ß1 -Adrenoceptor, but not ß2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo.

ABSTRACT

NEW FINDINGS: What is the central question of the study? The sympathetic system regulates heart rate via ß-adrenoceptors; this is impaired during diabetes. However, the specific ß-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 ß1 -adrenoceptor subtype, and not the ß2 -adrenoceptor, regulated the lower resting heart rate and increased ß-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. ß-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 ß1 - and ß2 -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 (ß1 - and ß2 -adrenoceptor agonist, 0.1-300 µg kg-1 ) in the presence of atenolol (ß1 -adrenoceptor antagonist, 2000 µg kg-1 ) or nadolol (ß1 - and ß2 -adrenoceptor agonist, 4000 µg kg-1 ) to determine the chronotropic contributions of the ß-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 ß-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 ß1 -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 ß1 -adrenoceptor is the main subtype to modulate chronotropic ß-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.