Biomedical subjects

E Ongini

Publications and source records attributed to E Ongini.

At least 55 records · Page 3Linked to original sources

PubMed1996

The selective adenosine A2A receptor antagonist SCH 58261 discriminates between two different binding sites for [3H]-CGS 21680 in the rat brain.

We have used quantitative autoradiography to further examine two previously described binding sites for [3H]-CGS 21680 in cortical regions and in striatum, respectively. The striatal binding sites largely represent classical adenosine A2A receptors whereas the cortical sites show characteristics that differ from those of recognised adenosine receptors. A recently developed non-xanthine A2A receptor antagonist SCH 58261 displaced the binding of [3H]-CGS 21680 from the A2A receptors in striatum with an estimated Ki value of 2.4 nM, but was more than 1000-fold less potent in displacing its binding from cortex. Conversely, the adenosine analogue 2-chloro-NECA was found to be some 10 times more potent in displacing CGS 21680 from the cortical binding sites than from A2A receptors. The results provide additional evidence that CGS 21680 binds not only to classical A2A receptors, but also to sites that differ from defined adenosine receptors. They also suggest that effects of CGS 21680 observed in the presence of SCH 58261 might reveal the functional significance (if any) of these sites.

Adenosine↗

PubMed1996

Effects of four antiepileptic drugs on sleep and waking in the rat under both light and dark phases.

Sedation is a common side effect of anticonvulsant drug therapy. To find out whether the new antiepileptic drugs, felbamate and lamotrigine, are able to produce sedation, we carried out electroencephalographic (EEG) studies in the rat to measure drug effects on sleep-wake patterns, during both light and dark phases. For comparison, the reference drugs, carbamazepine and phenobarbital, were also studied. EEG activity was recorded for 6 h after oral (PO) administration of drugs or vehicle, and the stages of wakefulness, rapid eye movements (REM) sleep and non-REM sleep were classified thereafter. In the light phase, felbamate (30-300 mg/kg) did not produce sedative effects, while lamotrigine (3-30 mg/kg) increased wakefulness at each dose tested. Carbamazepine (10-100 mg/kg) did not produce sleep-wake alterations, and phenobarbital (100 mg/kg) markedly suppressed REM. In the dark phase, felbamate (300 mg/kg), lamotrigine (30 mg/kg), and carbamazepine (100 mg/kg) reduced REM but did not change the total amount of sleep. Phenobarbital, at 100 mg/kg, markedly increased total sleep and greatly reduced REM. This study shows that the anticonvulsant drugs examined have different effects on the states of sleep and wakefulness in the rat. The data are discussed on the basis of the mechanism of action that characterizes each individual drug.

Animals↗

PubMed1996

Anticonvulsant activity of 5,7DCKA, NBQX, and felbamate against some chemoconvulsants in DBA/2 mice.

The anticonvulsant effects of felbamate (10-300 mg/kg, intraperitoneally, IP), and those of two representative antagonists of the excitatory amino acid receptors, 5-7 dichlorokynurenic acid (5-7DCKA; 0.6-30 nmol/mouse, intracerebroventricularly, ICV), and 2, 3-dihydroxy-6 nitro-7-sulfamoylbenzo (F) quinoxoline (NBQX; 1.1-33.6 mg/kg, IP) were studied in the DBA/2 mice. All drugs protected the animals from sound-induced seizures. The drugs were also effective against seizures induced by stimulation of the excitatory amino acid receptor complex using the agonists N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA). In separate studies, felbamate protected mice from seizures induced by ICV administration of the activator of dihydropyridine-sensitive calcium channels, methyl-1, 4-dihydro-2, 6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (Bay k 8644), with ED50 values of 26 and 46.9 mg/kg for tonus and clonus, respectively. Using Bay k 8644, NBQX (1-40 mg/kg IP) was uneffective, while 5,7DCKA (5-90 nmol/mouse, ICV) protected mice against tonus. Moreover, felbamate prevented seizures induced by blocking voltage-dependent K+ channels using alpha-dendrotoxin, with ED50 values of 22.6 mg/kg for tonus and of 34.8 mg/kg for clonus. Conversely, 5,7DCKA or NBQX did not significantly antagonize seizures induced by alpha-dendrotoxin. The present data indicate that felbamate is an effective anticonvulsant drug in DBA/2 mice with a broader anticonvulsant spectrum than 5,7DCKA and NBQX.

Acoustic Stimulation↗

PubMed1996

Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A adenosine receptor antagonist, to rat striatal membranes.

1. The present study describes the binding to rat striatal A2A adenosine receptors of the new potent and selective antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazol o [1,5-c] pyrimidine, [3H]-SCH 58261. 2. [3H]-SCH 58261 specific binding to rat striatal membranes ( > 90%) was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed that [3H]-SCH 58261 labelled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 microM GTP in the incubation mixture did not modify [3H]-SCH 58261 binding parameters. 3. Competition experiments showed that [3H]-SCH 58261 binding is consistent with the labelling of A2A striatal receptors. Adenosine receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-N-ethyl carboxamidoadenosine (2HE-NECA) > 5'-N-ethylcarboxamidoadenosine (NECA) > 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoadenosi ne (CGS 21680) > 2-phenylaminoadenosine (CV 1808) > R-N6-phenylisopropyladenosine (R-PIA) > N6-cyclohexyladenosine (CHA) = 2-chloro-N6-cyclopentyladenosine (CCPA) > S-N6-phenylisopropyladenosine (S-PIA). 4. Adenosine antagonists inhibited [3H]-SCH 58261 binding with the following order: 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo[1,5-c] quinazoline (CGS 15943) > 5-amino-8-(4-fluorobenzyl)-2-(2-furyl)-pyrazolo [4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine (8FB-PTP) = SCH 58261 > xanthine amine congener (XAC) = (E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S) > 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) > or = 8-phenyltheophylline (8-PT). 5. The Ki values for adenosine antagonists were similar to those labelled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the adenosine agonists and antagonists examined inhibited [3H]-SCH 58261 binding with Hill coefficients not significantly different from unity. 6. The present results indicate that [3H]-SCH 58261 is the first non-xanthine adenosine antagonist radioligand which directly labels A2A striatal receptors. High receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A adenosine receptor subtype in mammalian brain.

Adenosine↗

PubMed1996

Binding of the novel nonxanthine A2A adenosine receptor antagonist [3H]SCH58261 to coronary artery membranes.

This study demonstrates quantification of A2A adenosine receptors (A2AAdoRs) in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells. Radioligand binding assays were performed using the new selective A2AAdoR antagonist radioligand [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo [4,3-epsilon]-1,2,4-triazolo[1,5-c)pyrimidine ([3H]SCH58261). Binding of the radioligand to membranes was rapid, reversible, and saturable. The densities of A2AAdoRs in membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells were 900 +/- 61, 892 +/- 35, and 959 +/- 76 fmol/mg protein, respectively. Equilibrium dissociation constants (Kd values) calculated from results of saturation binding assays were 2.19, 1.20, and 0.81 nmol/L, and Kd values calculated from results of association and dissociation assays were 2.42, 1.01, and 0.40 nmol/L for [3H]SCH58261 binding to membranes prepared from porcine coronary arteries, porcine striatum, and PC12 cells, respectively. The specific binding of [3H]SCH58261 as a percentage of total binding at a radioligand concentration equal to the Kd value was 65% to 90% in the three membrane preparations. The order of ligand potencies determined by assay of competition binding to sites in porcine coronary membranes using [3H]SCH58261, unlabeled antagonists (SCH58261, 8-(3-chlorostyryl)caffeine [CSC], and xanthine amine congener [XAC]), and unlabeled agonists ([3H]2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoaden osine [CGS 21680], 2-hexynyl-5'-N-ethylcarboxamidoadenosine [HE-NECA], [3H]5'-N-ethylcarboxamidoadenosine [NECA], and R(-)N6-(2-phenylisopropyl)adenosine [R-PIA]) was SCH58261 > HE-NECA = CSC = CGS 21680 = XAC > NECA = R-PIA. The Hill coefficients of displacement by A2AAdoR ligands of [3H]SCH58261 binding were not significantly different from unity, indicating that [3H]SCH58261 bound to a group of homogeneous noninteracting sites in all membrane preparations. The order of ligand potencies to compete for [3H]SCH58261 binding sites in porcine striatal and PC12 cell membranes was, in part, different from that for porcine coronary arterial membranes. The different rank orders of potencies for agonists and antagonists at A2A receptors of porcine coronary arteries, striatum, and PC12 cells and significant differences in absolute values of potency of ligands in the three preparations may indicate the existence of different subtypes of A2AAdoRs. The antagonist radio-ligand [3H]SCH58261 should be of value for pharmacological characterization of A2A adenosine receptors in other preparations.

Animals↗

PubMed1996

Humoral effects of selective adenosine agonists in spontaneously hypertensive rats.

OBJECTIVE: We studied the dose-response effects of acute administration of the selective A1 adenosine receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA), the selective A2A agonists 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680) and the non-selective agonist N-ethylcarboxamidoadenosine (NECA) on plasma renin activity, atrial natriuretic peptide, cyclic guanosine 3',5'-monophosphate (cGMP) and endothelin-1 in spontaneously hypertensive rats. METHODS: The drugs were administered intraperitoneally in four doses to conscious rats. Systolic blood pressure and heart rate were measured by the tail-cuff technique. Both humoral and hemodynamic parameters were determined 1 h after dosing in separate sets of animals. RESULTS: All the compounds induced a dose-dependent decrease in systolic blood pressure that was associated with different changes in heart rate. Heart rate was decreased by all doses of CCPA and by the higher doses of the non-selective compound (NECA) and increased by both A2A agonists. Plasma renin activity also changed in opposite directions, being decreased by CCPA but increased dose-dependently by 2HE-NECA and CGS 21680 and only moderately by NECA. Plasma atrial natriuretic peptide and cGMP levels increased dose-dependently after CCPA and NECA, but were unaffected by the A2A agonists. None of the compounds altered plasma endothelin-1 levels. CONCLUSIONS: These results indicate that the renin-suppressive effect of the A1 agonist, which is associated with a cardiodepressant action, may be attributed either to a direct inhibition of renin release or to the concomitant increments in plasma atrial natriuretic peptide and its second messenger, cGMP. In contrast, the renin-stimulating effect of the A2A agonists may result either from direct stimulation of renin secretion or from reflex sympathetic activation secondary to the fall in blood pressure.

Adenosine↗

PubMed1996

The non-xanthine heterocyclic compound SCH 58261 is a new potent and selective A2a adenosine receptor antagonist.

We have characterized the in vitro pharmacological profile of the new potent and selective A2a adenosine receptor antagonist SCH 58261 [7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2, 4-triazolo[1,5-c]pyrimidine]. In binding studies on rat and bovine brain tissues, SCH 58261 showed affinity in the low nanomolar range at A2a adenosine striatal receptors and good A2a adenosine vs. A1 adenosine selectivity (about 50- to 100-fold in rat and bovine brain, respectively). SCH 58261 did not show affinity for either the A3 adenosine receptor or other receptors at concentrations up to 1 microM. Saturation experiments on rat A1 and A2a adenosine receptors indicated the competitive nature of the antagonism. SCH 58261 antagonized competitively the effects induced by the A2a adenosine-selective agonist CGS 21680 (2-[4-(2-carboxyethyl)-phenethyl-amino]-5'-N- ethylcarboxamidoadenosine) in two functional assays, such as inhibition of rabbit platelet aggregation and porcine coronary artery relaxation. Specifically, the compound showed pA2 values of 7.9 and 9.5, respectively. SCH 58261 (300 nM) failed to antagonize 5'-N-ethylcarboxamidoadenosine-induced vasorelaxation in the isolated guinea pig aorta, a response mediated by A2b adenosine receptors. Likewise, at the same concentration, the compound weakly inhibited the A1 adenosine-mediated negative chronotropic effect induced by 2-chloro-N6-cyclopentyladenosine in the isolated rat atria. These data show that SCH 58261 is a potent and selective non-xanthine A2a adenosine antagonist which has competitive properties in biological responses mediated by this receptor subtype. The compound is of interest for investigating the biological role of A2a adenosine receptors and deserves further attention to clarify the therapeutic potential of A2a antagonists.

Animals↗

PubMed1996

Labeling of A2A adenosine receptors in human platelets by use of the new nonxanthine antagonist radioligand [3H]SCH 58261.

The present study describes the binding to human platelet A2A adenosine receptors of the new potent and selective antagonist radioligand [3H]5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo [1,5-c] pyrimidine ([3H]SCH 58261). Saturation experiments revealed that [3H]SCH 58261 labels a single class of recognition sites with high affinity (Kd = 0.85 nM), limited capacity (apparent Bmax = 85 fmol/mg of protein) and good specific binding (about 60%). [3H]SCH 58261 binding was not modulated by either the divalent cation Mg(+2) or guanine nucleotides. In competition experiments, a series of both adenosine agonists and antagonists inhibited [3H]SCH 58261 binding to A2A platelet receptors with rank order of potency and affinity similar to those observed in rat striatal membranes with the same radioligand. This confirms that the platelet A2A receptor is similar to that labeled in the brain striatum. Binding data were also found to be in good agreement with the results from functional studies such as A2A agonist-induced stimulation of adenylate cyclase or platelet aggregation inhibition. The present findings indicate that [3H]SCH 58261 is the first radioligand available for the characterization of the A2A receptor subtype in platelets.

Binding, Competitive↗

PubMed1996

Pharmacology of adenosine A2A receptors.

Adenosine A2A receptors, which have been cloned from several mammalian species, are activated by physiological concentrations of adenosine to stimulate the formation of cAMP and other mediators. The A2A receptors are found on neutrophil leukocytes, platelets, blood vessels and, very abundantly, on some cells in the CNS. In the caudate nucleus they coexist with dopamine D2 receptors, and stimulation of A2A receptors causes a decrease in D2 receptor-mediated neurotransmission. Thus, drugs that act on A2A receptors can be used to modify dopaminergic neurotransmission known to be important in neurological and psychiatric disorders. In this review, Ennio Ongini and Bertil Fredholm describe how recently developed potent and selective A2A receptor antagonists can be used to delineate the physiological and pathological processes regulated by A2A receptors. Results from in vitro and in vivo pharmacology studies strengthen the notion that A2A receptors are an interesting target for drug development.

Animals↗

PubMed1995

Effects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat.

The protective effects of the selective adenosine A1 receptor agonist 2-chloro-N(6)-cyclopentyladenosine (CCPA), the selective adenosine A2A receptor agonist, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA), and the non-selective agonist, 5'-N-ethylcarboxamidoadenosine (NECA) were studied against lethal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). In acute studies there was a dose-dependent reduction of lethal seizures, as shown by the low dose's protecting 50% of animals (PD50): 0.11, 0.05 and 0.05 mg/kg i.p. for CCPA, 2HE-NECA and NECA, respectively. In the repeated administration studies the animals received either vehicle or drug i.p. twice daily for 12 days. The drug doses were twice the PD50 value: 0.3 mg/kg for CCPA or 0.1 mg/kg for both 2HE-NECA and NECA. 2HE-NECA and NECA maintained their protective activity against pentylenetetrazole-induced seizures (63% or 60% vs. 60% or 58% in acute studies, respectively). Conversely, repeated treatment with CCPA resulted in a marked decrease of its effects (67% vs. 30% in acute studies; P < 0.05). The data indicate that in addition to adenosine A1 the A2A receptors also appear to be involved in the protection from seizures. The anticonvulsant effects induced by repeated stimulation of adenosine A1 receptors are subject to tolerance, whereas effects depending on adenosine A2A receptor activation are maintained.

Adenosine↗

PubMed1995

2-[N'-(3-arylallylidene)hydrazino]adenosines showing A2a adenosine agonist properties and vasodilation activity.

A series of 2-[N'-(3-arylallylidene)hydrazino]adenosines were prepared and studied in binding and functional assays to assess their potency for the A2a compared with the A1 adenosine receptor. These analogs possess A2a receptor affinity in the low nanomolar range associated with weak interaction with the A1 receptor. Among the compounds, in rat tissues, 2-[N'-[3-(4-nitrophenyl)allylidene] hydrazinoadenosine (5g) had the most potent affinity for the A2a receptor, the K(i) value being 23 nM. The type and position of substituents on the phenyl ring show a moderate influence on biological activity, allowing the conclusion that the latter is mostly due to the allylidenehydrazino side chain. From functional experiments 2-[N'-(2-furylmethylidene)hydrazino]adenosine (4b), 2-[N'-(3-phenylallylidene)hydrazino]adenosine (5a) and 2-[N'-[3-(2-furyl)allylidene]hydrazino]adenosine (5b) appeared to be potent in inducing vasorelaxation (an A2a-mediated response) without appreciable effects on the heart rate (an A1-mediated action). While the lack of effects on heart rate is clearly explained by the poor affinity for A1 receptors, more difficult appears the interpretation of vasorelaxant properties displayed by some compounds. Affinity for A2a has a major role, but other types of interactions, yet to be identified, may play a part.

Adenosine↗

PubMed1995

2-Aralkynyl and 2-heteroalkynyl derivatives of adenosine-5'-N-ethyluronamide as selective A2a adenosine receptor agonists.

A series of new 2-aralkynyl and 2-heteroaralkynyl derivatives of NECA were synthesized and studied in binding and functional assays to assess their potency for the A2a compared to A1 adenosine receptors. Compounds bearing an aromatic or heteroaromatic ring, conjugated to the triple bond, showed generally weaker activity at the A2a receptor and lower selectivity (A2a vs A1) than the alkylakynyl derivatives previously reported. However, the (4-formylphenyl)-ethynyl derivative 17 showed affinity in the low nanomolar range and high selectivity (about 160-fold) for the A2a receptor. The presence of heteroatoms improved vasorelaxant activity, the 2-thiazolylethynyl derivative 30 being the most potent in the series. Introduction of methylene groups between the triple bond and the phenyl ring favored the A2a binding affinity, and the 5-phenyl-1-pentynyl derivative 24 was found to be highly potent and selective (about 180-fold) at A2a receptors. With regard to antiplatelet activity, the presence of aromatic or heteroaromatic rings decreased potency in comparison with that of NECA and of N-ethyl-1'-deoxy-1'-(6-amino-2-hexynyl-9H-purin-9-yl)-beta-D-ribofura nuronamide (HENECA). Introduction of a methylene group was effective in increasing antiaggregatory potency only when this group is linked to a heteroatom (31-35). From these data and those previously reported, the structure-activity relationships derived for the 2-alkynyl-substituted ribose uronamides would indicate that potentiation of A2a receptor affinity could be obtained by aromatic rings not conjugated with the triple bond or by heteroaromatic groups. As for A2a receptors on platelets, the presence of aromatic rings, either conjugated or unconjugated to the triple bond, is detrimental for the antiaggregatory activity. However, the introduction of polar groups alpha to the triple bond strongly increases the potency when steric hindrance is avoided. Some of the compounds included in this series retain interesting vasodilating properties and merit further investigation for their potential in the treatment of cardiovascular disorders.

Adenosine↗

PubMed1995

Modeling hemodynamic profiles by telemetry in the rat. A study with A1 and A2a adenosine agonists.

The newly developed radiotelemetry system offers a number of advantages for the measurement of blood pressure and heart rate in laboratory animals. However, no available statistical methods permit valid use of the many data gathered with this continuous recording of hemodynamic parameters. This study describes elaboration and testing of mathematical functions as applied to the measurement of the effects of drugs on blood pressure and heart rate in spontaneously hypertensive rats. We used parametric functions analogous to those for pharmacokinetic studies. Curve fitting is in fact the only approach that provides reasonable estimates of hemodynamic kinetic constants. Nonlinear functions were assessed by analyzing telemetric hemodynamic effects induced by three adenosine receptor agonists with different selectivity for the A1 or A2a receptor. After acute administration in conscious rats, the A1 agonist 2-chloro-N6-cyclopentyladenosine induced dose-related hypotension (eg, 0.03 mg/kg; peak, -70 mm Hg; time to peak, 0.34 hour) and bradycardia (eg, 0.03 mg/kg; peak, -186 beats per minute [bpm]; time to peak, 0.38 hour). The A2a agonist 2-hexynyl-5'-N-ethylcarboxamidoadenosine induced dose-related hypotension (eg, 0.003 mg/kg; peak, -36 mm Hg; time to peak, 0.32 hour) with reflex tachycardia (eg, 0.003 mg/kg; peak, 152 bpm; time to peak, 0.35 hour). The nonselective adenosine agonist 5'-N-ethylcarboxamidoadenosine (0.1 mg/kg) induced hypotension (peak, -75 mm Hg; time to peak, 2.2 hours) and bradycardia followed by tachycardia (first peak, -131 bpm; time to peak, 1.26 hours; second peak, 123 bpm; time to peak, 13.9 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1995

Telemetry monitoring of hemodynamic effects induced over time by adenosine agonists in spontaneously hypertensive rats.

Using the telemetry system in spontaneously hypertensive rats (SHR), we evaluated the hemodynamic effects of four adenosine analogs having different selectivity for A1 and A2a adenosine receptor subtypes. The selective A2a agonists, 2-hexynyl-5'-N-ethylcarboxamidoadenosine (2HE-NECA) and 2-[4-(2-carboxyethyl)-phenethylamino]-5'-N-ethylcarboxamidoaden osi ne (CGS 21680), the selective A1 agonist, 2-chloro-N6-cyclopentyl-adenosine (CCPA) and the nonselective agonist, 5'-N-ethyl-carboxamidoadenosine (NECA), were administered i.p. to conscious spontaneously hypertensive rats. For comparison, the calcium channel blocker, felodipine, was included. CCPA and 2HE-NECA were tested also by the oral route. Systolic and diastolic blood pressure and heart rate were recorded every 5 min for 24 hr after drug administration. Data were analyzed using the curve fitting model recently elaborated. All compounds caused dose-dependent antihypertensive effects. The i.p. dose inducing a decrease of 50 mm Hg (ED50) was calculated for both systolic and diastolic blood pressure. As regards diastolic blood pressure, ED50 values were: CCPA, 0.019 (0.013-0.027) mg/kg, 2HE-NECA, 0.009 (0.002-0.03) mg/kg, CGS 21680, 0.155 (0.084-0.246) mg/kg, NECA, 0.008 (0.004-0.016) mg/kg and felodipine, 5.16 (4.18-7.18) mg/kg. At equiactive doses, the antihypertensive effects of adenosine agonists were shorter lasting [t1/2 for DBP were: CCPA, 54 (44-76) min, 2HE-NECA, 57 (46-71) min, CGS 21680, 45 (21-94) min, NECA, 61(38-97) min] than those of felodipine [t1/2 = 233 (182-274) min]. After oral administration (0.3, 1 and 3 mg/kg), hypotension induced by 2HE-NECA was longer lasting than that of CCPA. 2HE-NECA, CGS 21680 and felodipine caused tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1995

Auditory impairment in guinea pigs treated with isepamicin.

Groups of adult guinea pigs were treated intramuscularly with isepamicin at doses of 100, 150 and 225 mg/kg/day for 21 days. For comparison, two other groups were administered either saline or amikacin 225 mg/kg/day. Auditory function, as measured by the Preyer pinna reflex and the brain stem evoked response, was impaired in both the isepamicin and amikacin groups treated with 225 mg/kg/day, and to a lesser extent in the group receiving isepamicin 150 mg/kg/day. Morphological evaluation of the organ in Corti, performed either by scanning electron microscopy or by light microscopy, showed the typical pattern of damage associated with the aminoglycosides. The greatest damage was observed at 225 mg/kg/day, with no difference between isepamicin and amikacin. Isepamicin 100 mg/kg/day produced no impairment in auditory function and very little change in the morphology of the organ of Corti.

Amikacin↗

PubMed1994

Felbamate displays in vitro antiepileptic effects as a broad spectrum excitatory amino acid receptor antagonist.

The in vitro antiepileptic activity of the novel anticonvulsant drug felbamate was tested in rat hippocampal slices on the CA1 epileptiform bursting induced by different chemical epileptogenic agents. The effects of felbamate were compared with those of the anticonvulsant drugs diphenylhydantoin and pentobarbitone and with the effects of excitatory amino acid antagonists acting at both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Like the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), felbamate at a minimum effective concentration of 1 mM induced a significant (P < 0.01) reduction of the duration of the CA1 epileptiform bursting due to the K+ channel blocker, 4-aminopyridine, and the excitatory amino acids, kainate and quisqualate. Like the NMDA receptor antagonist ketamine, felbamate (1.6 mM) significantly (P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by 'Mg(2+)-free' solutions. Conversely, felbamate (1.6 mM), CNQX (100 microM) and ketamine (100 microM) failed to affect the epileptiform bursting induced by the GABA antagonist penicillin. Pentobarbitone (100 microM) significantly (P < 0.01) decreased the duration of the CA1 epileptiform bursting caused by 'Mg(2+)-free' solutions, 4-aminopyridine or penicillin, while diphenylhydantoin (up to concentrations of 100 microM) failed to have an effect. The results indicate that felbamate displays a unique profile of in vitro antiepileptic effects as a broad spectrum antagonist of excitatory amino acid transmission.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Binding characteristics of the adenosine A2 receptor ligand [3H]CGS 21680 to human platelet membranes.

The binding characteristics of the selective adenosine A2 agonist [3H]CGS 21680 ([3H]2-[p-(2-carboxyethyl)-phenethyl-amino]-5'-N- ethylcarboxamidoadenosine) were determined in human platelet membranes. Specific binding was saturable, reversible and dependent upon protein concentration. Saturation experiments revealed a single class of binding sites with Kd and Bmax values of 1.4 microM and 5.9 pmol/mg of protein, respectively. Adenosine receptor agonists and antagonists competed for the binding of [3H]CGS 21680 (50 or 200 nM) to human platelet membranes showing a rank order of potency consistent with that typically found for interactions at the adenosine A2 receptor. Adenylate cyclase stimulation and platelet aggregation inhibition induced by adenosine agonists exhibited a rank order of potency close to that observed in binding experiments. However, the adenosine A1 receptor agonists, R- and S-N6-(2-phenylisopropyl)adenosine, (R-PIA) and (S-PIA), N6-cyclohexyladenosine (CHA) and 2-chloro-N6-cyclopentyladenosine (CCPA), which stimulate adenylate cyclase and inhibit platelet aggregation in the low microM range, displaced [3H]CGS 21680 only in the high microM range. In conclusion, we have found that [3H]CGS 21680, which is widely used as a specific A2 agonist in binding studies on brain tissues, is not appropriate for the characterization of the human platelet adenosine A2 receptor.

Adenosine↗

PubMed1994

Excitatory amino acid neurotransmission through both NMDA and non-NMDA receptors is involved in the anticonvulsant activity of felbamate in DBA/2 mice.

The anticonvulsant activity of felbamate against sound-induced seizures was studied in the DBA/2 mouse model. Felbamate (10-300 mg/kg, i.p.) produced dose-dependent effects with ED50 values for the suppression of tonic, clonic and wild running phases of 23.1, 48.8 and 114.6 mg/kg, respectively. Felbamate also protected DBA/2 mice from N-methyl-D-aspartate (NMDA)-induced seizures with ED50 values of 12.1 and 29 mg/kg for tonus and clonus, respectively. Pretreatment with glycine, an agonist to the glycine/NMDA receptors, shifted the dose-response effect of felbamate to the right (ED50 = 56.8 against tonus and 94.8 mg/kg versus clonus). Similarly, D-serine, an agonist at the glycine site, shifted the ED50 of felbamate against the tonic component of audiogenic seizures from 23.1 to 78.1, and that against clonus from 48.8 to 90.3 mg/kg. Felbamate was also potent to prevent seizures induced by administration of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), an AMPA/kainate receptor agonist (ED50 = 11.8 and 20.9 mg/kg, against tonus and clonus, respectively). The data indicate that felbamate is an effective anticonvulsant drug in the genetic model of seizure-prone DBA/2 mice. Our findings suggest that the anticonvulsant properties of felbamate depend upon its interaction with neurotransmission mediated by both the glycine/NMDA and the AMPA/kainate receptor complex.

Acoustic Stimulation↗