Action Potential Shape Differences Set Species-Dependent β-Adrenergic-Stimulation Response

Abstract

Background: The cardiac action potential (AP) shape is a species-dependent feature related to differences in ionic currents underlying repolarization. In guinea pigs (GP), dogs and humans, the AP is prolonged by a pronounced plateau phase. In canine and human, but not GP, myocytes, a spike-and-dome profile characterizes repolarization of specific regions within the heart and to a different extent according to heart rate. It is unclear whether the response to β-adrenergic stimulation is dictated by peculiarities of ion channels properties, or may results from differences in AP contour. Aim: The aim of this project is to test whether the presence of the spike-and-dome in the AP contour is, by itself, able to modify the response of membrane current to β-adrenergic stimulation in a rate-dependent fashion. Methods: We performed AP-clamp on GP myocytes with dog epicardial and endocardial AP waveforms to assess the contribution of the spike-and-dome in isoprenaline (ISO) sensitive current (IISO) at diastolic intervals (DI) of 1750ms and 300ms. We also performed dynamic clamp experiments on GP myocytes with a computational simulated canine transient outward current (Ito) to evaluate the ISO response on the AP duration (APD) in presence of an artificial spike-and-dome. Results: We found that: 1) At DI1750, IISO is more inward with dog endocardial rather than epicardial waveform; this difference was not evidenced at DI300. 2) The injection of a simulated canine Ito is not sufficient by itself to affect the direction of APD changes during β-adrenergic stimulation. Conclusions: The differences between dog and GP in setting β-adrenergic stimulation response are a species-dependent feature not only related to Ito and might be explained as a more complex mechanism involving AP shape and a diverse contribution of Ca2+ and K+ channels during the AP.