Characterization of L-type calcium channel activity in atrioventricular nodal myocytes from rats with streptozotocin-induced Diabetes mellitus

Abstract

Cardiovascular complications are common in patients with Diabetes mellitus (DM). In addition to changes in cardiac muscle inotropy, electrical abnormalities are also commonly observed in these patients. We have previously shown that spontaneous cellular electrical activity is altered in atrioventricular nodal (AVN) myocytes, isolated from the streptozotocin (STZ) rat model of type-1 DM. In this study, utilizing the same model, we have characterized the changes in L-type calcium channel activity in single AVN myocytes. Ionic currents were recorded from AVN myocytes isolated from the hearts of control rats and from those with STZ-induced diabetes. Patch-clamp recordings were used to assess the changes in cellular electrical activity in individual myocytes. Type-1 DM significantly altered the cellular characteristics of L-type calcium current. A reduction in peak ICaL density was observed, with no corresponding changes in the activation parameters of the current. L-type calcium channel current also exhibited faster time-dependent inactivation in AVN myocytes from diabetic rats. A negative shift in the voltage dependence of inactivation was also evident, and a slowing of restitution parameters. These findings demonstrate that experimentally induced type-1 DM significantly alters AVN L-type calcium channel cellular electrophysiology. These changes in ion channel activity may contribute to the abnormalities in cardiac electrical function that are associated with high mortality levels in patients with DM.

Altered profile of mRNA expression in atrioventricular node of streptozotocin-induced diabetic rats

“…Impaired Ca 2+ homeostasis, due to depressed SR Ca 2+ ATPase and NCX activity and NCX current have been demonstrated in ventricular myocytes from STZ-induced diabetic heart ( 6 , 42 , 43 ). The functional importance of NCX current in rabbit and mouse AVN cells has been demonstrated and depressed L-type Ca 2+ current has been reported in AVN cells from STZ rat heart ( 32 , 33 , 44 – 46 ). Upregulation of Slc8a1 mRNA and NCX1 protein in the AVN from STZ heart may provide a compensatory pathway to facilitate Ca 2+ influx and/or Ca 2+ efflux from the cell which may be required for the generation and recovery of action potentials in AVN cells.…”

“…TRPC1 is also expressed in mouse SAN and in single pacemaker cells and mouse SAN may exhibit store-operated Ca 2+ channel (SOCC) activity which may suggest that SOCCs are involved in regulating pacemaker firing rate ( 52 ). Upregulation of Trpc1 may be a consequence of hemodynamic disturbances in the diabetic heart which in turn stimulates mechano-sensitive TRPC channels thereby providing an alternative entry pathway for Ca 2+ in the face of depressed L-type Ca 2+ current in AVN cells and reduced heart rate in STZ-induced diabetic heart ( 32 , 33 ). Previous studies have reported elevation of mean arterial pressure in STZ-induced diabetic rats which may in turn lead to hypertrophy of the heart which would be consistent with the increase in heart weight to body weight ratio, which in turn might elicit an effect on the mechano-sensitive channels ( 53 ).…”

“…It was also interesting to note upregulation of Casq2 , an SR Ca 2+ binding protein, in AVN from STZ rat. Upregulation of Ryr2 may facilitate release of Ca 2+ from the SR which in turn might compensate for depressed L-type Ca 2+ current in AVN from STZ compared to control heart ( 32 , 33 ).…”

“…Previous studies have demonstrated increased action potential duration associated with a reduced action potential firing rate that is associated with reductions in L-type calcium current, delayed rectifier and hyperpolarization-activated currents in AVN cells from STZ-induced diabetic rat ( 32 , 33 ). Modification of ion channel properties either by altered trafficking and expression, or post-translational modification of channel gating properties, can therefore have a significant impact on AVN function, and result in clinical AVN abnormalities.…”

“…Slowing of electrical conduction has also been demonstrated in diabetic rat myocardium ( 24 ). Various experimental studies in animal models of DM have variously demonstrated changes in ion channel activity including depressed L-type calcium current, transient outward potassium current, rapid and slow delayed potassium rectifier currents all of which can result in a prolongation of action potential duration and reduced heart rate ( 23 , 25 – 33 ). DM can increase the duration of the sinoatrial node (SAN) action potential and prolong sino-atrial node conduction time and pacemaker cycle length which is associated with alterations in intercellular gap junctional coupling ( 23 , 34 ).…”