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1.
Cardiovasc Res ; 43(1): 125-34, 1999 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10536697

RESUMO

OBJECTIVE: The aim of this study was to show, whether ATP sensitive K+ channels (KATP channels), are involved in the modulation of norepinephrine (NE) release from the sympathetic nerves innervating the guinea-pig and human right atrium. METHODS: The resting and stimulation-evoked release of [3H]norepinephrine ([3H]NE) was measured from the isolated guinea-pig and human right atrium and the effect of activators and inhibitors of ATP sensitive K+ channels was studied. RESULTS: Cromakalim (30-300 microM), a KATP channel-agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a KATP channel-antagonist (30 microM). Diazoxide (30-300 microM), another activator of the KATP channels reduced the resting release of NE, and also attenuated the evoked release at a single concentration (100 microM), and this latter action was also counteracted by glibenclamide (30 microM). Pinacidil, increased dose-dependently the resting and stimulation-evoked release of NE in a glibenclamide-sensitive manner and reversed the inhibitory effect of cromakalim (100 microM), suggesting that it acts as an antagonist. Glibenclamide (30-300 microM), by itself enhanced the stimulation-evoked release of [3H]NE, and also increased the resting release of NE. On the other hand, 5-hydroxydecanoate, an ischemia-selective inhibitor of cardiac KATP channels did not change NE release. Adenosine, (30-300 microM), an A1-receptor agonist, clonidine (3 microM), an alpha 2-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 microM) all reduced the evoked release of [3H]NE, but these effects were not modified by glibenclamide (300 microM), indicating that neuronal adenosine (A1), adrenergic (alpha 2) and muscarinic (M3) receptors do not act on KATP channels. In the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [3H]NE. However, glibenclamide (30-300 microM) and pinacidil (30-300 microM) enhanced dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release. CONCLUSIONS: Our results indicate that sympathetic nerve endings of the human and guinea-pig atrium are endowed with ATP-sensitive K+ channels. These channels responded to agonists and antagonists under the experimental conditions applied and they could modulate the release of NE thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions.


Assuntos
Cromakalim/farmacologia , Glibureto/farmacologia , Norepinefrina/metabolismo , Canais de Potássio/agonistas , Sistema Nervoso Simpático/metabolismo , Adenosina/farmacologia , Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas de Receptores Adrenérgicos alfa 2 , Análise de Variância , Animais , Clonidina/farmacologia , Ácidos Decanoicos/farmacologia , Diazóxido/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Átrios do Coração/inervação , Humanos , Hidroxiácidos/farmacologia , Técnicas In Vitro , Masculino , Agonistas Muscarínicos/farmacologia , Oxotremorina/farmacologia , Pinacidil/farmacologia , Bloqueadores dos Canais de Potássio , Estimulação Química , Sistema Nervoso Simpático/efeitos dos fármacos
2.
Neuropharmacology ; 26(6): 621-6, 1987 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-3037424

RESUMO

Neurochemical evidence has been obtained that 4-aminopyridine, 3,4-diaminopyridine and 3,3-dimethyl-1-(4-amino-3-pyridyl)urea HBr (LF-14), concentration-dependently enhanced the stimulation-evoked release of [3H]norepinephrine ([3H]NE) from isolated guinea-pig atrium. The effects of aminopyridines, compounds known to inhibit potassium channels, were Ca0-dependent. High pressure liquid chromatography, combined with radiochemical detection, indicated that the increased stimulated release of radioactivity was due to [3H]NE. Since the aminopyridines studied also enhanced the release of [3H]NE from atrium treated with cocaine, a blocker of uptake1, it seems likely that the increased release of NE caused by the aminopyridines is due to the enhanced release of NE from sympathetic axon terminals and not to the inhibition of reuptake. It is probable that the sympathomimetic cardiac effects (positive inotropic and chronotropic effect) of aminopyridines observed in animal experiments is due to the increased release of NE, caused by these compounds.


Assuntos
Aminopiridinas/farmacologia , Coração/efeitos dos fármacos , Norepinefrina/metabolismo , 4-Aminopiridina , Amifampridina , Animais , Cálcio/fisiologia , Cocaína/farmacologia , Estimulação Elétrica , Feminino , Cobaias , Técnicas In Vitro , Masculino , Miocárdio/metabolismo
3.
Neuroscience ; 31(1): 259-67, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-2549449

RESUMO

In order to extend the characterization of muscarinic receptors at presynaptic sites their inhibitory effect on the stimulation-evoked release of [3H]noradrenaline and [3H]acetylcholine from different axon terminals was studied and the dissociation constants and potencies of different antagonists were estimated, in guinea-pig and rat. While oxotremorine reduced the release of [3H]acetylcholine and [3H]-noradrenaline in a concentration-dependent manner from different release sites (Auerbach plexus, noradrenergic neurons in the right atrium, cerebral cortex), McN-A 343, an M1 receptor agonist, enhanced their release evoked by field stimulation. When the inhibitory effect of oxotremorine on transmitter release was studied, pancuronium, pirenzepine and atropine were competitive antagonists of presynaptic muscarinic receptors located on the noradrenergic axon terminals of the atrium. While atropine and pirenzepine inhibited the muscarinic receptors of cholinergic axon terminals in the Auerbach plexus, pancuronium and gallamine had a very low affinity. Significant differences were found in the affinity constants of antagonists for muscarinic receptors located in the cholinergic axon terminals of Auerbach plexus and cerebral cortex, and noradrenergic axon terminals of the atrium. While atropine and pirenzepine exerted similar effects on these presynaptic sites, pancuronium, gallamine and (11-(2-[diethylamino)-methyl)-1-piperidinyl)acetyl)-5, 11-dihydro-6(1-pyrido(2,3-b)(1,4)-benzodiazepin-6-on) were much more effective on muscarinic receptors controlling acetylcholine release from the cerebral cortex and noradrenaline release from the heart. There was more than 100-fold (2.0 pA2 units) difference in affinities of these antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Fibras Adrenérgicas/fisiologia , Córtex Cerebral/fisiologia , Fibras Colinérgicas/fisiologia , Coração/inervação , Músculo Liso/inervação , Oxotremorina/farmacologia , Receptores Muscarínicos/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Fibras Adrenérgicas/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Fibras Colinérgicas/efeitos dos fármacos , Feminino , Cobaias , Coração/efeitos dos fármacos , Coração/fisiologia , Masculino , Antagonistas Muscarínicos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Parassimpatolíticos/farmacologia , Receptores Muscarínicos/classificação
4.
Neurochem Int ; 14(4): 433-8, 1989.
Artigo em Inglês | MEDLINE | ID: mdl-20504446

RESUMO

The effects of physostigmine, tetrahydroaminoacridine (THA) and LF-14 [3,3-dimethyl-1(4- amino-3-pyridyl)urea], a 3,4-diaminopyridine derivative, were compared on inhibition of acetyl- cholinesterase (AChE) activity, and release of [(3)H]acetylcholine (ACh) from rat brain cortical and hippocampal slices. All three compounds caused a concentration dependent inhibition of AChE, with an order of potency physostigmine > THA >LF-14. The electrically stimulated release of ACh from hippocampal and cortical slices was decreased by 10(?5)M physostigmine, although the effect was significant only in cortex. THA (5 x 10(5)M) caused a slight, but not significant, decrease in ACh release from both tissues. In contrast, LF-14 (5 x 10(?5) M) caused an approx. 3-fold enhancement of stimulated release. When AChE was inhibited by prior addition of physostigmine, THA caused only a slight enhancement of ACh release, whereas LF-14 greatly increased release. ACh release was also reduced by stimulation of presynaptic muscarinic receptors with oxotremorine. In this case, THA had no effect on ACh release, while LF-14 was able to reverse the inhibition. This study suggests that LF-14 acts to promote ACh release through blocking K(+) channels, and has a less potent AChE inhibitory effect. It is possible that a compound like LF-14 could be useful in treating diseases of cholinergic dysfunction such as Alzheimer's disease, by both promoting the release of ACh and inhibiting its breakdown.

5.
Neurochem Int ; 27(4-5): 345-53, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8845735

RESUMO

The effect of adenosine or its stable analogues (2-chloroadenosine, CADO: 5'-N-ethyl-carboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) and a non-selective A1 and A2-receptor antagonist, 8-phenyltheophylline (8-PT), or an A1-receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), on the stimulation-evoked release of [3H]norepinephrine ([3H]NE) and [3H]acetylcholine ([3H]ACh) from the isolated guinea pig right atrium was investigated. Adenosine and its stable analogues (CADO, NECA and CPA) inhibited the stimulation-evoked release of [3H]NE in a concentration-dependent manner. The order of potencies was CPA > NECA > CADO > adenosine. CGS 21680 (30 nM), an A2a receptor agonist, failed to affect the release. The inhibitory effect of adenosine and CADO on [3H]NE release was competitively antagonized by 8-PT. DPCPX also prevented the effect of adenosine (Kd = 5.2 nM) and CADO (Kd = 3.3 nM). The Kd value of 8-PT was 0.40 microM for the antagonism of CADO and 0.51 microM for the antagonism of adenosine. When the negative feedback modulation of NE release was inhibited by idazoxan, the inhibitory effect of adenosine and CADO on [3H]NE release was more pronounced. Under this condition DPCPX (10 nM) prevented the inhibitory effect of CADO, indicating that A1-purinoceptors are involved in this action. The release of [3H]NE is tonically modulated by ACh release from the vagal nerve endings, as evidenced by the finding that 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP), a M3-subtype selective muscarinic receptor antagonist, and atropine significantly enhanced the release of NE. Adenosine, its stable analogues (CADO and NECA), and 8-PT inhibition was eliminated by atropine, adenosine and CADO did not have any effect on [3H]ACh release. Quinpirole, a selective D2-receptor agonist, and neuropeptide Y (NPY) failed to affect the release of ACh. However, atropine and 4-DAMP, a selective M3-receptor antagonist, significantly enhanced the stimulation-evoked release of [3H]ACh. These findings indicate that there are no presynaptic heteroceptors (adenosine, D2, and NPY) on the vagal nerve endings of the guinea pig right atrium. It is concluded that the sympathetic nerve endings of the guinea pig right atrium are equipped with A1-, subclass of purinoceptors and alpha 2B-, and muscarinic (M3)-receptors. Cholinergic vagal nerve endings in the heart are only equipped with muscarinic autoreceptors. Therefore, adenosine liberated during hypoxia inhibits NE release from the cardiac sympathetic nerve and thereby protects against tachyarrhythmia caused by myocardial hypoxia. In contrast, adenosine does not inhibit the vagal innervation of the right atrium.


Assuntos
Acetilcolina/metabolismo , Adenosina/farmacologia , Miocárdio/metabolismo , Norepinefrina/metabolismo , Receptores Purinérgicos P1/fisiologia , 2-Cloroadenosina/farmacologia , Adenosina/análogos & derivados , Adenosina-5'-(N-etilcarboxamida) , Animais , Estimulação Elétrica , Cobaias , Átrios do Coração , Masculino , Teofilina/análogos & derivados , Teofilina/farmacologia , Xantinas/farmacologia
6.
Drug Alcohol Depend ; 1(5): 319-27, 1976 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-1017377

RESUMO

The intravenous (i.v.) administration of 4 mug/kg 6-deoxy-6-dihydroazido-isomorphine (6-AM) base to healthy, young adult male volunteers caused no circulatory and relatively little, short-lasting respiratory depression. Of the ten volunteers all felt lightheaded, two became euphoric and when they became ambulatory at the end of the experiment, three vomited and two other became nauseated. The intramuscular (i.m.) administration of the same dose of 6-AM had considerable analgesic effect against various types of experimental pain. It was more effective against ischemic pain, than against pain induced by electrical stimulation of the earlobe or the tooth pulp and it effected severe pain more than mild or moderate pain. In the six subjects investigated, 6-AM produced significant myosis. Of the 16 subjects who received 4 mug/kg 6-AM i.m. five experienced mild euphoria, two felt lightheaded, six became pale and sweaty in the course of the experiments carried out in the sitting position. When they becam ambulatory after the completion of the experiments, two subjects vomited and six others became nauseated. The findings of this study indicate that 6-AM causes less circulatory and respiratory depression than is to be expected from equianalgetic doses of morphine. Its other side effects (e.g., nausea, vomiting) are also less frequent and severe than those encountered after the administration of comparable doses of morphine to ambulating volunteers.


Assuntos
Derivados da Morfina , Derivados da Morfina/farmacologia , Adulto , Analgésicos , Pressão Sanguínea/efeitos dos fármacos , Emoções/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Humanos , Injeções Intramusculares , Injeções Intravenosas , Masculino , Derivados da Morfina/administração & dosagem , Derivados da Morfina/efeitos adversos , Náusea/induzido quimicamente , Pupila/efeitos dos fármacos , Respiração/efeitos dos fármacos , Fatores de Tempo , Vômito/induzido quimicamente
7.
Naunyn Schmiedebergs Arch Pharmacol ; 346(2): 197-202, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1333058

RESUMO

1. The effect of adenosine or its stable analogues (2-chloroadenosine, CADO; 5'-N-ethylcarboxamidoadenosine, NECA; and N6-cyclopentyladenosine, CPA) on the release of [3H]-acetylcholine ([3H]-ACh), and on the development of force of contraction evoked by electrical stimulation of the nerve, were studied in the mouse phrenic nerve-hemidiaphragm preparation. Evidence was obtained that the release of ACh is subject to presynaptic modulation through presynaptic A1(P1)-purinoceptors. 2. Adenosine or its stable analogues (CADO, NECA, CPA) inhibited, in a concentration-dependent manner, both the release of ACh and the force of the indirectly elicited contraction of hemidiaphragm preparation, provided in the latter case that the margin of safety was reduced by (+)-tubocurarine or magnesium. The order of potency in reducing ACh release was CPA greater than NECA greater than CADO greater than adenosine with IC50 values of 0.08 +/- 0.01, 0.74 +/- 0.05, 9.05 +/- 0.20, and 410.2 +/- 42.5 mumol/l, respectively. The order of potency in reducing twitch tension was CPA greater than NECA greater than CADO greater than adenosine with IC50 values of 0.11 +/- 0.02, 0.48 +/- 0.03, 2.07 +/- 0.49, and 240.4 +/- 20.0 mumol/l, respectively. 3. 8-Phenyltheophylline (8-PT) antagonized the inhibitory effects of the adenosine receptor agonists on ACh release and twitch tension.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Adenosina/análogos & derivados , Receptores Purinérgicos/fisiologia , Sinapses/fisiologia , 2-Cloroadenosina/farmacologia , Acetilcolina/metabolismo , Adenosina/farmacologia , Adenosina-5'-(N-etilcarboxamida) , Animais , Diafragma/efeitos dos fármacos , Diafragma/inervação , Dipiridamol/farmacologia , Estimulação Elétrica , Técnicas In Vitro , Magnésio/farmacologia , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Nervo Frênico/efeitos dos fármacos , Nervo Frênico/fisiologia , Antagonistas Purinérgicos , Receptores Purinérgicos/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Teofilina/análogos & derivados , Teofilina/farmacologia , Trítio , Tubocurarina/farmacologia , Xantinas/farmacologia
8.
Naunyn Schmiedebergs Arch Pharmacol ; 336(1): 11-5, 1987 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2819746

RESUMO

A radioisotope method has been developed for measuring the stimulation-evoked release of acetylcholine without the use of cholinesterase inhibitors from the mouse hemidiaphragm preparation which had been loaded with 3H-choline. Evidence has been obtained that 3H-choline was taken up by and released from both innervated and non-innervated mouse hemidiaphragm preparations. However, it was released in the form of 3H-acetylcholine in response to electrical field stimulation only from the innervated preparations. Long lasting (51 min) S1 stimulation of the preparations exhausted the radioactive acetylcholine stores to the extent that S2 did not evoke any release of 3H. These data suggest that when the labelled acetylcholine stores become exhausted, the labelled choline, still present in the tissue, cannot be released by electrical stimulation. Tetrodotoxin (1 mumol/l) administration and Ca withdrawal inhibited, 20-100 mumol/l 4-aminopyridine enhanced the release of 3H-acetylcholine in response to electrical stimulation. Activation of the presynaptic muscarinic receptors by the agonist oxotremorine (50 mumol/l) decreased the liberation of 3H-acetylcholine. The muscarinic antagonist atropine (1 mumol/l) abolished the inhibitory effect of oxotremorine and by itself increased the evoked release of the newly formed 3H-acetylcholine. Adenosine (50 mumol/l) reduced the evoked release of radioactivity. Theophylline (30 mumol/l) prevented the inhibitory effect of adenosine and itself enhanced the release. Xylazine (1 mumol/l), an alpha 2-adrenoceptor agonist did not affect the release. It is concluded that the stimulation-evoked release of 3H-acetylcholine from the mouse phrenic nerve hemidiaphragm preparation preloaded with 3H-choline is derived from the motor nerves. The release of acetylcholine is modulated by activation of presynaptic muscarinic and adenosine receptors.


Assuntos
Acetilcolina/metabolismo , Junção Neuromuscular/fisiologia , 4-Aminopiridina , Adenosina/farmacologia , Aminopiridinas/farmacologia , Animais , Atropina/farmacologia , Cálcio/farmacologia , Diafragma/efeitos dos fármacos , Diafragma/metabolismo , Estimulação Elétrica , Técnicas In Vitro , Masculino , Camundongos , Oxotremorina/farmacologia , Tetrodotoxina/farmacologia , Teofilina/farmacologia , Xilazina/farmacologia
9.
Toxicon ; 22(1): 75-84, 1984.
Artigo em Inglês | MEDLINE | ID: mdl-6539006

RESUMO

The action of Ptychodiscus brevis "brevetoxins" T17 and T34 on rat phrenic nerve-stimulated hemidiaphragm contraction is reported. The potency of T34 is greater than the potency of T17, but both cause a complete block of neuromuscular transmission in the nM to pM concentration ranges. Preparations exposed to low concentrations of T17 can recover in the presence of the toxin, whereas the effects of T34 are irreversible. The initial contracture produced by each is prevented by tetrodotoxin or curare. Neuromuscular block does not appear to be due to acetylcholine depletion, as determined by electron microscope examination of the neuromuscular junctions of blocked preparations. Persistent nerve depolarization is believed to be responsible for the neuromuscular block.


Assuntos
Dinoflagellida/fisiologia , Toxinas Marinhas/toxicidade , Bloqueadores Neuromusculares , Oxocinas , Animais , Estimulação Elétrica , Técnicas In Vitro , Masculino , Junção Neuromuscular/efeitos dos fármacos , Nervo Frênico/efeitos dos fármacos , Ratos , Ratos Endogâmicos
10.
J Clin Anesth ; 4(2): 106-10, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1348620

RESUMO

STUDY OBJECTIVES: To determine the effect of priming on the intubation and onset times of vecuronium 0.3 mg/kg. DESIGN: Randomized, unblinded study. SETTING: Operating rooms and postanesthetic recovery unit of a university-affiliated general hospital. PATIENTS: Thirty female ASA physical status I and II patients scheduled for intraperitoneal surgery divided into two groups of 15 each. INTERVENTIONS: Anesthesia was induced and maintained with sufentanil, droperidol, thiopental sodium, and nitrous oxide in oxygen. Patients in Group 1 were given vecuronium 0.015 mg/kg 4 minutes before induction and vecuronium 0.285 mg/kg 1 minute after induction. Patients in Group 2 received a single 0.3 mg/kg dose of vecuronium 1 minute after thiopental sodium. The ulnar nerve was stimulated every 10 seconds with train-of-four supramaximal impulses of 0.2 millisecond duration at 2 Hz. The compound electromyogram (EMG) of the adductor pollicis was continuously recorded. The trachea was intubated when the amplitude of the EMG decreased to 15% to 25% of control. At the end of surgery, residual neuromuscular block was reversed with edrophonium 0.75 mg/kg. MEASUREMENTS AND MAIN RESULTS: All patients in Group 1 could be intubated in 80 seconds or less, and the longest onset time was 120 seconds. In Group 2, the longest intubation time was 140 seconds, and the longest onset time was 200 seconds. Clinical durations in both groups were unpredictable, ranging from 47 to 185 minutes in Group 1 and from 63 to 160 minutes in Group 2. Ten of the 30 patients required an additional 0.5 mg/kg of edrophonium for antagonism of the residual neuromuscular block. There were no significant changes in heart rate or blood pressure attributable to vecuronium. CONCLUSIONS: Seventy-five percent to 85% neuromuscular block of the adductor pollicis, required for atraumatic tracheal intubation, developed in 80 seconds or less when vecuronium 0.3 mg/kg was administered in divided doses and in 140 seconds or less when it was injected as a single bolus dose. Clinical duration of vecuronium 0.3 mg/kg is long and unpredictable, and reversal of residual neuromuscular block may require larger doses of anticholinesterases. It is recommended that an intubating dose of vecuronium 0.3 mg/kg be used only in patients undergoing long surgical procedures that require prolonged postanesthetic mechanical ventilation.


Assuntos
Intubação Intratraqueal/métodos , Brometo de Vecurônio/administração & dosagem , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Fatores de Tempo
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