β 2 -adrenoceptors indirectly support impaired β 1 -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 indirectly support function in the diabetic heart.

ABSTRACT: Impaired β-adrenoceptor (β-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, however 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 isoproterenol (1 × 10-11 -3 × 10-8  mol L-1 ) with or without selective β1 -AR antagonist CGP20712A (3 × 10-8  mol L-1 ) or 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 vs. diabetic 151 ± 23 bpm, 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 β1 -AR antagonist, and partially impaired by 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 vs. diabetic 2.30 ± 0.25 arbitrary units, p < 0.05). In conclusion, the β1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic β-AR responses in the healthy, as well as the type 2 diabetic, heart. The β2 -AR subtype indirectly, supports the β1 -AR functional response in the diabetic heart. This suggests β2 -ARs could be an indirect target to improve the function of the heart under type 2 diabetic conditions. This article is protected by copyright. All rights reserved.