β₁‐Adrenoceptor, but not β₂‐adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo

Abstract

Edited by: Marc Kaufman New Findings r 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. r What is the main finding and its importance?Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β 1 -adrenoceptor subtype, and not the β 2 -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 β 1 -and β 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 (β 1 -and β 2 -adrenoceptor agonist, 0.1-300 μg kg −1 ) in the presence of atenolol (β 1 -adrenoceptor antagonist, 2000 μg kg −1 ) or nadolol (β 1 -and β 2 -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 β 1 -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 β 1 -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.

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

“…The ZDF fa/fa rats had higher blood glucose concentrations and body weights than their ZDF +/+ and ZDF +/− littermates (Table ), confirming their type 2 diabetes and obese status, as previously shown (Bussey, de Leeuw, & Lamberts, ; Cook et al., ; Thaung et al., ). Heart weight, tibia length and their ratio were not different between groups.…”

“…The present study also found no difference in the β 1 ‐AR chronotropic responsiveness in the denervated isolated type 2 diabetic rat heart compared with non‐diabetics, which is in line with assessment of non‐specific β‐AR chronotropic responsiveness in previous studies (Thaung et al., ). Importantly, these results provide new evidence that the increased β 1 ‐AR chronotropic responsiveness in vivo in ZDF rats (Cook et al., ) does not reside within the heart, but must be the result of systemic non‐cardiac adaptations. As suggested previously by Cook et al.…”

“…As suggested previously by Cook et al. (), this could include changes in autonomic axo‐axonal synapses (Hasan, ), reorganization of sinoatrial heterogeneity at the neuromyocardial interface (Giles, ) or altered compartmentalization of cAMP and phosphodiesterases (Logue & Scott, ). The denervated isolated heart experiments also showed that the reduced intrinsic HR, observed in diabetic rodent models (Thaung et al., ), was not affected by specific blockade of the β 1 ‐ or β 2 ‐AR subtypes.…”

Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

“…Given that we recently showed in Zucker diabetic fatty rats that only the β 1 ‐AR subtype was directly responsible for the contractile responses (Cook et al., ), we only confirmed the reduced expression of the β 1 ‐AR subtype. This, however, does not exclude the possibility that other β‐AR subtypes could be affected during obesity (Chatelain et al., ; Jiang et al., ; Strassheim et al., ) or play an important supportive role in the pathophysiology of obesity and diabetes (Cook et al., ; Li et al., ; Perez‐Schindler et al., ). More importantly, given that from a clinical viewpoint targeting β‐ARs with β‐blockers is commonly advised against in obese individuals owing to their unfavourable metabolic effects (Gress et al., ; Sharma et al., ) and given that β‐AR downregulation is most probably not the sole mechanism underlying the reduced β‐adrenergic responsiveness of the heart in obesity (Ferron et al., ; Vileigas et al., ), alternative mechanisms should be explored.…”

“…Higher levels of muscle (Agapitov, Correia, Sinkey, & Haynes, ; Huggett et al., ) and cardiac (Thaung, Baldi et al., ) sympathetic nerve activity indicate a systemic sympathetic overdrive, but importantly, increased sympathetic input directly to the heart. Consequently, several studies have demonstrated decreased β‐adrenoceptor (β‐AR) expression in, and reduced β‐AR responsiveness of, the heart in obesity (Bass & Ritter, ; Bunag, Tomita, & Krizsan, ; Chatelain et al., ; Jiang et al., ; Sherwood, Hill, Blumenthal, Johnson, & Hinderliter, ; Strassheim, Houslay, & Milligan, ), with similar reports in diabetes (Cook, Bussey, Mellor, Cragg, & Lamberts, ; Dincer et al., ; Dincer, Onay, Ari, Ozcelikay, & Altan, ; Lamberts et al., ; Thaung, Baldi et al., ).…”