Rationale In type I diabetes mellitus (T1DM) there is increased risk of bradyarrhythmias as a result of dysfunction of the sinoatrial-node/the primary pacemaker of the heart. We showed that streptozocin (STZ)- induced T1DM rats had decreased in-vivo heart rate (1). The aim of this study was to investigate the cellular basis of T1DM on the sinoatrial-node using the STZ rat model.
Methods Diabetes was induced with STZ in male Wistar rats as previously described (1). Extracellular potential and whole cell patch clamp recordings were used. Protein expression was investigated using immunohistochemistry. The research was conducted in accordance with the Guide for the Care and Use for Laboratory Animals in UAE and UK.
Results Compared to controls, diabetic rats showed higher heart-to-body weight ratio (16%) and blood glucose (428%) (n = 32, P < 0.05) and ex-vivo beating rate of the sinoatrial-node preparation was reduced by 17% (n = 4, 305 vs 252 bpm, P < 0.05). Application of ryanodine (2 µM, n = 3 preparations) caused irregular beats/arrhythmias. Funny/pacemaker current was measured in isolated nodal cells from diabetic rats (33 cells, n = 3 rats). The current density was (14.28 ± 1.18 pA/pF). Immunolabelling showed that HCN4 channel (responsible for funny current, involved in membrane clock) expression was increased, whereas RyR2 (Ca2+−release channel involved in Ca2+−clock) expression was decreased in diabetic sinoatrial-node compared to controls (173% and 34%, respectively). Down-regulation of RyR2 expression suggests Ca2+−clock is responsible for the lower heart rate. Up-regulation of HCN4 could be a compensatory mechanism.
Conclusion Complex interplay between membrane currents and Ca2+-clock signalling may increase risk of bradyarrhythmia.
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