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

Abstract

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.

Sarco/endoplasmic reticulum calcium ATPase activity is unchanged despite increased myofilament calcium sensitivity in Zucker type 2 diabetic fatty rat heart

“…Non-fasting blood glucose was higher in the diabetic versus non-diabetic rats (30.6 ± 0.9 mmol/L vs. 11.9 ± 0.5 mmol/L, respectively, P < 0.0001), confirming their diabetic status, as previously reported 3 , 27 . However, body weight was not different between the diabetic and non-diabetic rats (403.0 ± 17.3 g vs. 395.4 ± 15.2 g, respectively, P = 0.75).…”

“…Diabetes impairs heart function 1 , and is associated with increased rates of heart failure 2 . Our group 3 – 5 and others 6 , 7 have found that contractility is impaired in type 2 diabetic hearts, in advance of heart failure development. Decades of research has suggested that abnormal calcium (Ca 2+ ) flux impairs cardiac contractility and relaxation in the type 2 diabetic heart 8 , 9 .…”

“…In both type 1 and type 2 diabetic animal models, myofilament Ca 2+ sensitivity of cardiomyocytes has been reported as unaltered 6 , 24 , increased 25 or decreased 26 . The obese Zucker diabetic fatty (ZDF) rat is a type 2 diabetic model with well-established cardiac inotropic and lusitropic dysfunction 3 , 6 , 27 . Our group recently found that myofilament Ca 2+ sensitivity was increased in 20-week-old type 2 diabetic ZDF rat cardiomyocytes, and this was associated with reduced phosphorylation of cTnI at Ser23/24 28 .…”

Effects of obesity and diabesity on heart rhythm in the Zucker rat

“…Intrinsic defects in the electrical conduction system of the heart may also be involved in the changed HR in ZDF rats. Previous isolated perfused heart studies have demonstrated a reduction in basal HR in the ZDF rat 43,44,54 . Experiments in the authors laboratory have also demonstrated reduced HR in ZDF (100 ± 5 BPM, n = 16) and ZF (135 ± 15 BPM, n = 12) compared to ZL controls (176 ± 11 BPM, n = 11) in the isolated perfused spontaneously beating heart (unpublished data).…”

Mechanisms underlying electro-mechanical dysfunction in the Zucker diabetic fatty rat heart: a model of obesity and type 2 diabetes

“…In summary, β1-adrenoceptors are the main subtype regulating heart rate, contraction, and relaxation which in turn regulate chronotropic, inotropic, and lusitropic β-AR responses in the healthy heart and the T2DM heart. Moreover, the β2-AR subtype indirectly supports the β1-AR functional response in the diabetic heart [66].…”