Abstract
Background
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 β1- and β2-adrenoceptor subtype contributions to chronotropic responses in type 2 diabetes in vivo, which are currently unknown.
Methods
Type 2 diabetic and non-diabetic rats were implanted with radio-telemeters to measure arterial blood pressure and derive heart rate under conscious conditions. Vascular access ports were implanted to inject isoproterenol (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 β-adrenoceptor subtype chronotropic contributions.
Results
Resting heart rate was reduced in diabetic rats (388 ± 62 vs. 290 ± 37 bpm non-diabetic vs. diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall β-adrenoceptor chronotropic responsiveness was increased in diabetic rats (Δ heart rate at highest dose isoproterenol: 135 ± 66 vs. 205 ± 28 bpm, non-diabetic vs. diabetic, P < 0.05), a difference that diminished after β1-adrenoceptor blockade with atenolol (Δ heart rate at highest dose isoproterenol: 205 ± 37 vs. 195 ± 22 bpm, non-diabetic vs. diabetic, P < 0.05).
Conclusion
The β1-adrenoceptor is the main subtype to modulate chronotropic β-adrenoceptor responses in healthy, as well as diabetic rats. This study provides novel insights in the understanding of the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting the diabetic chronotropic incompetence.
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