Abstract

Diabetic hearts exhibit decreased responsiveness to stimulation by β-adrenoreceptor (β-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of β-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to β₁-AR agonist stimulation, but not to β₂-AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac β₁-, β₂-, and β₃-ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that β₁-AR mRNA and protein levels decreased by 34.9 ± 5.8 and 44.4 ± 5.8%, respectively, in 14 week-STZ-treated diabetic rat hearts when compared with age-matched controls. On the other hand, mRNA levels encoding β₂- and β₃-ARs increased by 72.5 ± 16.6 and 97.3 ± 26.1%, respectively. Although the latter translated into a proportional increase in β₃-AR protein levels (100.0 ± 17.0%), β₂-AR protein levels decreased to 82.6 ± 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored β₁-AR mRNA and protein levels to 60.1 ± 8.4 and 83.2 ± 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding β₂- and β₃-ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of β-AR agonists may be due to a decrease in β₁-AR and an increase β₃-AR expression.