Efectos de la administración exógena de rhGH sobre la ingesta, composición corporal y nómica Canaria

Tesis de la Universidad Complutense de Madrid, Facultad de Farmacia, Departamento de Fisiología (Fisiología Animal), leída el 24-02-1994Sección Deptal. de Fisiología (Farmacia)Fac. de FarmaciaTRUEpu

Hormona de crecimiento, destete y estado nutritivo

The GH-IGF-I system constitutes the major determinant of body size, specially in postnatal growth. It is well established that exogenous GH increases muscle mass and decreases lipid content, leading to the alteration of nutrients repartitioning. The mechanism involves, at least, an increase in the protein synthesis and creates a status of positive nitrogen balance by increasing nitrogen retention and decreasing protein catabolism in animals fed an adequate diet. GH can act directly on tissues inducing these metabolic changes and can also stimulate IGF-I in an endocrine, autocrine or paracrine fashion. Body fat decreases by the increase of triglycerides hydrolysis and the decrease of free fatty acid re-esterification. The magnitude of the response to exogenous GH is variable and at least partly attributable to the nutritional status and to the growth stage of animal. The action of growth hormone is minimal between the 2nd and the 3rd week of age and is manifested at 31 days of age, increasing its efficacy at puberty. The reason for this refractoriness to GH treatment is unknown but it can be related to the biphasic response developed in mice fed two dietary protein levels between 21 to 50 days of age, when administered with rhGH. The GH-induced fall of feed intake in mice between 21 and 30 days old provokes a loss of body and skeletal muscle components due to the lack of nutrients leading to the impairment of growth. Later on (35-50 days) the self-controlled increase of feed intake let the recovery of the body weight, through of a catch-up growth phenomenon, characterized by a higher lipid body accretion, similar to the compensatory growth developed during refeeding after protein-energy malnutrition, and possibly contemporary of a GH-resistance status of the fat mass. However, the GH anabolic action is clearly seen on the muscle mass, specially in the well-nourished mice, with increased fractional protein synthesis rate that allows higher both muscle protein deposit and muscle cellular size. Thus, GH administration throughout weaning seems to interfere with the delicate adaptive mechanisms to the solid diet, impeding normal growth bet ween the 3rd and 4th week of age and inducing a compensatory growth from 35 days of age.El eje GH-IGF-I es el regulador fundamental del crecimiento postnatal y el determinante del tamaño corporal. El tratamiento con GH aumenta la masa muscular y disminuye el depósito graso, modificando la redistribución de los depósitos corporales. Por su capacidad de aumentar la síntesis y de disminuir el catabolismo proteico genera un balance nitrogenado positivo, bien actuando directamente a nivel tisular o mediante la acción endocrina, paracrina o autocrina del factor IGF-I. De forma paralela, la hormona somatotropa incrementa la hidrólisis de los triglicéridos y disminuye la lipogénesis. Esta respuesta metabólica a la GH exógena varía con diversos factores, entre los que destacan el nivel nutritivo y la etapa de crecimiento del animal. Se conoce por una parte, que la acción somatotropa requiere de un aporte suficiente de nutrientes en la dieta y por otra, que sus efectos son mínimos entre la segunda y tercera semana de crecimiento postnatal, aumentando su eficacia entre los 31 días de vida y la pubertad. Aunque no se conoce la causa de esta refractoriedad al tratamiento con GH en estas primeras etapas de la vida, podría estar relacionada con la respuesta bifásica a la GH, desarrollada en ratones BALB/c machos rhGH-tratados entre los 21 y 50 días de vida y alimentados con dos concentraciones de proteína en la dieta (12 y 20%). La hipofagia GHinducida entre los 21 y 30 días de vida es la causa primordial del estado de subnutrición que aparece en estos animales y que da lugar a la detención del crecimiento por falta de sustratos, eliminando la acción anabólica de la hormona. Posteriormente, el incremento autorregulado de la ingesta favorece la recuperación del crecimiento entre los 35 y 50 días de vida, periodo en el que se desarrolla un crecimiento de carácter compensador, caracterizado por un acúmulo excesivo de la masa grasa, similar al determinado por el crecimiento que sigue a la realimentación después de malnutrición, lo que puede coexistir con un estado de resistencia del tejido adiposo a la GH. Sin embargo el efecto anabólico de la somatotropa parece manifestarse, en los animales bien nutridos, por un mayor depósito de la proteína muscular al incrementar la tasa fraccional de síntesis proteica, que permite la aparición de un fenómeno de hipertrofia compensadora. Por lo tanto, la administración de rhGH en el momento del destete parece interferir con los delicados mecanismos de adaptación a la alimentación sólida característicos de este periodo, e inducir el cese del crecimiento entre los 21 y 30 días, generando más tarde un crecimiento de carácter compensador que se inicia a partir de los 35 días de vida

Implementación de un sistema b-learning en la enseñanza práctica de Fisiopatología

Fac. de FarmaciaFALSEsubmitte

Impacto de la implementación del aprendizaje basado en problemas en combinación con las prácticas de laboratorio clínico y virtual de Fisiopatología para el desarrollo de competencias profesionales

Sección Deptal. de Fisiología (Farmacia)Fac. de FarmaciaFALSEsubmitte

Adaptación a un entorno semipresencial de una nueva herramienta mixta del aprendizaje basado en problemas en combinación con las prácticas de laboratorio clínico a la nueva asignatura Bases Anatómicas y Fisiología del Cuerpo Humano

Sección Deptal. de Fisiología (Farmacia)Fac. de FarmaciaFALSEsubmitte

Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors.

Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR

Analogues of cannabinoids as multitarget drugs in the treatment of Alzheimer’s disease

Given that neuronal degeneration in Alzheimer's disease (AD) is caused by the combination of multiple neurotoxic insults, current directions in the research of novel therapies to treat this disease attempts to design multitarget strategies that could be more effective than the simply use of acetylcholinesterase inhibitors; currently, the most used therapy for AD. One option, explored recently, is the synthesis of new analogues of cannabinoids that could competitively inhibit the acetylcholinesterase (AChE) enzyme and showing the classic neuroprotective profile of cannabinoid compounds. In this work, molecular docking has been used to design some cannabinoid analogues with such multitarget properties, based on the similarities of donepezil and Δ9-tetrahydrocannabinol. The analogues synthesized, compounds 1 and 2, demonstrated to have two interesting characteristics in different in vitro assays: competitive inhibition of AChE and competitive antagonism at the CB1/CB2 receptors. They are highly lipophilic, highlighting that they could easily reach the CNS, and apparently presented a low toxicity. These results open the door to the synthesis of new compounds for a more effective treatment of AD.Ministerio de Ciencia, Innovación y Universidades (España)Depto. de Química en Ciencias FarmacéuticasFac. de FarmaciaTRUEpu