RESUMEN
Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.
Asunto(s)
Fármacos Antiobesidad/farmacología , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Nitrilos/farmacología , Pirrolidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Animales , Depresores del Apetito/farmacología , Conducta Animal/efectos de los fármacos , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Calcio/metabolismo , Clonación Molecular , Diagnóstico por Imagen , Dieta , Grasas de la Dieta/farmacología , Fenfluramina/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imagen por Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Ensayo de Unión Radioligante , Ratas , Pérdida de Peso/efectos de los fármacosRESUMEN
PURPOSE: To evaluate the feasibility of using dynamic contrast-enhanced magnetic resonance imaging (MRI) for assessment of muscle perfusion in a rat model of hind-limb ischemia. MATERIALS AND METHODS: The acute alteration and chronic recovery in muscle perfusion and perfusion reserve after femoral artery ligation were quantified using the maximum Gd-DTPA uptake rate obtained by a T(1)-weighted gradient-recalled echo sequence. Radionuclide-labeled microsphere blood flow measurements were performed for comparison with the MR perfusion measurement on a separate set of animals. RESULTS: After femoral artery ligation, a significant reduction in resting muscle perfusion was only observed at 1 hour post-ligation during the 28-day follow-up period. Muscle perfusion reserve was severely diminished following the ligation. Despite significant recovery over time, perfusion reserve to the ligated limb reached only 63% of the perfusion capacity in the unaffected limb by 42 days post ligation. A strong correlation (r = 0.86) between MR perfusion and microsphere blood flow measurements was observed for evaluation of relative changes in muscle perfusion. CONCLUSION: Dynamic contrast-enhanced MRI with Gd-DTPA is useful to assess time-dependent changes in muscle perfusion and perfusion reserve in this hind-limb ischemia model.