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A M Sebastião

Publications and source records attributed to A M Sebastião.

49 records · Page 3Linked to original sources
PubMed1990

Interactions between adenosine and phorbol esters or lithium at the frog neuromuscular junction.

1. Interactions between the effects of adenosine or 2-chloro-adenosine (CADO) and the effects of substances that interfere with the phosphoinositides/protein kinase C transducing system or with the adenylate cyclase transducing system, on endplate potentials (e.p.ps), were investigated. The preparation used was the innervated sartorius muscle of the frog in which twitches had been prevented with high magnesium concentrations. 2. The activator of protein kinase C, 4 beta-phorbol-12,13-diacetate (PDAc), reversibly increased the amplitude and the quantal content of e.p.ps and attenuated the inhibitory effects of adenosine and CADO on e.p.p. amplitude. The affinity of the adenosine receptor antagonist, 8-phenyltheophylline, was not modified by PDAc. 3. The phorbol ester 4 alpha-phorbol-12,13-didecanoate, which does not activate protein kinase C, did not modify either e.p.p amplitude or the inhibitory effect of adenosine on e.p.ps. 4. The inhibitor of protein kinase C, polymyxin B, reversibly decreased the amplitude and the quantal content of e.p.ps, prevented the enhancement caused by PDAc on e.p.p. amplitude, but did not modify the inhibitory effect of adenosine on e.p.ps. H-7, another inhibitor of protein kinases, also decreased e.p.p. amplitude but did not modify the effect of PDAc on the amplitude of e.p.ps. 5. Lithium chloride, which alters phosphoinositide signal transduction by inhibiting the breakdown of inositol phosphates, reversibly increased the amplitude and the quantal content of the e.p.ps. In the presence of adenosine or CADO the effect of lithium on e.p.p. amplitude was markedly attenuated. 6. The activator of adenylate cyclase, forskolin, reversibly increased the amplitude and the quantal content of the e.p.ps. 7. The results suggest that the phosphoinositides/protein kinase C transducing system, but not the adenylate cyclase transducing system, might be involved in the inhibitory effect of adenosine on neuromuscular transmission.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat: antagonism by 1,3,8-substituted xanthines.

1. The ability of 1,3,8-substituted xanthines to antagonize the inhibitory effects of adenosine receptor agonist on the amplitude of nerve-evoked twitches of the rat phrenic-diaphragm and on the amplitude of orthodromically-evoked population spikes, recorded from the CA1 pyramidal cells of rat hippocampal slices, was investigated. 2. 1,3-Dipropyl-8-cyclopenthylxanthine (DPCPX), 1,3-dipropyl-8-(carboxymethyloxyphenyl)xanthine (XCC), 1,3-dipropyl-8-(4-[2-aminoethyl)amino)carbonylmethyloxyphenyl)x ant hine (XAC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), 8-phenyltheophylline (8-PT), 1,3-diethyl-8-phenylxanthine (DPX) and PD 115,199, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right in a near parallel manner the log concentration-response curve for the inhibitory effect of 2-chloroadenosine (CADO) on nerve-evoked twitches of the phrenic-diaphragm. Linear Schild plots with slopes near to unity were obtained for all the xanthines. 3. The order of potency of the xanthines as antagonists of the effect of CADO in the phrenic-diaphragm was DPCPX (Ki = 0.54 nM) greater than XCC (Ki = 10 nM), XAC (Ki = 11 nM), PACPX (Ki = 13 nM) greater than DPX (Ki = 22 nM), 8-PT (Ki = 25 nM) greater than PD 115,199 (Ki = 57 nM). The potency of DPCPX in antagonizing the inhibitory effects of R-N6-phenylisopropyladenosine (R-PIA) and 5'-N-ethylcarboxamide adenosine (NECA) on nerve-evoked twitch response was not statistically different from its potency in antagonizing the inhibitory effect on CADO. 4. In the hippocampal slices, DPCPX, XCC and XAC, used in concentrations virtually devoid of effect on population spike amplitude, shifted to the right in a near parallel manner the log concentrationresponse curve for the inhibitory effect of CADO on the amplitude of the population spikes. The Schild plots were linear with slopes near unity. 5. The potencies of DPCPX (K, = 0.45 nM) and XAC (K, = 11 nM) in antagonizing the inhibitory adenosine receptor at the hippocampus were similar to their potencies for antagonism of the inhibitory adenosine receptor at the phrenic-diaphragm. XCC was only slightly more potent (K, = 5.4 nM) as an antagonist of the adenosine receptor in the hippocampus than in the phrenic-diaphragm. 6. The results suggest that the inhibitory adenosine receptors in the phrenic-diaphragm and in the hippocampus of the rat are similar, and that according to the antagonist potencies, these receptors belong to the A1-adenosine receptor subtype.

Animals↗
PubMed1989

1,3,8- and 1,3,7-substituted xanthines: relative potency as adenosine receptor antagonists at the frog neuromuscular junction.

1. The ability of 1,3,8-substituted xanthines (1,3-dipropyl-8-(4-(2-aminoethyl)amino)carbonylmethyloxyphenyl) xan thine (XAC), 1,3-dipropyl-8-(4-carboxymethyloxyphenyl)xanthine (XCC), 1,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX), 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), 1,3-diethyl-8-phenylxanthine (DPX) and 8-phenyltheophylline (8-PT)), of 1,3,7-substituted xanthines (1-propargyl-3,7-dimethylxanthine (PGDMX) and caffeine), and of a 3-substituted xanthine (enprofylline) to antagonize the inhibitory effect of 2-chloroadenosine (CADO) on the amplitude of nerve-evoked twitches was investigated in innervated sartorius muscles of the frog. 2. All the 1,3,8-substituted xanthines, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right, in a near parallel manner the log concentration-response curve for CADO. Linear Schild plots with slopes near to unity at concentration-ratios less than 14 were obtained for XAC, XCC, DPCPX, DPX and 8-PT. 3. The order of potency of the 1,3,8-substituted xanthines as antagonists of the effect of CADO was XAC (Ki = 23 nM) greater than or equal to DPCPX (35 nM) greater than 8-PT (200 nM) greater than or equal to DPX (295 nM) greater than XCC (1905 nM) greater than or equal to PACPX (2291 nM). No correlation was found between the potency of these xanthines as antagonists of the adenosine receptor at the frog neuromuscular junction and their reported potency as antagonists of the A1- or A2-adenosine receptors. 4. The 1,3,7-substituted xanthines, PGDMX and caffeine, in concentrations virtually devoid of effect on neuromuscular transmission, also caused parallel shifts to the right of the log concentration-response curves for CADO, but were less potent than the 1,3,8-substituted xanthines. PGDMX was more than 20 times more potent than caffeine. 5. Enprofylline in concentrations up to 100 microM did not antagonize the inhibitory effect of CADO on neuromuscular transmission. 6. It is concluded that the antagonist profile of the adenosine receptor mediating inhibition of transmission at the frog neuromuscular junction is different from the antagonist profile of the A1- and A2-adenosine receptors.

2-Chloroadenosine↗
PubMed1988

N6-cyclohexyladenosine inhibits veratridine-stimulated 22Na uptake by rat brain synaptosomes.

The effect of the stable adenosine analogue, N6-cyclohexyladenosine, on 22Na uptake by rat brain synaptosomes stimulated by veratridine was investigated. In the presence of N6-cyclohexyladenosine, both the initial rate and the maximum sodium uptake were decreased. The inhibitory effect of N6-cyclohexyladenosine on sodium uptake by synaptosomes after 5 s of incubation with 22Na was concentration-dependent, antagonized by 1,3-dipropyl-8-p-sulfophenylxanthine, and attenuated by increasing the concentration of veratridine. The possibility that the adenosine analogue, by activating a xanthine-sensitive adenosine receptor, can operate inhibition of the voltage-dependent sodium channels is discussed.

Adenosine↗
PubMed1988

On the adenosine receptor and adenosine inactivation at the rat diaphragm neuromuscular junction.

1. The effects of adenosine and adenosine analogues 2-chloroadenosine (CADO), L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) on evoked endplate potentials (e.p.ps) and on twitch tension were investigated in innervated diaphragms of the rat. 2. Adenosine and its analogues decreased, in a concentration-dependent manner, the amplitude of both the e.p.ps and the twitch responses evoked by nerve stimulation. The order of potency in decreasing the twitch tension was CHA, L-PIA, NECA greater than D-PIA greater than CADO greater than adenosine. L-PIA was about 8 times more potent than D-PIA. Neither adenosine nor the adenosine analogues affected the twitch responses of directly stimulated tubocurarine-paralysed muscles. 3. 8-Phenyltheophylline (8-PT), theophylline and isobutylmethylxanthine (IBMX), in concentrations virtually devoid of effect on neuromuscular transmission, antagonized the inhibitory effect of 2-chloroadenosine. The order of potency of the alkylxanthines as antagonists of the adenosine receptor at the rat diaphragm neuromuscular junction was 8-PT greater than IBMX greater than theophylline. The antagonism by these xanthines was shown to be competitive, the pA2 value for 8-PT being 7.16. In concentrations slightly higher than those used to test its ability to antagonize the adenosine receptor, IBMX and 8-PT increased the amplitude of e.p.ps without modifying their decay phase or the resting membrane potential of the muscle fibre. 4. The adenosine uptake inhibitor, nitrobenzylthioinosine (NBI) and the adenosine deaminase inhibitor, erythro-9(2-hydroxy-3-nonyl)adenine (EHNA), in concentrations virtually devoid of effect on neuromuscular transmission, potentiated the inhibitory effect of adenosine at the rat diaphragm neuromuscular junction. The potentiation factors were about 2.6 for NBI (5 microM), 2.2 for EHNA (25 microM) and 4.6 for the combination of NBI (5 microM) and EHNA (25 microM). 5. It is concluded that both uptake and deamination contribute to the inactivation of adenosine at the rat diaphragm neuromuscular junction and that in this preparation the inhibitory effect of adenosine on transmission is mediated by a xanthine-sensitive adenosine receptor with an agonist profile which does not fit the criteria for its classification either as an A1 or A2-adenosine receptor.

1-Methyl-3-isobutylxanthine↗
PubMed1987

On the role, inactivation and origin of endogenous adenosine at the frog neuromuscular junction.

1. The effects of adenosine deaminase, inosine, alkylxanthines (8-phenyltheophylline (8-PT), theophylline and isobutylmethylxanthine (IBMX], dipyridamole, alpha, beta-methylene ADP (AOPCP) and ATP analogues (alpha, beta-methylene ATP and beta, gamma-methylene ATP) on evoked end-plate potentials (e.p.p.s) were investigated in innervated sartorius muscles of the frog, in which twitches had been prevented with tubocurarine. The effects of 8-PT and IBMX on the amplitude and quantal content of e.p.p.s were also investigated in innervated sartorius muscles of the frog, in which twitches had been prevented with high-magnesium solutions. 2. Adenosine deaminase reversibly increased the amplitude of e.p.p.s and prevented the reduction caused by exogenously applied adenosine on e.p.p. amplitude. The increase caused by adenosine deaminase was equivalent to the decrease caused by 12 +/- 5.8 microM-adenosine on e.p.p. amplitude. 3. Inosine, the product of adenosine deamination, was virtually devoid of effect on e.p.p.s. 4. The adenosine receptor antagonists at the frog neuromuscular junction, 8-PT and theophylline, increased in a concentration-dependent manner the amplitude of e.p.p.s in the presence of tubocurarine. 8-PT increased the amplitude and quantal content of e.p.p.s in the presence of high magnesium. IBMX, which does not behave as an adenosine receptor antagonist at the frog neuromuscular junction, decreased the amplitude of e.p.p.s in the presence of tubocurarine or high-magnesium solutions. 5. Dipyridamole, an adenosine uptake blocker, decreased the amplitude of e.p.p.s, and in a concentration that did not affect neuromuscular transmission potentiated the depressing effect of adenosine, but not that of 2-chloroadenosine, on the amplitude of e.p.p.s. 6. AOPCP, an inhibitor of 5'-nucleotidase, increased the amplitude of e.p.p.s and markedly attenuated the depressing effect of ATP, but not that of adenosine, on e.p.p. amplitude. 7. The ATP analogue, alpha, beta-methylene ATP, which is not a substrate for 5'-nucleotidase, was virtually devoid of effect on e.p.p.s. beta, gamma-Methylene ATP, which can be a substrate for 5'-nucleotidase, mimicked the depressing effect of ATP on e.p.p. amplitude, an effect which was also reduced by AOPCP. 8. It is concluded that in conditions in which the initial quantal content is assumed to be normal (1) endogenous adenosine depresses neuromuscular transmission, (2) at the neuromuscular junction adenosine is inactivated through a dipyridamole-sensitive uptake process, and (3) released adenine nucleotides might contribute to the pool of endogenous adenosine which modulates neuromuscular transmission.

5'-Nucleotidase↗
PubMed1985

Enhancement of transmission at the frog neuromuscular junction by adenosine deaminase: evidence for an inhibitory role of endogenous adenosine on neuromuscular transmission.

Adenosine deaminase reversibly increased the amplitude and the quantum content of the end-plate potentials (EPPs) recorded from superficial muscle fibers of frog sartorius preparations in which twitches have been prevented with high-magnesium solutions. Adenosine deaminase prevented the inhibitory effect of exogenously applied adenosine but not that of 2-chloroadenosine on the amplitude of EPPs. The effect of adenosine deaminase was abolished by erythro-9(2-hydroxy-3-nonyl)adenine (EHNA). The results suggest that endogenous adenosine exerts an inhibitory 'tone' over neuromuscular transmission.

Adenosine↗
PubMed1985

Inhibitory effects of forskolin and papaverine on nerve conduction partially blocked by tetrodotoxin in the frog sciatic nerve.

The effects of forskolin, sodium fluoride and papaverine on compound action potentials were investigated in de-sheathed sciatic nerve preparations of the frog. Forskolin decreased in a concentration-dependent manner the amplitude of compound action potentials when nerve conduction was partially blocked by tetrodotoxin (TTX). In the presence of TTX a 50% decrease in the action potential amplitude recorded was obtained with about 2.5 microM forskolin. Sodium fluoride did not modify the amplitude of compound action potentials partially blocked by TTX. Papaverine also decreased the amplitude of compound action potentials partially inhibited by TTX. A 50% decrease in the action potential amplitude recorded in the presence of TTX was obtained with about 10 microM papaverine. The possibility that cyclic AMP modulates axonal excitability by interfering with the entry of sodium through the TTX-sensitive sodium channel is discussed.

Animals↗
PubMed1985

On the type of receptor involved in the inhibitory action of adenosine at the neuromuscular junction.

The effects of adenosine and adenosine analogues (L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-cyclohexyladenosine (CHA), N6-methyladenosine, 5'-N-ethylcarboxamide adenosine (NECA) and 2-chloroadenosine) on evoked endplate potentials (e.p.ps) and on twitch tension were investigated in innervated sartorius muscles of the frog. Adenosine and its analogues decreased, in a concentration-dependent manner, the amplitude of both the e.p.ps and the twitch responses evoked by indirect stimulation. The order of potencies in decreasing twitch tension was: L-PIA, CHA, NECA greater than 2-chloroadenosine greater than D-PIA greater than N6-methyladenosine, adenosine. L-PIA was about ten fold more potent than D-PIA. None of the adenosine analogues tested affected the twitch responses of directly stimulated tubocurarine-paralyzed muscles. In concentrations that did not modify neuromuscular transmission, theophylline and 8-phenyltheophylline (8-PT) but not isobutylmethylxanthine (IBMX), antagonized the inhibitory action of 2-chloroadenosine at the neuromuscular junction. 8-PT behaved as a competitive antagonist and was about forty fold more potent than theophylline. It is concluded that the R-type adenosine receptor at the neuromuscular junction should not be classified in the A1/A2 system. The possibility of calcium-linked adenosine receptors having pharmacological profiles distinct from those originally defined as modulating adenylate cyclase is discussed.

2-Chloroadenosine↗
PubMed1984

Antagonism of tetrodotoxin- and procaine-induced axonal blockade by adenine nucleotides in the frog sciatic nerve.

The effects of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine on compound action potentials were investigated in de-sheathed frog-sciatic nerve preparations. ATP and ADP but not adenosine antagonized the inhibitory action of tetrodotoxin (TTX) on nerve conduction. AMP had little or no antagonistic effect on TTX-induced axonal block. ATP was more effective than ADP. The effects of the nucleotides were related to the degree of the TTX-induced inhibition and were more evident where the blockade was more intense. ATP and ADP but not adenosine antagonized the procaine-induced axonal blockade which, in some experiments, was completely reversed by these nucleotides. ATP and ADP were of similar potency. The axonal blockade induced by pentobarbitone was not antagonized by ATP, ADP, AMP or adenosine. The possibility that ATP stimulates a TTX-sensitive sodium channel is discussed.

Action Potentials↗
PubMed1984

Enhancement of tetrodotoxin-induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve.

The effects of adenosine, adenosine analogues (N6-cyclohexyladenosine (CHA), L-N6-phenylisopropyladenosine (L-PIA), D-N6-phenylisopropyladenosine (D-PIA), N6-methyladenosine and 2-chloroadenosine), adenine, inosine, hypoxanthine, cyclic AMP and its analogue the dibutyryl cyclic AMP (db cyclic AMP), and methylxanthines (theophylline, caffeine and isobutylmethylxanthine (Ibmx) on compound action potentials were investigated in de-sheathed sciatic nerve preparations of the frog. Adenosine and its analogues enhanced, in a concentration-dependent manner, the inhibitory action of tetrodotoxin (TTX) on nerve conduction. The order of potencies was: CHA greater than D-PIA greater than L-PIA greater than N6-methyladenosine greater than 2-chloroadenosine greater than adenosine. The adenosine metabolites, inosine and hypoxanthine, were inactive on TTX-induced axonal blockade. Adenine enhanced the inhibitory action of TTX on nerve conduction, but was less effective than adenosine. db Cyclic AMP, but not cyclic AMP, mimicked the inhibitory effect of adenosine on nerve conduction. Methylxanthines did not antagonize the effect of adenosine on TTX-induced axonal block and in high concentrations also mimicked the effect of adenosine on nerve conduction. The possibility of adenosine acting on TTX-induced axonal block through an adenosine receptor positively coupled to adenylate cyclase is discussed.

2-Chloroadenosine↗