Transverse propagation of action potentials between parallel chains of cardiac muscle and smooth muscle cells in PSpice simulations

BACKGROUND: We previously examined transverse propagation of action potentials between 2 and 3 parallel chain of cardiac muscle cells (CMC) simulated using the PSpice program. The present study was done to examine transverse propagation between 5 parallel chains in an expanded model of CMC and smooth muscle cells (SMC). METHODS: Excitation was transmitted from cell to cell along a strand of 5 cells not connected by low-resistance tunnels (gap-junction connexons). The entire surface membrane of each cell fired nearly simultaneously, and nearly all the propagation time was spent at the cell junctions, the junctional delay time being about 0.3 – 0.5 ms (CMC) or 0.8 – 1.6 ms (SMC). A negative cleft potential (V(jc)) develops in the narrow junctional clefts, whose magnitude depends on the radial cleft resistance (R(jc)), which depolarizes the postjunctional membrane (post-JM) to threshold. Propagation velocity (θ) increased with amplitude of V(jc). Therefore, one mechanism for the transfer of excitation from one cell to the next is by the electric field (EF) that is generated in the junctional cleft when the pre-JM fires. In the present study, 5 parallel stands of 5 cells each (5 × 5 model) were used. RESULTS: With electrical stimulation of the first cell of the first strand (cell A1), propagation rapidly spread down that chain and then jumped to the second strand (B chain), followed by jumping to the third, fourth, and fifth strands (C, D, E chains). The rapidity by which the parallel chains became activated depended on the longitudinal resistance of the narrow extracellular cleft between the parallel strands (R(ol2)); the higher the R(ol2 )resistance, the faster the θ. The transverse resistance of the cleft (R(or2)) had almost no effect. Increasing R(jc )decreases the total propagation time (TPT) over the 25-cell network. When the first cell of the third strand (cell C1) was stimulated, propagation spread down the C chain and jumped to the other two strands (B and D) nearly simultaneously. CONCLUSIONS: Transverse propagation of excitation occurred at multiple points along the chain as longitudinal propagation was occurring, causing the APs in the contiguous chains to become bunched up. Transverse propagation was more erratic and labile in SMC compared to CMC. Transverse transmission of excitation did not require low-resistance connections between the chains, but instead depended on the value of R(ol2). The tighter the packing of the chains facilitated transverse propagation

HCN Channels and Cardiac Pacemaking

Cardiomyocytes located in the central part of the sinoatrial node are responsible for generating the electrical rhythm of the heart since they are endowed with the fastest automaticity of the entire conduction system. The source of this automaticity is the diastolic pacemaker phase which consists of the slow depolarization that links the end of each action potential with the beginning of the next, and the funny current (\u201cIf\u201d) is the primary contributor of this phase. Each f-channel results from the assembly of four single subunits belonging to the family of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which includes four isoforms (HCN1\u2013HCN4). The biophysical and modulatory properties of the f/HCN current will be presented together with some of the underlying molecular details which have been partly unraveled by the recent structural definition of the channel obtained by cryo-electron microscopy studies. The chapter will also provide an extensive review of the mutations of the HCN4 channels in humans associated with sinus arrhythmias and left ventricular noncompaction cardiomyopathy. Functional studies based on HCN transgenic and knockout mouse models confirm the importance of the If current in sustaining the pacemaker activity since its suppression affects the cardiac performance and autonomic modulation of heart rate. These studies also provide the evidence that cardiac HCN currents are required for proper cardiac development and embryo survival. Finally, the clinical relevance of HCN channels as targets of drugs aimed to selectively reduce the heart rate will be also discussed