Altered chronotropic regulation but normal cardiac sympathetic nerve activity in type 2 diabetic rat model

Abstract

Autonomic control of cardiac function is impaired in diabetes mellitus, contributing to heart disease and premature death. Specifically, global elevated sympathetic nerve activity (SNA) coupled with dysregulated post-receptor β-adrenergic signaling pathways have been presented as major driving force for cardiac dysfunction and subsequent heart disease in diabetes. However sympathetic outputs to various organs are differentially regulated depending on the specific requirements of the individual organ. Therefore, a global increase in SNA cannot be translated to increased sympathetic drive to the heart per se. The present Masters project aimed to firstly, quantify resting cardiac SNA, and secondly, determine baroreflex control of heart rate and cardiac SNA in the Zucker Diabetic Fatty (ZDF) rats. To discriminate between cardiac and systemic effects, cardiac responsiveness to β-adrenoceptor agonist in isolated hearts of ZDF rats was also determined. An anaesthetised preparation was used to investigate SNA in the diabetic and non- diabetic ZDF rat. Sympathetic nerve activity in vivo was obtained via direct recording of the left cardiac sympathetic branch of the stellate ganglion. Diabetic rats showed normal resting cardiac SNA relative to the non-diabetic control (1.98 ± 0.25 and 1.56 ± 0.18 μV.s, p > 0.05, respectively). In vivo resting cardiac and haemodynamic function was preserved in diabetes. Baroreflex control of heart rate but not cardiac SNA, tested using phenylephrine (50 μg/kg, bolus) and sodium nitroprusside (50 μg/kg, bolus), was impaired in diabetic ZDF rats in vivo. A fascinating finding was that the unpaced isolated hearts of diabetic rats had a significantly lower intrinsic resting heart rate compared to non-diabetic controls (145 ± 23 and 234 ± 13 bpm, p < 0.05, respectively). Myocardial chronotropic responsiveness to β-adrenergic agonist, dobutamine (1 × 10-9 to 1× 10-5 M) was increased with preserved inotropic responsiveness in isolated diabetic hearts. In conclusion, the diabetic ZDF rat had preserved resting sympathetic nerve input to the heart and resting cardiac function, however exposed an impaired baroreflex system in vivo. Isolated diabetic myocardium had attenuated intrinsic resting heart rate with increased chronotropic and preserved inotropic responsiveness to β-adrenergic stimulation ex vivo. Together, these data suggest that in our diabetic ZDF model the β-adrenergic system and its downstream signaling pathways remained functional in the diabetic myocardium in vivo. Therefore, altered chronotropic regulation could precede impairment of the SNS and cardiac function in type 2 diabetic rats. Future research is essential to further elucidate the role of SNS activity in cardiac dysfunction as well as β-adrenergic signaling pathways in diabetes.