Abstract:

The heart rate is mediated by the G protein-coupled muscarinic receptor (M2R) activating the acetylcholine (ACh)-dependent K+ current (IKACh). Here, a novel model for IKACh gating is presented based on recent findings that M2R agonist binding is voltage-sensitive. Furthermore, ACh and pilocarpine (Pilo) manifest opposite voltage-dependent IKACh modulation. In a previous work, a 4-state Markov model of M2R reconstructing the voltage-dependent change in agonist affinity was proposed. In this work, a 2-state Markov model of IKACh gating purely dependent on the Gβγ concentration is proposed. IKACh is modeled based on the description of Zhang et al. Measurement data are used to parametrize the combined M2R and IKACh model for both ACh and Pilo. The channel model has a linear Gβγ dependent forward and a constant backward rate. For ACh and Pilo, optimal values of model parameters are found reconstructing the measured opposite voltage-dependent change in agonist affinity. The combined model is able to reconstruct the measured data regarding the agonist and voltage-dependent properties of the M2R-IKACh channel complex. In future studies, this channel will be integrated in a sinus node model to investigate the effect of the channel properties on heart rate

Abstract:

In this computer based work, the dose-dependent effect of 4-Aminopyridine on chronic atrial fibrillation in a virtual model was investigated. The CRN model was used and adjusted to do so. Additionally, a method of detection of the Vulnerable Window was de- veloped and the effect of 4-AP on it was examined. Furthermore, the minimal stimulation amplitude for a better comparison of various simulations was introduced.4-AP is a potent inhibitor of those potassium channels, which determine repolarization. The dose-dependent effects on these ion channels can be described by the reduction of their conductances. In order to modify the conductances, it was necessary to fit data from literature to the Hill equation.Afterwards, the effects on the restitution properties and on VW for normal and remodeled tissue could be examined. The simulations were performed for seven different concentra- tions in each case. The two lowest concentrations did not deviate from the control cases for any simulation, whereas the two highest concentrations caused very unphysiological effects.The other doses of 4-AP prolonged APD, ERP and WL, especially in remodeled tissue. The conduction velocity was almost unaffected. Thus, 4-AP shows antiarrhythmic prop- erties for doses between 10 μM and 1mM.The Vulnerable Window is about the width of 1.2 ms, both in normal and remodeled tissue, if the tissue is stimulated by twice the minimal stimulation amplitude. The width of VW depends strongly on the stimulation amplitude. For smaller BCLs, the width of VW is constant in the remodeled case, but in the normal case the width increases. This effect is much more pronounced under the influence of 4-AP. By that, the risk of occur- rence of an unidirectional block increases in healthy tissue, which is a proarrhythmic effect.Finally, 2D simulations of atrial fibrillation in remodeled tissue were realized. After the initiation of four stable rotors, the effect of the various concentrations on the persistence of these rotors were observed and the time course of the rotor wave tips was evaluated. Doses between 10 μM and 100 μM can reduce the number of rotors, but they cannot prevent perpetuation. At doses of 100 μM and higher, 4-AP is able to stop perpetuation of reentries. However, the side effects of these doses are lethal.At clinical doses such as in MS therapy, no effects of 4-AP for any simulations are found, neither antiarrhythmic nor proarrhythmic.