Abstract 17779: Impaired Parasympathetic Nervous System Regulation of the Sinoatrial Node in Type 1 Diabetes Mellitus
Diabetes mellitus is associated with a reduced ability of the autonomic nervous system to regulate heart rate which is determined by the spontaneous activity of the sinoatrial node (SAN). The effects of parasympathetic nervous system (PNS) activation on the SAN in diabetes are not well understood; therefore, we measured the effects of carbachol (CCh; PNS agonist) on SAN electrophysiology using high resolution optical mapping of the SAN and patch-clamping of isolated SAN myocytes in wildtype (WT) and type 1 diabetic Akita mice. In WT mice CCh (100 nM) increased the cycle length of spontaneously active atrial preparations from 137.4±4.3 to 429.6±31.2 ms (P<0.05; n=9 hearts). This occurred in conjunction with an inferior shift in the leading pacemaker site in the right atrial posterior wall and a slowing of SAN conduction velocity from 10.7±0.9 to 3.9±0.5 cm/s (P<0.05). In Akita mice the effects of CCh were significantly (P<0.05) impaired whereby cycle length of atrial preparations was only increased from 140±4.8 to 311.1±16.1 ms (P<0.05; n=9 hearts) and SAN conduction velocity was only reduced from 8.3±0.4 to 5.7±0.1 cm/s (P<0.05). In isolated SAN myocytes CCh (100 nM) reduced (P<0.05; n=6 myocytes) spontaneous action potential (AP) frequency in WT mice from 178±11 to 96±19 APs/min in association with a hyperpolarization of the maximum diastolic potential (MDP; -67.1±0.7 to -71.9±1.2 mV) and a reduction in the slope of the diastolic depolarization (DD slope; 40.3±3.4 to 14±3.7 mV/s). In contrast, CCh only slowed (P<0.05; n= 6 myocytes) AP frequency in Akita SAN myocytes from 164±13 to 146±11 APs/min in association with less MDP hyperpolarization (-67.3±1 to -69.2±1.2 mV) and a smaller reduction in DD slope (34.9±3.3 to 26.8±2.9 mV/s). The density of the acetylcholine activated K+ current (IKACh) activated by CCh was reduced (P<0.05) in Akita SAN myocytes (-9.1± 1.1 pA/pF at -100 mV) compared to WT (-7.2±0.8 pA/pF) in association enhanced IKACh desensitization (42.4±3.6 vs. 15.7±2.7%; P<0.05) and faster recovery during CCh washoff (61.6±5.6 vs. 78.2±4.3 ms; P<0.05) in Akita myocytes. These data demonstrate that the effects of CCh on the SAN are impaired in Akita mice and provide novel insight into the mechanisms of impaired PNS regulation of the SAN in diabetes.
- © 2013 by American Heart Association, Inc.