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Diabetic patients often have impaired heart rate (HR) control. HR is regulated both intrinsically within the sinoatrial node (SAN) and via neuronal input. Previously, we found lower ex vivo HR in type 2 diabetic rat hearts, suggesting impaired HR generation within the SAN. The major driver of pacemaking within the SAN is the activity of hyperpolarisation-activated cyclic nucleotide-gated 4 (HCN(4)) channels. This study aimed to investigate whether the lower intrinsic HR in the type 2 diabetic heart is due to changes in HCN4 function, protein expression and/ or distribution. The intrinsic HR response to HCN4 blockade was determined in isolated Langendorff-perfused hearts of Zucker type 2 Diabetic Fatty (ZDF) rats (DM) and their non-diabetic ZDF littermates (nDM). HCN4 protein expression and membrane localisation were determined using western blot and immunofluorescence, respectively. We found that the intrinsic HR was lower in DM compared to nDM hearts. The change in intrinsic HR in response to HCN4 blockade with ivabradine was diminished in DM hearts, which normalised the intrinsic HR between the groups. HCN4 protein expression was decreased in the SAN of DM compared to nDM controls with no change in the fraction of HCN4 localised to the membrane of SAN cardiomyocytes. The lower intrinsic HR in DM is likely due to decreased HCN4 expression and depressed HCN4 function. Our study provides a novel understanding into the intrinsic mechanisms underlying altered HR control in type 2 diabetes. [ABSTRACT FROM AUTHOR]

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−1versus 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. [ABSTRACT FROM AUTHOR]

New Findings What is the central question of the study? The sympathetic system regulates heart rate via β-adrenoceptors; this is impaired during diabetes. However, the specific β-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β1-adrenoceptor subtype, and not the β2-adrenoceptor, regulated the lower resting heart rate and increased β-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of β1- and β2-adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (β1- and β2-adrenoceptor agonist, 0.1–300 μg kg−1) in the presence of atenolol (β1-adrenoceptor antagonist, 2000 μg kg−1) or nadolol (β1- and β2-adrenoceptor agonist, 4000 μg kg−1) to determine the chronotropic contributions of the β-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min−1 non-diabetic versus diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall β-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 ± 66 versus 205 ± 28 beats min−1, non-diabetic versus diabetic, P < 0.05), a difference that diminished after β1-adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 ± 37 versus 195 ± 22 beats min−1, non-diabetic versus diabetic, P < 0.05). In conclusion, the β1-adrenoceptor is the main subtype to modulate chronotropic β-adrenoceptor responses in healthy and diabetic rats. This study provides new insights into the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting diabetic chronotropic incompetence. [ABSTRACT FROM AUTHOR]