Departamento de Ciências Médicas
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- Efectos del haloperidol y nuevas butirofenonas de sintesis sobre las contracciones inducidas por dopamina en conducto deferente de rataPublication . Verde, Ignacio; Loza, M.; Orallo, Francisco; Cadavid, Isabel; Gato, A.; Calleja, José MariaEI objetivo inicial de este trabajo fué el de estudiar los efectos de dos potenciales agentes neurolépticos (el p-clorobenzoato de pseudotropanol (I) y el p-F-fenil 2-4-o metoxifenilpiperazinometilciclopenitilcetona (II) frente a las contracciones inducidas por dopamina en conducto deferente aislado de rata. Pero, aunque está clara la presencia de dopamina (DA) y noradrenalina (NA) (1), al revisar la bibiografía encontramos datos contradictorios sobre la existencia de receptores postsinápticos específicos para la dopamina en esta preparación. Así, por una parte algunos autores (2) proponen que la DA activa una población de receptores postsinápticos que se diferencian de los activados por la NA, basándose en el hecho de que encontraron valores de pA2, distintos para la NA y para la DA utilizando varias antagonistas. Por otro lado, otros autores (3, 4) proponen que tanto la NA como la DA activan una población homogénea de receptores en vaso deferente de rata. Para demostrarlo utilizan una solución de Krebs especial a la que añaden inhibidores de la recaptaci6n, bloqueantes de receptores beta-adrenérgicos, y además modifican el tiempo de preincubación del antagonista. En nuestro trabajo estudiamos el efecto del haloperidol frente a las contracciones inducidas por NA y DA en ausencia y en presencia de inhibidores de la recaptaci6n neuronal (cocaina), extraneuronal (estradiol), y de un bloqueante beta adrenérgico (propranolol); y el de los dos potenciales neurolépticos (compuestos I y II) frente a las contracciones inducidas por dopamina en condiciones normales.
- Efectos de la glaucina sobre las contracciones y el influjo de 45Ca2+ inducido por noradrenalina y K+ en la aorta de rataPublication . Verde, Ignacio; Orallo, Francisco; Loza, M.; Gil-Longo, José; Cadavid, Isabel; Calleja, José MariaLa glaucina es un alcaloide aislado del Glaucium flavum Crantz (1). Se conocen sus efectos sobre varios neurotransmisores centrales (2), su acción neuroendocrina (3), y sus propiedades relajantes musculares atribuidas al efecto inhibidor de la fosfodiesterasa del 3º-5º AMPc aunque algunos autores (4) sugieren que este mecanismo no es suficiente para justificar su efecto relajante a nivel del musculo liso. Con objeto de aportar nuevos datos que contribuyan a esclarecer este mecanismo, en el presente trabajo se realiza un estudio de los efectos de la glaucina sobre las contracciones inducidas por noradrenalina (NA) y K+ en anillos de aorta de rata, y sobre el influjo de 45Ca basal y evocado por los dos agentes vasoconstrictores.
- Modulacion por el endotelio de las contracciones induzidas por distintos agonistas alfa-adrenérgicos en la aorta de rataPublication . Verde, Ignacio; Loza, M.; Gil-Longo, José; Campos, M.; Orallo, Francisco; Calleja, José MariaDesde que Furchgott (5), (6) descubri6 que la presencia de endolelio es imprescindible para la acción relajante vascular de la acetilcolina, han aparecido múltiples estudios que demuestran que las células endoteliales pueden desempeñar un papel decisivo CD la modulaci6n de determinados procesos biológicos, como por ejemplo, el tono vascular (1), (9), (13), (15) Y 105 efectos de distintos fármacos (1), (14). Es más, se ha descrito la presencia de receptores alfa2 CD e1 endotelio vascular cuya activación puede estimular la liberaci6n de EDRF (3), (4). Con el objeto de confirmar la presencia de dichos receptores, CD el presente trabajo se estudia la posible modulaci6n por el endotelio de Las contracciones inducidas por distintos agonistas alfaadren6rgicos en la aorta de rata.
- 5-HT2 antagonist activity of 3-aminomethyltetralonesPublication . Verde, Ignacio; Loza, M.; Castro, Maria Elena; Orallo, Francisco; Fontenla, José Angel; Calleja, José Maria; Ravina, Enrique; Cortizo, L.; Deceballos, M. L.The affinity of four 3-aminomethyltetralones for 5-HT2 receptors is reported, together with their inhibitory activity against serotonin-induced contractions in rat aorta rings stripped of endothelium. Compound 4, which has a p-fluorobenzoyl-piperidine fragment, exhibited activity similar to that of methysergyde.
- Role of the endothelial system in Bay-K-8644 enantiomer and nifedipine vasomodulator action in rat aortaPublication . Verde, Ignacio; Gil-Longo, José; Orallo, Francisco; Campos, Manuel; Calleja, José MariaThe potential importance of the endothelial system in regulating the effects of (−)-Bay K 8644 (0.1 μM), (+)-Bay K 8644 (0.1 μM) and nifedipine (10 nM) on resting tension, on contractile responses to noradrcnaline (NA) and Ca2+ (in a Ca2+-free high-K+ solution), and on basal, NA-induced and K+-induced 45Ca2+ uptake, was investigated in rat aorta rings. Mechanical removal of endothclium considerably potentiated the contractile response induced by NA in standard medium and by Ca2+ in Ca2+-free high-K' (15 mM) medium, but did not modify the response induced by Ca2+ in Ca2+-frcc high-K+ (55 mM) medium or by NA in Ca2+-free medium. Furthermore, the basal 45Ca2+ uptake and that induced by NA (10 μM) or KCl (15 and 55 mM) were similar in endothelium-rubbed and intact rings. (−)-Bay K 8644 (0.1 μM) shifted the NA and Ca2+ concentration-response curves to the left with potentialion of the maximal contraction. However, (+)-Bay K 8644 (0.1 μM) and nifedipine (10 nM) caused a shift to the right, with depression of the maximal contraction. The NA concentration-response curves, and those of Ca2+ in Ca2+-free high-K+ (55 mM) medium, were affected by the drugs to similar extents, and were not modified by the presence or absence of endothelial cells. The drugs tested did not affect resting tension. Basal 45Ca2+ uptake was not modified by either nifedipine or the Bay K 8644 enantiomers. On the other hand, (−)-Bay K 8644 increased with equal effectives both NA- and KCl-induccd 45Ca2+ uptake, whilst (+)-Qay K 8644 and nifedipine inhibited both uptakes. The presence or absence of endothelium did not modify these effects. These results suggest that, in rat aorta, the endothelial system does not modulate either the agonist effect of (−)-Bay K 8644 or the antagonistic effects of (+)-Bay K S644 and nifedipine. Furthermore, our data indicate that the effects of Bay K 8644 enantiomers and nifedipine on the contractile responses and 45Ca2+ uptake elicited by NA and high-K+ (55 mM) solutions are similar.
- Effects of platelet-activating-factor on contractions and 45Ca2+ influx induced by noradrenaline and potassium in rat rubbed and intact aorta - comparison with its hypotensive effect in anesthetized normotensive ratsPublication . Verde, Ignacio; Orallo, Francisco; Loza, Isabel; Alzueta, A. F.; Campos,Manuel; Freire-Garabal, ManuelIn order to clarify the mechanism of hypotensive activity of platelet activating factor (PAF), the effects of this drug on blood pressure in anaesthetized normotensive rats, on KCl- and noradrenaline-induced 45Ca uptake and contractile responses in rat aorta rings with and without endothelium were studied. PAF (3 micrograms kg-1, i.v.) showed long-lasting hypotensive effects in anaesthetized normotensive rats accompanied by a significant increase in heart rate. PAF (0.1-10 microM) did not relax the contractions induced by noradrenaline (10 microM) or K+ (60 mM) in rubbed or intact rat aorta. PAF did not affect the basal uptake of 45Ca2+ nor that induced by the two vasoconstrictor agents. In experiments in a calcium free medium, PAF (10 microM) had no effect on the noradrenaline- (10 microM) induced contractions. These results suggest that the hypotensive activity of PAF in normotensive anaesthetized rats is not due to a direct effect on rubbed and intact rat aorta rings (acting within the cell or blocking Ca2+ influx through L-type transmembrane calcium channels).
- Efecto del endotelio sobre las contracciones inducidas por noradrenalina y K+ en aortas de rata genéticamente hipertensa y rata normotensaPublication . Verde, Ignacio; Orallo, Francisco; Gil-Longo, José; Campos, M.Desde que Furchgott (1, 2) descubrió que la presencia de endotelio era imprescindible para la acción relajante vascular de la acetilcolina, han aparecido diversos y variados estudios que demuestran su participación en la relajación provocada por diversos agentes (ATP, serotonina, histamina, ...) (3. 4, 5, 6). Es mas, se han descrito diversos mecanismos en células del endotelio vascular que, al ser activados, pueden estimular la liberación de varios factores endoteliales (7). También se ha demostrado la existencia de una posible disfunción o mal funcionamiento del sistema endotelial en procesos de hipertensión, debido. bien a una dificultad en la liberación de EDRF (endothelium derived relaxing factor)(8), o bien a un aumento en la liberación de EDCF (endothelium derived contracting factor)(9. 10). Con el objeto de confirmar la Influencia de los procesos de hipertensión sobre el estado del endotelio, en el presente trabajo se estudia la posible modulación por el sistema endotelial de las contracciones inducidas por noradrenalina y. CaCI2 (en media despolarizante) en aorta de rata normotensa e hipertensa.
- A study of glaucine-induced relaxation of rat aortaPublication . Verde, Ignacio; Orallo, Francisco; Loza, Isabel; Gil-Longo, José; Calleja, José Maria; Cadavid, IsabelThe vasorelaxant effect of glaucine, the major alkaloid of Platycapnos spicata (L.) Bernh., was studied. At concentrations of 10 microM-0.3 mM in normal Krebs solution it was almost equieffective in relaxing K(+)-induced and noradrenaline-induced tension in rat aortic rings without endothelium, with IC50 values of 160 +/- 16 microM and 90 +/- 14 microM respectively. In experiments in a calcium-free medium, 10 microM glaucine strongly inhibited noradrenaline-induced contractions. Glaucine (0.3 mM) did not affect basal uptake of 45Ca, but induced uptake was reduced to 100% (K+) and 97.7% (noradrenaline) of the basal value. These results suggest that glaucine has an intracellular effect and also acts on the cell membrane by blocking voltage-dependent and receptor-operated calcium channels.
- Pyridazine derivatives. XI: Antihypertensive activity of 3-hydrazinocycloheptyl[1,2-C]pyridazine and its hydrazone derivativesPublication . Gil-Longo, José; Laguna, Maria de los Reyes; Verde, Ignacio; Castro, Elena; Orallo, Francisco; Fontenla, Jose A.; Calleja, José Maria; Ravina, Enrique; Terán, Carmen3-Hydrazinocycloheptyl[1,2-c]pyridazine (4) and its hydrazone derivatives 3-[N1-(isopropylidene)]hydrazinocycloheptyl[1,2-c]pyridazine [correction of hydrazinocyclohexyl] (5) and 3-[N1-(isobutylidene)]hydrazinocycloheptyl[1,2-c]pyridazine (6) were prepared, and their activity against genetic, neurogenically-induced, and deoxycorticosterone acetate -NaCl-induced hypertension was found to be at least as great as that of hydralazine. The results of studying vasorelaxation of rat aorta by 4 and hydralazine suggest that both these compounds owe their antihypertensive activity to direct relaxation of vascular smooth muscle.
- Antiserotoninergic activity of 2-aminoethylbenzocyclanones in rat aorta: Structure-activity RelationshipsPublication . Verde, Ignacio; Loza, Isabel; Ferreiro, T. G.; Sanz, F.; Lozoya, E.; Rodriguez, J.; Manaut, F.; Castro, Elena; Fontenla, José Angel; Cadavid, Isabel; Honrubia, M.; Fueyo, J.; Ravina, EnriqueSubcellular targeting of the components of the cAMPdependent pathway is thought to be essential for intracellular signaling. Here we have identified a novel protein, named myomegalin, that interacts with the cyclic nucleotide phosphodiesterase PDE4D, thereby targeting it to particulate structures. Myomegalin is a large 2,324-amino acid protein mostly composed of a-helical and coiled-coil structures, with domains shared with microtubule-associated proteins, and a leucine zipper identical to that found in the Drosophila centrosomin. Transcripts of 7.5–8 kilobases were present in most tissues, whereas a short mRNA of 2.4 kilobases was detected only in rat testis. A third splicing variant was expressed predominantly in rat heart. Antibodies against the deduced sequence recognized particulate myomegalin proteins of 62 kDa in testis and 230–250 kDa in heart and skeletal muscle. Immunocytochemistry and transfection studies demonstrate colocalization of PDE4D and myomegalin in the Golgi/centrosomal area of cultured cells, and in sarcomeric structures of skeletal muscle. Myomegalin expressed in COS-7 cells coimmunoprecipitated with PDE4D3 and sequestered it to particulate structures. These findings indicate that myomegalin is a novel protein that functions as an anchor to localize components of the cAMP-dependent pathway to the Golgi/centrosomal region of the cell.