Journal
EXPERIMENTAL PHYSIOLOGY
Volume 104, Issue 6, Pages 808-818Publisher
WILEY
DOI: 10.1113/EP087437
Keywords
Cardiac; beta-adrenoceptors; cardiac function; heart rate; type 2 diabetes
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Funding
- HealthCare Otago Charitable Trust [09335]
- New Zealand National Heart Foundation [1491]
- Otago Medical Research Foundation (Laurenson Award) [LA306]
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Impaired beta-adrenoceptor (beta-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of beta(1)- and beta(2)-AR subtypes to beta-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific beta(1)- and beta(2)-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 beta-AR agonist isoprenaline (1 x 10(-11) to 3 x 10(-8) mol l(-1)) with or without the selective beta(1)-AR antagonist CGP20712A (3 x 10(-8) mol l(-1)) or the beta(2)-AR antagonist ICI-118,551 (5 x 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 beta-AR-induced increase in HR was similar and was completely blocked by the beta(1)-AR antagonist, but not by the beta(2)-AR antagonist. The beta-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the beta(1)-AR antagonist and partly impaired by the beta(2)-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 beta(1)-AR is the main subtype regulating chronotropic, inotropic and lusitropic beta-AR responses in the healthy heart and the type 2 diabetic heart. The beta(2)-AR subtype indirectly supports the beta(1)-AR functional response in the diabetic heart. This suggests that beta(2)-ARs could be an indirect target to improve the function of the heart in type 2 diabetes.
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