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Abstract
The sino-atrial node (SAN) provides the electrical stimulus to initiate every heart beat. Cellular processes underlying this activity have been debated extensively, especially with regards to the role of intracellular calcium. We have used whole-cell application of 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA), a rapid calcium chelator, to guinea pig isolated SAN myocytes to assess the effect of rapid reduction of intracellular calcium on SAN cell electrical activity. High-dose (10 mM) BAPTA induced rapid and complete cessation of rhythmic action potential (AP) firing (time to cessation 5.5 ± 1.7 s). Over a range of concentrations, BAPTA induced slowing of action potential firing and disruption of rhythmic activity, which was dose-dependent in its time of onset. Exposure to BAPTA was associated with stereotyped action potential changes similar to those previously reported in the presence of ryanodine, namely depolarization of the most negative diastolic potential, prolongation of action potentials and a reduction in action potential amplitude. These experiments are consistent with the view that cytosolic calcium is essential to the maintenance of rhythmic pacemaker activity.
Highlights
It has been proposed that cytosololic calcium including that released from the sarcoplasmic reticulum (SR) plays an important role in the generation of pacemaker activity in both mammalian and amphibian pacemaker tissue (Rigg and Terrar, 1996; Ju and Allen, 1998, 1999; Rigg et al, 2000), as well as in subsidiary pacemaker (Zhou and Lipsius, 1993) and atrioventricular cells (Hancox et al, 1994)
If cytosolic calcium has no effect on cellular beating rate, carrying out experiments in the absence of amphotericin would allow us to confirm that the perforation technique itself was not causing any confounding effects
We performed some of these experiments after loading cells with the calcium indicator Fluo5F to demonstrate that rhythmic cellular activity was present before rapid chelation of calcium, as it was common that cells stopped before the switch to current clamp could be completed
Summary
It has been proposed that cytosololic calcium including that released from the sarcoplasmic reticulum (SR) plays an important role in the generation of pacemaker activity in both mammalian and amphibian pacemaker tissue (Rigg and Terrar, 1996; Ju and Allen, 1998, 1999; Rigg et al, 2000), as well as in subsidiary pacemaker (Zhou and Lipsius, 1993) and atrioventricular cells (Hancox et al, 1994). An important challenge to the possible importance of cytosolic calcium for pacemaking was provided by the work of Himeno et al (2011) who recorded spontaneous electrical activity in guinea pig isolated pacemaker myocytes under perforated patch conditions, and ruptured the membrane beneath the patch to apply the calcium chelator BAPTA to the cytosol from the patch pipette solution. Under these conditions, spontaneous action potentials were observed to continue at least for 30 s in the presence of cytosolic BAPTA, pacemaker activity did become erratic or stop after several minutes. These observations have in turn been challenged, at least in part on the basis of arguments concerning possible changes in the seal resistance (Maltsev et al, 2011; Yaniv et al, 2013)
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