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

New findings: 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.

Abstract: 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 mol l^-1 ) with or without the selective β₁ -AR antagonist CGP20712A (3 × 10^-8 mol l^-1 ) or the β₂ -AR antagonist ICI-118,551 (5 × 10^-8 mol l^-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216 ± 17 beats min^-1 versus diabetic 151 ± 23 beats min^-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 ± 0.19 a.u. versus diabetic 2.30 ± 0.25 a.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 type 2 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.