The anxiolytic drug opipramol inhibits insulin-induced lipogenesis in fat cells and insulin secretion in pancreatic islets

The antidepressant drug opipramol has been reported to exert antilipolytic effect in human adipocytes, suggesting that alongside its neuropharmacological properties, this agent might modulate lipid utilization by peripheral tissues. However, patients treated for depression or anxiety disorders by this tricyclic compound do not exhibit the body weight gain or the glucose tolerance alterations observed with various other antidepressant or antipsychotic agents such as amitriptyline and olanzapine, respectively. To examine whether opipramol reproduces or impairs other actions of insulin, its direct effects on glucose transport, lipogenesis and lipolysis were investigated in adipocytes while its influence on insulin secretion was studied in pancreatic islets. In mouse and rat adipocytes, opipramol did not activate triglyceride breakdown, but partially inhibited the lipolytic action of isoprenaline or forskolin, especially in the 10–100 μM range. At 100 μM, opipramol also inhibited the glucose incorporation into lipids without limiting the glucose transport in mouse adipocytes. In pancreatic islets, opipramol acutely impaired the stimulation of insulin secretion by various activators (high glucose, high potassium, forskolin...). Similar inhibitory effects were observed in mouse and rat pancreatic islets and were reproduced with 100 μM haloperidol, in a manner that was independent from alpha2-adrenoceptor activation but sensitive to Ca2+ release. All these results indicated that the anxiolytic drug opipramol is not only active in central nervous system but also in multiple peripheral tissues and endocrine organs. Due to its capacity to modulate the lipid and carbohydrate metabolisms, opipramol deserves further studies in order to explore its therapeutic potential for the treatment of obese and diabetic states. (AU)

Protein kinase C cross-talk with gonadotrope progesterone receptor is involved in GnRH-induced LH secretion

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In the absence of progesterone (P), the anti-P at the receptor RU486 reduces basaland GnRH-stimulated LH secretion both in vivo and in vitro, demonstrating theexistence of a ligand-independent activation of progesterone receptor (LIAPR). Theaim of the present study was to determine which component of the intracellular LHsecretory pathway activated by GnRH is responsible for LIAPR. To do this, anteriorpituitary dispersed cells from female rats in proestrus, cultured in the presence of17â-estradiol, were incubated with activators or inhibitors of PKC, cAMP-PKA signallingpathways or intracellular calcium (Ca2+) traffic, in the presence or absence ofRU486. Results showed that RU486 reduced both GnRH- and the PKC activatorPMA-induced LH secretion. In GnRH-stimulated cells incubated with the PKCinhibitor BIS-I or treated with PMA “overnight”, RU486 had no effect on reducedLH secretion, nor on stimulated LH secretion elicited by the Ca2+ ionophore ionomycin.Moreover, when GnRH- or PMA-treated cells were co-incubated with 1 µMof the L-type Ca2+ channel blocker nifedipine or the intracellular Ca2+ chelatorBAPTA-AM, RU486 potentiated the expected inhibition of these drugs on LHsecretion. Activation (forskolin, 8-Br-cAMP) or inhibition (MDL-12,330A) of thecAMP-PKA signalling cascade affected neither the GnRH- and PMA-inducedincrease of LH secretion nor the reduction of LH secretion due to RU486. Takentogether, the data point to the existence of a Ca2+-independent PKC-PR cross-talkmechanism as part of the intracellular signalling of GnRH-stimulated LH secretion

Efecto del AMPC sobre la función de las células endoteliales y la proliferación fibromuscular tras la lesión de las arterias carótida y coronaria en un modelo porcino / Effect of cAMP on Endothelial Cell Function and Fibromuscular Proliferation in an Injured Swine Carotid and Coronary Artery

Introducción y objetivos. El adenosinmonofosfato cíclico (AMPc) restablece la función de barrera del endotelio vascular y previene la liberación de citocinas proinflamatorias. Evaluamos in vivo si el aumento de las concentraciones de AMPc acelera la reendotelización y atenúa la proliferación fibromuscular. Métodos. Media hora antes de causar la lesión de ambas arterias carótidas con balón, 5 cerdos fueron tratados con 2 ml (10 mg) intravenosos en bolo de forskolin, un activador de la adenilciclasa, y otros cinco con 2 ml de suero fisiológico. Estos animales fueron sacrificados a los 8 días y se valoró el grado de reendotelización. En otros 19 cerdos se causó con aterotomo la lesión de la arteria coronaria descendente anterior. Nueve animales fueron tratados con forskolin en bolo y otros 10 con suero fisiológico. Se midió el AMPc intraleucocitario basal, a los 28 y 60 min de administrar el suero o el forskolin, y a los 90 de causar la lesión de la coronaria descendente anterior. Estos animales fueron sacrificados a las 4 semanas y se valoraron el grado de reestenosis y el remodelado arterial geométrico en ambos subgrupos. Resultados. La reendotelización fue superior en el grupo tratado que en el control (p = 0,02) y el número de células CD31 positivas fue significativamente superior en el grupo de estudio (38 ñ 11 células) que en el control (11 ñ 9 células). El grado de lesión causado con el aterotomo fue similar en la totalidad de las arterias. En el grupo control se produjo reestenosis en el 40 por ciento de los animales. El análisis de correlación demostró que tanto en el grupo de estudio como en el control las concentraciones de AMPc elevadas se relacionan con una menor proliferación fibromuscular y un aumento del diámetro de la luz del vaso lesionado. Conclusiones. Nuestros resultados sugieren que el aumento de las concentraciones de AMPc incide en la reendotelización precoz de los segmentos lesionados. El AMPc intracelular puede condicionar el remodelado del vaso y el calibre de su luz (AU)