The role of sympathetic activation - α1 adrenergic receptor axis in diabetes-related cardiac vagal neuronal and myocardial dysfunction

Cardiovascular disease is the leading cause of death in type 2 diabetes mellitus (T2DM). T2DM affects cardiac vagal and sympathetic nerve function, leading to sympathetic predominance and vagal activity withdrawal. This increases the risk of silent myocardial death, heart failure, and sudden death. We hypothesized that sympathetic activation via the α1-adrenergic receptor axis reduces cardiac vagal function in T2DM. We induced T2DM in male and female Sprague Dawley rats using a high-fat diet for 12 weeks plus a one-time intraperitoneal injection of streptozocin (30 milligrams/kilogram). We measured cardiac vagal function using whole-cell patch-clamp. T2DM exhibited decreased nAChR currents (213.9 ± 25.6 pA/pF for T2DM, 375.5 ± 44.3 pA/pF for sham) and cell excitability (9.1 ± 0.5 spikes/s for T2DM, 19.9 ± 1.4 spikes/s for sham) of intracardiac (ICG) vagal neurons. We measured cardiomyocyte size using hematoxylin-eosin staining and cardiac function using echocardiography. We also measured mRNA expression of the cardiac hypertrophy marker atrial natriuretic peptide (ANP) by real-time polymerase chain reaction (RT-PCR). T2DM induced cardiac hypertrophy and diastolic dysfunction with preserved ejection fraction and increased ANP levels compared with sham (10.1 ± 2.4 for T2DM, 1.1 ± 0.2 for sham). We determined the mRNA and protein expression of α1 adrenergic receptors in the ICG of sham and T2DM by RT-PCR and western blot. We found that T2DM increased mRNA (2 ± 0.1 for T2DM vs. 1.1 ± 0.3 for sham) and protein expression (0.3 ± 0.06 for T2DM vs. 0.1± 0.04 for sham) of α1-adrenergic receptors in the ICG. Our findings revealed that elevated levels of α1-adrenergic receptors in the ICG of T2DM are associated with cardiac vagal neuronal and myocardial dysfunction. In future experiments, we will downregulate α1-adrenergic receptors via the transfection of α1-adrenergic receptor shRNA into the ICG of T2DM rats to improve cardiac vagal activity and cardiac function, aiming to establish a potential therapeutic target. This study was supported by NIH R01HL168500 to Yu-Long Li. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.