The role of sorbitol pathway and treatment effect of aldose reductase inhibitor ONO2235 in the up-regulation of cardiac M2-muscarinic receptors in streptozotocin-induced diabetic rats

This study investigated the role of the sorbitol pathway on the genetic up-regulation of the cardiac M(2) muscarinic receptor (M(2)-mAChR) in streptozotocin (STZ)-induced diabetic rats. Three-month-old male Wistar rats were divided into five groups: (1) normal controls; (2) rats rendered diabetic by streptozotocin; (3) rats fed with glucose; (4) rats injected with sorbitol; and (5) diabetic rats treated with ONO-2235, an aldose reductase inhibitor. The M(2) muscarinic receptor (M(2)-mAChR) protein and mRNA densities of the heart tissue were measured by Western immunoblotting and Northern blotting, respectively. The densities of M(2)-mAChR protein and mRNA in the heart were significantly increased in diabetic rats, and rats given either glucose or sorbitol. When diabetic rats were treated with ONO-2235, the increases in heart M(2)-mAChR protein and mRNA were significantly reduced. The findings suggest that hyperglycemia and the sorbitol pathway are involved in the pathogenesis of diabetic heart disease in STZ-induced diabetic rats. Aldose reductase inhibitors may be useful in the treatment and prevention of cardiac complication in diabetes.