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

• Published in: Experimental physiology Vol. 104; no. 6; pp. 808 - 818
• Main Authors: Cook, Rosalind F., Bussey, Carol T., Fomison‐Nurse, Ingrid C., Hughes, Gillian, Bahn, Andrew, Cragg, Patricia A., Lamberts, Regis R.
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01-06-2019
• Subjects: Adrenal glands; Adrenergic receptors; cardiac function; Cardiac β‐adrenoceptors; Contraction; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Energy metabolism; Heart; Heart rate; Phosphorylation; Physical growth; type 2 diabetes; Western blotting
• ISSN: 0958-0670; 1469-445X
• DOI: 10.1113/EP087437

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.
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.