Abstract
beta-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 beta(1)- and beta(2)-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 (beta(1)- and beta(2)-adrenoceptor agonist, 0.1-300 mu g kg(-1)) in the presence of atenolol (beta(1)-adrenoceptor antagonist, 2000 mu g kg(-1)) or nadolol (beta(1)- and beta(2)-adrenoceptor agonist, 4000 mu g kg(-1)) to determine the chronotropic contributions of the beta-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 +/- 62 versus 290 +/- 37beatsmin(-1) non-diabetic versus diabetic, P<0.05, mean +/- SD), which remained after atenolol or nadolol administration. Overall beta-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 +/- 66 versus 205 +/- 28beatsmin(-1), non-diabetic versus diabetic, P<0.05), a difference that diminished after beta(1)-adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 +/- 37 versus 195 +/- 22beatsmin(-1), non-diabetic versus diabetic, P<0.05). In conclusion, the beta(1)-adrenoceptor is the main subtype to modulate chronotropic beta-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.