the atria by propranolol (0.1 microM). The inhibitory effect of 5-HT on the pacemaker responses to nerve stimulation was prevented by the 5-HT receptor antagonists methysergide (1.0 microM) and pizotifen (1.0 microM) and also by the alpha-adrenoreceptor antagonist phentolamine (0.1 microM). The selective alpha 2-adrenoreceptor agonist clonidine (0.01 microM) reduced to the same extent as 5-HT (1.0 microM) the responses to the guinea-pig atria to nerve stimulation. The inhibitory effect of clonidine was prevented by the alpha-adrenoreceptor blocker phentolamine (0.1 microM) but not by the 5-HT receptor blocker pizotifen (1.0 microM). With the exception of propranolol, which in the atria shifted to the right the concentration-response curve to exogenous noradrenaline (NA), neither 5-HT nor the different antagonists employed modified the sensitivity to NA in the tissues studied. The present observations show that 5-HT can produce a dual effect on the sympathetic neurotransmission. It is proposed that a modification in the overflow of NA in response to nerve stimulation is caused by 5-HT and results from the interaction of 5-HT with specific receptors located on the sympathetic fibres. These presynaptic 5-HT receptors behave as excitatory (cat nictitating membrane) or inhibitory (guinea-pig atria) depending on the tissue studied.

Animals↗
PubMed1983

Comparison of the effects of beta-phenylethylamine and d-amphetamine on rat isolated atria.

beta-Phenylethylamine (PEA) produced a positive chronotropic effect in the spontaneously beating isolated rat atria. The concentration-response curves to PEA and to d-amphetamine (AMPH) were virtually superimposed and potentiated to the same extent by inhibition of monoamine oxidase with pargyline. As reported for AMPH, the rate accelerating effect of PEA was abolished by pretreatment with reserpine. In the reserpinized tissue, the responses to PEA were partly restored by pargyline pretreatment and fully restored after the incubation with norepinephrine (NE). Repeated exposures to high concentrations of both PEA and AMPH produced tachyphylaxis to low concentrations of the amines but did not modify the endogenous atrial content of NE. in atria labeled with [3H]NE, PEA (6.4 microM) and AMPH (7.9 microM) increased the overflow of tritium mainly as unmetabolized [3H] NE (90%). For both drugs the increase in 3H-transmitter outflow coincided with the positive chronotropic response and it was independent on external Ca++. Cocaine (3.3 microM), which inhibits the uptake mechanism of catecholamines, displaced to the right the concentration-response curves to both PEA and AMPH and reduced the overflow of [3H]NE elicited by either amine. The release of 3H-products elicited by PEA was not modified by drugs that inhibit the uptake mechanism of NE accumulation, such as 26 microM corticosterone or 28 microM hydrocortisone. The results presented show that PEA behaves as AMPH as far as the mechanism of their indirect sympathomimetic effect is concerned. If accepted that PEA and AMPH, due to their high lipid solubility, might freely diffuse into nerves, the antagonism caused by cocaine on the effects of both amines could be interpreted as being the result of the inhibition by this drug of the carrier-mediated efflux of NE.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1980

Modulatory role of alpha adrenoceptors on the release of [3H]norepinephrine elicited by preganglionic stimulation of the cat superior cervical ganglion.

In the isolated cat superior cervical ganglion labeled in vitro with [3H]norepinephrine ([3H]NE), the overflow of radioactivity evoked by preganglionic stimulation at 10 Hz (80 V, 2 msec duration for 5 min) was reduced to 50% of control values by the alpha adrenoceptor agonists clonidine (0.001 microM) and methoxamine (12.0 microM). The alpha adrenoceptor antagonist phenoxybenzamine (2.9 microM) produced a 2-fold increase in the overflow of [3H]NE elicited by nerve stimulation. Preincubation with drugs that reduce the neuronal uptake of norepinephrine in the isolated ganglion (8.8 microM cocaine and 0.33 microM desipramine) did not modify the release of [3H]NE by preganglionic stimulation. However, a higher concentration of desipramine (3.3 microM) produced a 4-fold increase in the overflow of tritium evoked by stimulation. As this concentration of desipramine produced a shift to the right in the concentration-response curve to methoxamine in the isolated nictitating membrane of the cat, the conclusion is drawn that a feedback mechanism mediated through presynaptic alpha adrenoceptors regulates the release of [3H]NE induced by preganglionic stimulation of the cat superior cervical ganglion. In addition, it is suggested that regulatory mechanisms for norepinephrine release by nerve stimulation are not restricted to nerve terminals but are also present in dendrites of the postganglionic adrenergic neurons.

Adrenergic alpha-Agonists↗
PubMed1980

Comparison of the release of endogenous and of 3H-acetylcholine from slices of rat cerebral cortex.

A comparison of the release of endogenous and of tritiated acetylcholine (3H-ACh) was performed in eserinized slices of rat cerebral cortex labelled in vitro in the presence of 0.43 microM tityustoxin (TsTX), a scorpion venom known to increase the overflow of endogenous acetylcholine. The endogenous and the radioactive ACh were spontaneously released into the organ bath. At the moment when the spontaneous efflux had levelled off, the endogenous ACh collected during 1 min accounted for 1.03 +/- 0.14% of the tissue content and a similar value (0.80 +/- 0.26%) was found for 3H-ACh. The basal outflow as well as the tissue retention of ACh and of 3H-ACh were not modified by exposure to the scorpion venom. In the presence of 20 mM KCl for 1 min, the overflow of both radioactive and endogenous ACh was increased up to approximately 100% above basal levels and this K+-evoked release was almost doubled under the action of TsTX. The results presented are compatible with the view that no major functional differences exist in the rat cortex between responses of pools storing 3H-ACh synthesized from 3H-choline and those storing ACh formed from endogenous substrate.

Acetylcholine↗
PubMed1978

Metabolic fate of 3H-noradrenaline released from the mouse hypothalamus.

In slices of mouse hypothalamus labelled in vitro with 3H-noradrenaline (3-H-NA), the deaminated metabolite 3H-3,4-dihydroxyphenylglycol (3H-DOPEG), represented 40.2 +/- 2.6% of the total outflow of radioactivity and was the main fraction in the spontaneous efflux. Inhibition of neuronal monoamine oxidase by exposure to 60 micron bretylium, reduced the outflow of 3H-DOPEG to 9.7 +/0 0.3%. At the same time, the proportion of 3H-normetanephrine (3H-NMN) was significantly increased. On the other hand, an increased outflow of 3H-DOPEG and a lower proportion of 3H-NMN was obtained in the presence of 2.9 micron of the reserpine like agent Ro 4-1284. It is suggested that in the mouse hypothalamus, the deaminated metabolite, DOPEG, is formed inside the nerve terminals, while the O-methylated metabolite, NMN, might result from the activity of extraneuronal catechol O-methyltransferase.

Animals↗
PubMed1977

Possible physiological significance of the initial step in the catabolism of noradrenaline in the central nervous system of the rat.

The hypothalamus, the cerebral cortex and the cerebellar cortex of the rat were labelled in vitro with 3H-noradrenaline (3H-NA) and the metabolism of the tritiated transmitter was studied during spontaneous outflow and under conditions of release elicited by exposure to 20 mM K+. In the three areas of the central nervous system of the rat 3H-NA accounted for approximately 40% of the total radioactivity in spontaneous outflow while the 3H-O-methylated deaminated fraction (3H-OMDA) and 3H-3,4-dihydroxyphenylglycol (3H-DOPEG) were the main metabolites. Exposure to the reserpine-like agent, Ro 4-1284 induced a selective increase in the spontaneous outflow of 3H-DOPEG, while the contribution of the 3H-OMDA metabolites to the release induced by Ro 4-1284 was very small. During 3H-transmitter release elicited by exposure to 20 mM K+, approximately 80% of the radioactivity was collected as unmetabolized 3H-NA, while 3H-DOPEG was the main metabolite formed under these experimental conditions. Exposure to cocaine prevented 3H-DOPEG formation from 3H-NA released by K+, indicating that 3H-DOPEG was formed after neuronal reuptake of the transmitter released by K+. After in vitro labelling with 3H-NA, the unmetabolized transmitter represented approximately 70% of the total radioactivity retained in the tissue. However, when 3H-NA was administered in vivo, by intraventricular injection, only 30% of the total radioactivity retained by the tissue was accounted for by 3H-NA, and 60% of the radioactivity corresponded to the 3H-OMDA fraction, most of which was retained as 3H-MOPEG sulfate. When the rats were pretreated with pyrogallol, free 3H-DOPEG accounted for nearly 50% of the radioactivity retained in the three areas of the central nervous system after in vivo labelling with 3H-NA. When monoamine oxidase was inhibited by pargyline and 3H-NA was administered by intraventricular injection, 3H-NMN accounted for approximately 50% of the total radioactivity retained in the three areas of the central nervous system of the rat. The results obtained are compatible with the view that formation of the deamined glycol is the first step in the metabolism of 3H-NA in the rat central nervous system. In addition, it is concluded that the determination of the levels of some NA metabolites retained in the central nervous system does not necessarily represent an accurate reflection of the degree of central noradrenergic activity or of selective metabolic pathways. Consequently, in studies on the metabolism of NA it is important to take into account not only the transmitter and its metabolites in the tissue but also in the outflow from the structures studied either under in vivo or in vitro conditions.

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗
PubMed1975

Prejunctional effects of a purified toxin from the scorpion Tityus serrulatus: release of 3H-noradrenaline and enhancement of transmitter overflow elicited by nerve stimulation.

The effects of a purified fraction of the venom of the Brazilian scorpion, Tityus serrulatus, were studied in isolated guinea-pig atria previously labelled with 3H-noradrenaline. Exposure to 0.3 and 1.0 mug/ml of the scorpion toxin resulted in a long lasting positive chronotropic effect which was concentration-dependent. The increase in atrial rate coincided with an enhancement in spontaneous outflow of radioactivity. The increase in outflow of radioactive products elicited by exposure to 1.0 mug/ml of the scorpion toxin was approximately 3-fold. 3H-noradrenaline accounted for 60% of the total increase in outflow of radioactivity elicited by the scorpion toxin and the 3H-deaminated glycol (3,4-dihydroxyphenyl-glycol) represented the main metabolite formed, accounting for approximately 35% of the total release. 20 min after exposure to 1.0 mug/ml of the scorpion toxin the overflow of the labelled transmitter elicited by accelerans nerve stimulation (4 Hz, during 60 sec. supramaximal voltage) was increased 8-fold. This effect of the scorpion toxin appears to be unrelated to inhibition of neuronal uptake, block of alpha-adrenoceptors or stimulation of beta-adrenoceptors. Consequently, in addition to releasing noradrenaline, the scorpion toxin enhances transmitter overflow elicited by nerve stimulation through a prejunctional effect which appears to reflect a nove mechanism of action.

Animals↗