Impaired regulation of heart rate and sinoatrial node function by the parasympathetic nervous system in type 2 diabetic mice

Abstract

Heart rate (HR) and sinoatrial node (SAN) function are modulated by the autonomic nervous system. HR regulation by the parasympathetic nervous system (PNS) is impaired in diabetes mellitus (DM), which is denoted cardiovascular autonomic neuropathy. Whether blunted PNS effects on HR in type 2 DM are related to impaired responsiveness of the SAN to PNS agonists is unknown. This was investigated in type 2 diabetic db/db mice in vivo and in isolated SAN myocytes. The PNS agonist carbachol (CCh) had a smaller inhibitory effect on HR, while HR recovery time after CCh removal was accelerated in db/db mice. In isolated SAN myocytes CCh reduced spontaneous action potential firing frequency but this effect was reduced in db/db mice due to blunted effects on diastolic depolarization slope and maximum diastolic potential. Impaired effects of CCh occurred due to enhanced desensitization of the acetylcholine-activated K+ current (IKACh) and faster IKACh deactivation. IKACh alterations were reversed by inhibition of regulator of G-protein signaling 4 (RGS4) and by the phospholipid PIP3. SAN expression of RGS4 was increased in db/db mice. Impaired PNS regulation of HR in db/db mice occurs due to reduced responsiveness of SAN myocytes to PNS agonists in association with enhanced RGS4 activity.

Structural and Electrical Remodeling of the Sinoatrial Node in Diabetes: New Dimensions and Perspectives

“…CCh showed an attenuated effect on slowing the spontaneous AP firing which was associated with a smaller decrease in the slope of diastolic depolarization and a reduced hyperpolarization of the MDP. CCh did not produce significant hyperpolarization in SAN cardiomyocytes isolated from male and female db/db mice ( 58 ). The results of this study provided some evidence for cellular and molecular mechanisms that might lead to the attenuated regulation of PNS on HR in T2DM ( 58 ).…”

“…CCh did not produce significant hyperpolarization in SAN cardiomyocytes isolated from male and female db/db mice ( 58 ). The results of this study provided some evidence for cellular and molecular mechanisms that might lead to the attenuated regulation of PNS on HR in T2DM ( 58 ). The acetylcholine-activated K + current ( I KACh ) becomes desensitized and its amplitude diminishes in the presence of an M2R agonist such as CCh ( 80 – 82 ).…”

“…One of the most important determinants of cardiac function and performance is the HR, which is modulated by the intrinsic rhythmical firing of the SAN. DM is associated with significant cardiovascular complications and neuropathies ( 57 , 58 ). The regulation of HR by the ANS has been shown to be impaired in diabetic patients ( 59 , 60 ).…”

“…The ionic currents include the hyperpolarization-activated current or funny current ( I f ), and a rapidly activating delayed rectifier K + currents ( I Kr ) generated by ether-a-go-go (ERG) channels ( 7 , 28 , 79 ). The PNS reduces HR by activation of inhibitory G proteins associated with M2R and attenuating spontaneous firing of AP in SAN myocytes ( 58 ). While the primary pacemaker activity of the SAN is spontaneously generated, the rate of this activity and, therefore the HR, can be modified by factors such as ANS, hormones and neurotransmitters, medications, ions, hypoxia, as well as disease states.…”

“…In a recent study, Liu et al. ( 58 ) examined the effects of carbachol (CCh) on HR and SAN function in isolated SAN cardiomyocytes of male and female db/db mice, an animal model exhibiting features of T2DM. CCh showed an attenuated effect on slowing the spontaneous AP firing which was associated with a smaller decrease in the slope of diastolic depolarization and a reduced hyperpolarization of the MDP.…”