β2 -Adrenoceptors indirectly support impaired β1 -adrenoceptor responsiveness in the isolated type 2 diabetic rat heart.

Abstract

What is the central question of this study? Are there specific contributions of β1 - and β2 -adrenoceptor subtypes to the impaired β-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the β1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the β2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. Impaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β1 - and β2 -AR subtypes to β-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific β1 - and β2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the β-AR agonist isoprenaline (1×10-11 to 3×10-8 moll-1 ) with or without the selective β1 -AR antagonist CGP20712A (3×10-8 moll-1 ) or the β2 -AR antagonist ICI-118,551 (5×10-8 moll-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216±17beatsmin-1 versus diabetic 151±23beatsmin-1 , P<0.05). However, the β-AR-induced increase in HR was similar and was completely blocked by the β1 -AR antagonist, but not by the β2 -AR antagonist. The β-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the β1 -AR antagonist and partly impaired by the β2 -AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non-diabetic 1.62±0.19a.u. versus diabetic 2.30±0.25a.u., P<0.05). In conclusion, the β1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic β-AR responses in the healthy heart and the type2 diabetic heart. The β2 -AR subtype indirectly supports the β1 -AR functional response in the diabetic heart. This suggests that β2 -ARs could be an indirect target to improve the function of the heart in type 2 diabetes.