Efecto inotrópico y cronotrópico del propranolol sobre aurículas extraídas de ratas con insulina-resistencia inducida por fructosa / Inotropic and chronotropic effects of propranolol in isolated atrium of rats with fructose-induced insulin-resistance

La insulina-resistencia (IR) es una deficiencia metabólica asociada princi palmente con diabetes tipo 2 y comúnmente relacionada a la etiopatogenia de enfermedades cardiovasculares, siendo el factor determinante del síndrome metabólico. La investigación pretende conocer los efectos cronotrópico e inotrópico del propranolol sobre aurículas de ratas IR. Para ello, 16 ejemplares Sprague-Dawley, fueron divididos en Grupo control, alimentado ad libitum con alimento para perros Perrarina® y Grupo experimental, alimentado con Perrarina®-manteca vegetal, y suministro de agua con fructosa (20%)-sacarosa (20%) durante ocho meses. Al finalizar este periodo, se verificó la insulina-resistencia y las aurículas extraídas se mantuvieron en solución Krebs (37ºC, pH 7,4; 95% O2 - 5% CO2), en baño de órganos aislados marca Letica®, conectado a un polígrafo Grass®, registrándose la frecuencia de los latidos y evaluando las diferencias a través de la prueba t de Student (grado de significancia p<0,05). Se establecieron curvas dosis-respuesta acumulativas con isoproterenol y previa incubación de 15 minutos con propranolol (1x10 -6 M), registrándose un efecto cronotrópico negativo en el grupo control mas no así en las ratas IR, estableciéndose diferencias significativas entre el porcentaje de incremento de los latidos/seg en ambos grupos (Control 58,81±4,08; IR 68,84±4,16; p<0,001). La máxima fuerza de contracción auricular alcanzada por el grupo IR con propranolol (278,47±11,22), generó diferencias significativas (p<0,001), en comparación con el grupo control (42,60±3,13), evidenciándose que el propranolol no generó bloqueo sobre los receptores beta-adrenérgicos auriculares de las ratas insulina-resistentes.

Insulin resistance (IR) is a metabolic deficiency associated with type 2 diabe tes and commonly related to the pathogenesis of cardiovascular diseases, being the determining factor of the metabolic syndrome. This research aims to understand the chronotropic and inotropic effects of Propranolol in isolated atrium of rats with fructose-induced insulin-resistance. For this reason, 16 male Sprague-Dawley rats were assigned to two groups and given ad libitum access to one of the following diets: Perrarina® dog chow or Perrarina® dog chow supplemen ted with vegetable shortening and with fructose (20%) and sucrose (20%) added to the water supply. Both groups were maintained on their respective dietary regimens for eight months. At the end of this period insulin resistance was verified by routine blood test. The rat hearts were rapidly removed, and the atria were dissected and kept in Krebs solutions (37ºC, pH 7.4; 95% O2 - 5% CO2) in an isolated organ bath Letica®, connected to a polygraph Grass®, registering atria frequency. The Student ́s t-test was used to evaluate statistical differences between the two groups (p<0.05). Cumulative dose-response curves with isoproterenol were established in basal condition, and after fifteen minutes of pre-incubation with propranolol (1x10 -6 M). A significant positive chronotropic effect was observed in IR rats (8.84±4.16 vs 58.81±4.08 beats/sec of control; p<0.001). The maximum force of atrial contraction after pre-incubation with propranolol was significantly higher in the IR group (278.47±11.22 atrial contraction percentage; p<0.001). These findings suggest that a blunted response of atrial β-adrenoceptor to propranolol exists in rats with fructose-induced insulin-resistance.

Calcium modulatory properties of O,O-diphenyl O-N-cyclooctyl phosphoramidate [corrected] isolated from Ptychodiscus brevis in rat atria and smooth muscle.

Calcium modulatory activity of a marine toxin has been studied employing in vitro preparations. The toxin induced contracture in rat diaphragm was not modified by denervation, d-tubocurarine and tetrodotoxin (TTX). In contrast, varying concentrations of calcium, EGTA and ryanodine inhibited the contracture significantly. The toxin produced a series of repeating contractions in vas deferens. Experiments with TTX, adrenoceptor blockers and other agents exclude a release of neuromediators or direct stimulation of post synaptic receptors to account for the rhythmic effect in vas deferens. The dependence of rhythmicity on external Ca2+ concentration and inhibiting effect of Mn2+, ryanodine and nifedipine indicate a direct activation of voltage-sensitive calcium channel. The toxin also evoked a similar pattern of response in paced atria mediated through Ca2+ influx.

Calcium-antagonists, a comparative study on isolated guinea-pig atria and on liposomes

The effect of three well known calcium antagonists [verapamil, diltiazem and nifedipine] on the force of contraction of left guinea-pig atria and on the physicochemical properties of differently composed liposomes was investigated at three external calcium concentrations. The physicochemical properties of liposomes were assessed by the drug-induced change in the surface potential measured by laser Doppler electrophoresis. High calcium concentrations cause a shift in the calcium antagonist concentration-response curves performed in experiments on the force of contraction as well as on the membrane surface potential. The calcium induced shift was highest for verapamil and lowest for nifedipine. The same sequence was observed for the drug-induced surface potential change on liposomes; nifedipine, an uncharged molecule at physiological pH had no effect at all. The sequence of drug receptor affinities, however, was as follows: Nifedipine > verapamil > diltiazem. It may be concluded that charged molecules like verapamil and diltiazem exert their negative inotropic action via two mechanisms; namely, a calcium channel blockade and a change in the electrostatic potential of the membrane, while nifedipine acts only via its calcium blocking activity