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2.
Nat Commun ; 8: 14024, 2017 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-28102222

RESUMEN

Electron pairing in the vast majority of superconductors follows the Bardeen-Cooper-Schrieffer theory of superconductivity, which describes the condensation of electrons into pairs with antiparallel spins in a singlet state with an s-wave symmetry. Unconventional superconductivity was predicted in single-layer graphene (SLG), with the electrons pairing with a p-wave or chiral d-wave symmetry, depending on the position of the Fermi energy with respect to the Dirac point. By placing SLG on an electron-doped (non-chiral) d-wave superconductor and performing local scanning tunnelling microscopy and spectroscopy, here we show evidence for a p-wave triggered superconducting density of states in SLG. The realization of unconventional superconductivity in SLG offers an exciting new route for the development of p-wave superconductivity using two-dimensional materials with transition temperatures above 4.2 K.

3.
Phys Rev Lett ; 117(14): 147201, 2016 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-27740785

RESUMEN

We report a spin valve with a few-layer graphene flake bridging highly spin-polarized La_{0.67}Sr_{0.33}MnO_{3} electrodes, whose surfaces are kept clean during lithographic definition. Sharp magnetic switching is verified using photoemission electron microscopy with x-ray magnetic circular dichroism contrast. A naturally occurring high interfacial resistance ∼12 MΩ facilitates spin injection, and a large resistive switching (0.8 MΩ at 10 K) implies a 70-130 µm spin diffusion length that exceeds previous values obtained with sharp-switching electrodes.

4.
Can J Physiol Pharmacol ; 85(10): 1004-11, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18066101

RESUMEN

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 mumol/L) flattened the concentration-response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 mumol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration-response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 +/- 0.1) > clomipramine (pA2, 7.0 +/- 0.1) > fluoxetine (pKB, 6.5 +/- 0.1) = mibefradil (pKB, 6.6 +/- 0.1) > amitriptyline (pKB, 6.3 +/- 0.1) = maprotiline (pKB, 6.2 +/- 0.1) > fluvoxamine (pKB, 5.9 +/- 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.


Asunto(s)
Antidepresivos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Cloruro de Calcio/farmacología , Íleon/efectos de los fármacos , Sustancia P/farmacología , Animales , Canales de Calcio/metabolismo , Relación Dosis-Respuesta a Droga , Antagonismo de Drogas , Cobayas , Íleon/metabolismo , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Masculino , Antagonistas del Receptor de Neuroquinina-1 , Sustancia P/fisiología
5.
Pharmacol Toxicol ; 87(4): 156-60, 2000 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-11097268

RESUMEN

The effect of the melatonin receptor ligand, 2-phenylmelatonin, has been assessed in isolated strips of the guinea-pig proximal colon. 2-Phenylmelatonin (0.01 nM-1 microM) caused a concentration-dependent contractile response. The potency value (-log EC50) was 9.3 +/- 1.0. The maximum effect was 25 +/- 4%, of that elicited by the maximally effective concentration (0.3 microM) of 5-HT and 43 +/- 3%, of that by the maximally effective concentration (10 microM) of melatonin. When used as an antagonist, 2-phenylmelatonin (0.01 nM and 0.1 nM) concentration-dependently inhibited melatonin-induced contractions with depression of the maximum response by 25% and 54%, respectively. Higher (1 nM) 2-phenylmelatonin concentrations failed to antagonize melatonin-induced response. Prazosin (0.3 microM), a selective antagonist of melatonin MT3 sites, antagonized melatonin-induced contractions to an extent similar to that induced by 0.01 nM 2-phenylmelatonin (with 30% reduction of the maximum effect to melatonin). The combination of 0.3 microM prazosin and 0.01 nM 2-phenylmelatonin caused antagonism similar in extent to that caused by each individual antagonist. 2-Phenylmelatonin at subnanomolar concentrations behaves as an antagonist of melatonin-induced contractile responses while at nanomolar/micromolar concentrations it behaves as a weak contractile agonist.


Asunto(s)
Melatonina/análogos & derivados , Melatonina/antagonistas & inhibidores , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Receptores de Superficie Celular/agonistas , Receptores Citoplasmáticos y Nucleares/agonistas , Antagonistas Adrenérgicos alfa/farmacología , Análisis de Varianza , Animales , Colon/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/farmacología , Cobayas , Masculino , Melatonina/farmacología , Prazosina/farmacología , Receptores de Melatonina , Serotonina/farmacología
6.
Naunyn Schmiedebergs Arch Pharmacol ; 362(3): 284-9, 2000 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10997731

RESUMEN

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.


Asunto(s)
Antidepresivos/farmacología , Músculo Liso/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Serotonina/análogos & derivados , Animales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Cobayas , Íleon/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Serotonina/farmacología
7.
Fundam Clin Pharmacol ; 13(3): 330-6, 1999.
Artículo en Inglés | MEDLINE | ID: mdl-10392309

RESUMEN

The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol-precontracted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-1 microM) induced concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM-1 microM) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 microM-300 microM) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 microM) and a low (3 microM-300 microM) potency phase. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 microM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg-1 per day, for two days), to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous-by-class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant antagonism of litoxetine response (P = 0.037: ANOVA for continuous-by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 microM) increased the relaxant effects of 5-HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5-HT, without changing its potency value. Fluoxetine (1 microM) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner. In conclusion, litoxetine up to 1 microM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5-HT, which in turn activates 5-HT4 receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that blockade of 5-HT reuptake can participate in the action of litoxetine, since fluoxetine, a 5-HT reuptake inhibitor equipotent to litoxetine, was ineffective in the same range of concentrations. The antimuscarinic activity of litoxetine, previously demonstrated in the isolated guinea-pig intestine, played a role at concentrations greater than 1 microM. The 5-HT-releasing action of litoxetine could account for the potentation by litoxetine of 5-HT-induced relaxation in tissues from untreated rats, which was reversed by pCPA treatment. Under these conditions, litoxetine depressed relaxations to high 5-HT concentrations only. In tissues from untreated rats, fluoxetine slightly but unsurmountably antagonized 5-HT-induced relaxations, thus confirming previous observations in the guinea-pig small intestine.


Asunto(s)
Esófago/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Receptores de Serotonina/fisiología , Inhibidores de la Captación de Serotonina/farmacología , Animales , Carbacol/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Fenclonina/análogos & derivados , Fenclonina/farmacología , Fluoxetina/farmacología , Técnicas In Vitro , Indoles/farmacología , Masculino , Piperidinas/farmacología , Ratas , Ratas Wistar , Antagonistas de la Serotonina/farmacología , Sulfonamidas/farmacología
10.
Naunyn Schmiedebergs Arch Pharmacol ; 357(6): 654-61, 1998 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-9686942

RESUMEN

The alpha-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonists and subtype-selective antagonists. Noradrenaline, the alpha1-selective agonist phenylephrine and the alpha1-/alpha2-agonist oxymetazoline caused the preparations to contract with potency (pD2) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline, phenylephrine and oxymetazoline induced 93% and 78% of noradrenaline maximum effect. Conversely, the two alpha2-selective agonists clonidine and B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precontracted with phenylephrine. The alpha2-selective antagonist yohimbine antagonized oxymetazoline- and phenyleprine-induced contractions with affinity (pA2) values (6.80 and 6.74, respectively) consistent with alpha1-adrenoceptor interaction. This suggests that the pig splenic artery possesses only functional alpha1-adrenoceptors. The alpha1-adrenoceptor antagonists of varying subtype selectivities like WB-4101, 5-methylurapidil, benoxathian and BMY 7378 competitively antagonized phenylephrine-induced contractions with affinity values of 9.46, 8.26, 9.06 and 6.91, respectively. These values correlated highly with published affinity values for functional alpha1A-adrenoceptors (r=0.92) and alpha1a-clones (r=0.94) and less well with affinity values for functional alpha1B-adrenoceptors (r=0.84) and alpha1b-clones (r=0.87). Conversely, correlation with functional alpha1D-adrenoceptors (r=0.26) and alpha1d-clones (r=0.33) was poor. In addition the alpha1D-selective antagonist BMY 7378 had a low affinity value compared to that reported for alpha1D-adrenoceptors. Therefore, based on correlation studies, the plot that resembled the line of equal values most closely was that for the alpha1A-subtype. The alpha1A-selective antagonist RS-17053 antagonized phenylephrine-induced contractions in an apparently non-competitive manner and gave an apparent pA2 value of 7.06 which is similar to the "low" affinity values reported in other alpha1A-containing tissues. Exposure to the irreversible alpha1B/D-antagonist chloroethylclonidine slightly decreased maximum response to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethylclonidine-insensitive. It is concluded that splenic artery strips from the pig contract in response to phenylephrine through activation of alpha1-adrenoceptors which display the pharmacological profile of the alpha1A-subtype for which the recently reported alpha1A-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the alpha1B-subtype in the overall contractile response is elusive while no evidence was obtained for the involvement of the alpha1D-subtype. The contribution of functional alpha2-adrenoceptors to the contractile response was ruled out.


Asunto(s)
Músculo Liso Vascular/fisiología , Receptores Adrenérgicos alfa/fisiología , Arteria Esplénica/fisiología , Agonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 1 , Agonistas de Receptores Adrenérgicos alfa 2 , Antagonistas de Receptores Adrenérgicos alfa 2 , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Arteria Esplénica/efectos de los fármacos , Porcinos
11.
Br J Pharmacol ; 121(8): 1775-81, 1997 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-9283717

RESUMEN

1. The interaction of melatonin (N-acetyl-5-methoxytryptamine) with 5-hydroxytryptamine4 (5-HT4) receptors and/or with melatonin receptors (ML1, ML2 sites) has been assessed in isolated strips of the guinea-pig proximal colon. In the same preparation, the pharmacological profile of a series of melatonin agonists (2-iodomelatonin, 6-chloromelatonin, N-acetyl-5-hydroxytryptamine (N-acetyl-5-HT), 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT)) was investigated. 2. In the presence of 5-HT1/2/3 receptor blockade with methysergide (1 microM) and ondansetron (10 microM), melatonin (0.1 nM-10 microM), 5-HT (1 nM-1 microM) and the 5-HT4 receptor agonist, 5-methoxytryptamine (5-MeOT: 1 nM-1 microM) caused concentration-dependent contractile responses. 5-HT and 5-MeOT acted as full agonists with a potency (-log EC50) of 7.8 and 8.0, respectively. The potency value for melatonin was 8.7, but its maximum effect was only 58% of that elicited by 5-HT. 3. Melatonin responses were resistant to atropine (0.1 microM), tetrodotoxin (0.3 microM), and to blockade of 5-HT4 receptors by SDZ 205,557 (0.3 microM) and GR 125487 (3, 30 and 300 nM). The latter antagonist (3 nM) inhibited 5-HT-induced contractions with an apparent pA2 value of 9.6 GR 125487 antagonism was associated with 30% reduction of the 5-HT response maximum. Contractions elicited by 5-HT were not modified when melatonin (1 and 10 nM) was used as an antagonist. 4. Like melatonin, the four melatonin analogues concentration-dependently contracted colonic strips. The rank order of agonist potency was: 2-iodomelatonin (10.8) > 6-chloromelatonin (9.9) > or = N-acetyl-5-HT (9.8) > or = 5-MCA-NAT (9.6) > melatonin (8.7), an order typical for ML2 sites. In comparison with the other agonists, 5-MCA-NAT had the highest intrinsic activity. 5. The melatonin ML1B receptor antagonist luzindole (0.3, 1 and 3 microM) had no effect on the concentration-response curve to melatonin. Prazosin, an alpha-adrenoceptor antagonist possessing moderate/ high affinity for melatonin ML2 sites did not affect melatonin-induced contractions at 0.1 microM. Higher prazosin concentrations (0.3 and 1 microM) caused a non-concentration-dependent depression of the maximal response to melatonin without changing its potency. Prazosin (0.1 and 1 microM) showed a similar depressant behaviour towards the contractile responses to 5-MCA-NAT. 6. In the guinea-pig proximal colon, melatonin despite some structural similarity with the 5-HT4 receptor agonist 5-MeOT, does not interact with 5-HT4 receptors (or with 5-HT1/2/3 receptors). As indicated by the rank order of agonist potencies and by the inefficacy of luzindole, the most likely sites of action of melatonin are postjunctional ML2 receptors. However, this assumption could not be corroborated with the use of prazosin as this 'ML2 receptor antagonist' showed only a non-concentration-dependent depression of the maximal contractile response to both melatonin and 5-MCA-NAT. Further investigation with the use of truly selective antagonists at melatonin ML2 receptors is required to clarify this issue.


Asunto(s)
Colon/efectos de los fármacos , Melatonina/farmacología , Contracción Muscular/efectos de los fármacos , Receptores de Superficie Celular/fisiología , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de Serotonina/fisiología , Animales , Colon/fisiología , Relación Dosis-Respuesta a Droga , Cobayas , Técnicas In Vitro , Masculino , Prazosina/farmacología , Receptores de Melatonina , Receptores de Serotonina 5-HT4 , Tetrodotoxina/farmacología
13.
Br J Pharmacol ; 114(5): 1017-25, 1995 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-7780635

RESUMEN

1. A combined study of receptor binding in central neuronal cell membranes and functional responses in isolated segments of guinea-pig small intestine allowed characterization of the interaction of four antidepressant drugs with central and peripheral 5-HT3 and 5-HT4 receptors. 2. Clomipramine, paroxetine and fluoxetine inhibited [3H]-DAU 6215 binding to 5-HT3 recognition sites in NG 108-15 cells with IC50 values in the range 1.3-4 microM. Litoxetine had an IC50 of 0.3 microM. The specific binding of [3H]-GR 113808 to 5-HT4 recognition sites in pig striatal membranes was inhibited by all four antidepressants with negligible potency (IC50 values > or = 20 microM). 3. In whole ileal segments, concentration-response curves to 5-HT were biphasic, with the high- and low-potency phases involving 5-HT4 and 5-HT3 receptors, respectively. Curves to 2-methyl-5-hydroxytryptamine (2-methyl-5-HT: a 5-HT3 receptor agonist) and 5-methoxytryptamine (5-MeOT: a 5-HT4 receptor agonist) were monophasic. All antidepressants were used at concentrations lacking anticholinoceptor properties, as demonstrated in both electrically stimulated longitudinal muscle-myenteric plexus preparations (LMMPs) and in unstimulated LMMPs following addition of acetylcholine (100 nM). 4. Fluoxetine (0.1-1 microM) and litoxetine (0.3-3 microM) antagonized both the high- and low-potency phases of the 5-HT curve. Schild analysis for the low-potency phase yielded pA2 estimates of 6.6 +/- 0.3 (Schild slope of 1.1) and of 6.6 +/- 0.1 (Schild slope of 1.1), respectively. At higher concentrations (3 microM), fluoxetine markedly inhibited the 5-HT response maximum. Clomipramine (10-300 nM) inhibited, by a mechanism independent of concentration, both phases of the 5-HT curve with a reduction of the maximum response. Paroxetine (1 microM) was ineffective on the high-potency phase, but caused a rightward shift of the low-potency phase (pKB: 6.1 +/- 0.01). 5. Responses to 2-methyl-5-HT were inhibited by 1 microM fluoxetine (pKB: 5.4 +/- 0.02). Like clomipramine(30 and 100 nM), litoxetine (1 and 3 microM) produced rightward displacements of 2-methyl-5-HT-induced contractions, which were virtually independent of antidepressant concentration (pKB values: 6.0 +/- 0.02 and 5.5 +/- 0.01, respectively). At higher concentrations, fluoxetine (3 microM) and clomipramine (300 nM)markedly reduced the 2-methyl-5-HT response maximum. Paroxetine (1 micro M) was ineffective.6. Responses to 5-MeOT were shifted to the right by fluoxetine (0.1-1 micro M) and litoxetine (1 and 3 microM)in a concentration-dependent manner. At higher concentrations, fluoxetine (3 microM) markedly reduced the 5-MeOT response maximum, an effect also observed with 100 and 300 nM clomipramine. Paroxetine(1 microM) was ineffective.7. In unstimulated LMMPs, the excitatory effects evoked by 5-HT, 2-methyl-5-HT and 5-MeOT and the antagonism produced by 300 nM clomipramine were comparable to those obtained in whole ileal segments. This suggests that 5-HT contained in the mucosa of whole preparations does not interfere with agonist-induced contractile responses and with the inhibitory effect of antidepressant drugs.8. In conclusion, our results show that clomipramine, fluoxetine, paroxetine and litoxetine possess low to moderate potency/affinity at both central and peripheral (enteric) 5-HT3 receptors. In contrast, all four antidepressants are virtually ineffective at central 5-HT4 receptors. Inhibition of 5-HT4 receptor mediated ileal contractions by fluoxetine, litoxetine and clomipramine may result from allostericant agonism or, more likely, from post-receptor blockade of second messenger generation. The interaction of antidepressants with central and peripheral 5-HT3 and 5-HT4 receptors may be relevant for both potential therapeutic action and adverse effects at gastrointestinal level.


Asunto(s)
Antidepresivos de Segunda Generación/farmacología , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Periférico/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Inhibidores de la Captación de Serotonina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Estimulación Eléctrica , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Plexo Mientérico/efectos de los fármacos , Plexo Mientérico/fisiología , Neuroblastoma/metabolismo , Antagonistas de la Serotonina/farmacología , Porcinos , Células Tumorales Cultivadas
14.
Br J Pharmacol ; 112(3): 763-8, 1994 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-7921600

RESUMEN

1. Experiments were carried out to characterize the receptors mediating the indirect excitatory response to 5-hydroxytryptamine (5-HT) in the guinea-pig isolated trachea. 2. 5-HT caused concentration-dependent contractions of tracheal strips, and the resulting concentration-response curve was biphasic in nature. The first phase was obtained with agonist concentrations in the range of 0.01-3 nM and achieved a maximum which was 30% of the total 5-HT response, while the second phase was in the range 10 nM-1 microM. 3. Atropine (0.1 microM) and tetrodotoxin (TTX: 0.3 microM) significantly reduced both phases of the 5-HT curve. Morphine (10 microM), which can act to inhibit neuronal acetylcholine release, abolished the first phase and reduced the second phase. This suggests that the first phase is mainly neurogenic (cholinergic) in nature, while the second phase is in part neurogenic and in part due to direct activation of the effector cells. 4. The 5-HT2A receptor antagonist, ketanserin (0.01, 0.1 microM) markedly depressed the first phase and shifted the second phase to the right in a parallel manner, with some depression of the 5-HT response maximum. The less selective (5-HT1/5-HT2A) antagonist, methiothepin (0.1 microM) mimicked the action of ketanserin, albeit with less potency. Concomitant administration of ketanserin and methiothepin (each at 0.1 microM) produced an antagonism similar to that caused by ketanserin (0.1 microM) alone. 5. The 5-HT3 receptor antagonists, ondansetron (0.1 microM) and granisetron (0.01 microM) slightly but significantly inhibited the first phase of the 5-HT curve without altering the second phase. SDZ 205,557(0.3 MicroM), a 5-HT4 receptor antagonist, was ineffective.6. Our results suggest that neural 5-HT2A and, to a lesser extent, 5-HT3 receptor subtypes mediate the first phase of the 5-HT curve in the guinea-pig trachea. The second phase is mediated by 5-HT2Areceptors, which are probably located at both the neural and muscular level. No evidence for the participation of 5-HT1 receptors in the 5-HT response has been obtained.


Asunto(s)
Músculo Liso/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Tráquea/efectos de los fármacos , Animales , Cobayas , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Serotonina/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología
15.
J Auton Pharmacol ; 12(2): 61-72, 1992 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-1583026

RESUMEN

1. The aim of the present study was to see whether contractile responses induced by muscarinic agonists in the rat jejunum and urinary bladder were differently affected by procedures that mainly influence the steps following agonist-receptor interaction. Thus, the effects of ex vivo lithium pretreatment (6.8 mmol kg-1 i.p. for 3 days) and in vitro cooling from 37 degrees C to 20 degrees C) on the contractile responses to full and partial agonists, carbachol, oxotremorine, muscarine and pilocarpine were studied. 2. Lithium pretreatment did not affect muscarinic responses on the urinary bladder. It significantly reduced responses to carbachol and oxotremorine but not to muscarine and pilocarpine on the rat jejunum. 3. A decrease of the bath temperature from 37 degrees C to 20 degrees C potentiated responses to carbachol, muscarine and oxotremorine and abolished those to pilocarpine in the urinary bladder. The same lowering of the bath temperature potentiated responses to carbachol, did not affect those to muscarine and to oxotremorine and reduced those to pilocarpine in the jejunum. 4. Together the findings indicate that differences exist in the stimulus-response coupling induced by muscarinic agonists between the two tissues and that, in a given tissue, differences exist among agonists in their ability to activate the agonist-receptor-transducer complex.


Asunto(s)
Frío , Litio/farmacología , Músculo Liso/efectos de los fármacos , Parasimpaticomiméticos/farmacología , Animales , Técnicas In Vitro , Yeyuno/efectos de los fármacos , Masculino , Contracción Muscular/efectos de los fármacos , Cloruro de Potasio/farmacología , Ratas , Ratas Endogámicas , Vejiga Urinaria/efectos de los fármacos
16.
Farmaco Sci ; 42(12): 921-30, 1987 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-3449392

RESUMEN

A selected number of acyclic analogs of muscarine were synthesized and tested on rat jejunum. A conformational analysis carried out on compounds (I) and (II), with the Allinger's MM2 program, evidenced that their very low muscarinic activity can be related to the low percentage of the "active conformation" present in solution.


Asunto(s)
Parasimpaticomiméticos/síntesis química , Animales , Fenómenos Químicos , Química , Íleon/efectos de los fármacos , Técnicas In Vitro , Ligandos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Parasimpaticomiméticos/farmacología , Ratas
17.
Farmaco Sci ; 42(6): 409-24, 1987 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-3653389

RESUMEN

The results of a pharmacological investigation on a series of meta-substituted benzyltrimethylammonium salts possessing an antimuscarinic activity are reported. Correlative analysis shows that the pharmacodynamic activity is a function of the hydrophobic-lipophilic parameter associated with the substituent.


Asunto(s)
Parasimpatolíticos/síntesis química , Compuestos de Amonio Cuaternario/síntesis química , Animales , Fenómenos Químicos , Química , Cromatografía Líquida de Alta Presión , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Compuestos de Amonio Cuaternario/farmacología , Ratas , Relación Estructura-Actividad
18.
Farmaco Sci ; 41(5): 336-45, 1986 May.
Artículo en Inglés | MEDLINE | ID: mdl-3720943

RESUMEN

Proceeding in our study on the muscarinic receptor site, a refinement of its topology by means of Quantitative Structure-Activity Relationships has been carried out. Specific key structures have been selected considering not only muscarine and the corresponding desether derivative, but also a set of cyclopentenyltrimethylammoniummethyl salts. These derivatives, considered in a correlation equation extended to all of the five-membered cyclic structures previously examined, significantly improve understanding of contributions of critical ligand substructures to the overall interaction. The results obtained reinforce the reliability of correlation equations in structure-activity studies.


Asunto(s)
Parasimpaticomiméticos/síntesis química , Fenómenos Químicos , Química Física , Ligandos , Muscarina/farmacología , Parasimpaticomiméticos/farmacología , Relación Estructura-Actividad
19.
Naunyn Schmiedebergs Arch Pharmacol ; 332(3): 213-8, 1986 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-3713868

RESUMEN

This study was undertaken to determine the potencies of seven muscarinic agonists (methylfurtrethonium, dioxolane, oxathiolane, carbachol, muscarine, muscarone and oxotremorine) on the postjunctional muscarinic receptors of seven isolated preparations (guinea pig taenia-coli, ileum, jejunum, trachea and atria and rat jejunum and urinary bladder). The results indicate that the rank order of sensitivity of the preparations varies independently of the potency of the agonist used and it is almost the same for all the compounds with the exception of oxotremorine. Muscarone was the most potent compound in all the tissues. Intergroup comparisons in each preparation and the evaluation of the equieffective molar ratios relative to muscarone revealed that carbachol possesses a certain degree of cardioselectivity and oxathiolane, on the other hand, is much less active on the cardiac tissue than on the others. Oxotremorine is a peculiar compound endowed with cardioselectivity.


Asunto(s)
Unión Neuromuscular/efectos de los fármacos , Parasimpaticomiméticos/farmacología , Animales , Colon/efectos de los fármacos , Cobayas , Corazón/efectos de los fármacos , Íleon/efectos de los fármacos , Técnicas In Vitro , Yeyuno/efectos de los fármacos , Masculino , Músculo Liso/efectos de los fármacos , Ratas , Ratas Endogámicas , Especificidad de la Especie , Tráquea/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos
20.
Pharmacol Res Commun ; 17(8): 787-801, 1985 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-2996036

RESUMEN

Previous researches demonstrated that in the rat vas deferens the effects of noradrenaline released by tyramine were more easily affected than those induced by exogenous noradrenaline by the non selective alpha-blockers, phentolamine and dihydroergocristine. The investigation has now been extended to the effects of selective alpha-blockers, prazosin and yohimbine with the aim to see whether the major sensitivity of tyramine to alpha-blockade correlates with the type of receptor activated. The results obtained with the two antagonists which selectively block alpha 1 and alpha 2 receptors strongly resemble each other and those previously obtained with the non selective alpha-adrenoceptor blockers. Thus, the peculiar sensitivity to alpha-blockade of noradrenaline released by tyramine with respect to exogenous noradrenaline does not seem to be dependent on the type (alpha 1 or alpha 2) of receptor involved.


Asunto(s)
Norepinefrina/antagonistas & inhibidores , Prazosina/farmacología , Tiramina/antagonistas & inhibidores , Yohimbina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas , Receptores Adrenérgicos alfa/efectos de los fármacos , Conducto Deferente/efectos de los fármacos
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