Chronic ritodrine treatment induces refractoriness of glucose-lowering β2 adrenoceptor signal in female mice

Adverse events in tocolytic therapy with β2-adrenergic agents compromise cardiovascular and non-cardiovascular functions, including blood glucose regulation and liver function. Here, we have examined the effects of the β2 agonist ritodrine on glucose metabolism and liver injury in mice. Under fasting conditions, ritodrine significantly increased serum insulin levels and decreased glucose concentrations. This contrasts with the β2 agonist-induced hyperglycemia observed in previous studies on humans and other animals. After 14 days of ritodrine treatment, the mice showed a decrease in the total mass of epididymal fat pads, whereas their body weights increased significantly. Chronic ritodrine treatment attenuated the glucose-lowering effect observed during acute administration. Ritodrine also significantly increased serum levels of liver enzymes, which returned to control levels after 14 days of treatment. Thus, ritodrine responsiveness changes between acute and chronic treatment, indicating that close monitoring of blood glucose and serum liver enzymes is necessary in patients with reduced glucose tolerance. The findings reported here of glucose homeostasis in mice provide a unique opportunity to understand refractoriness of β2-adrenoceptor signaling in response to β2 agonists during the course of treatment.

► Ritodrine increased serum insulin levels and decreased serum glucose concentrations.
► Ritodrine-induced liver injuring model was established.
► Chronic ritodrine administration significantly increased total body weight.
► The glucose-lowering effect was attenuated after repeated ritodrine injections.