Title : New aspects of regulation of cardiac action potential duration
Abstract:
I n this talk three basic features of regulation of action potential duration (APD) are discussed, each based on changes in the net membrane current (Inet) during the plateau of the AP. 1. The reverse rate-dependent nature of drug effects on APD means that any drug-induced change in APD is more pronounced at longer than at shorter cycle lengths. Similar results are obtained when repolarization is modified by injection of inward or outward current pulses. On the other hand, all drug-induced or current-induced changes in APD well correlate with the baseline value of APD in all mammalian preparations studied, including the human heart. Since I net is inversely proportional to APD, and consequently to cycle length, it is concluded that that reverse rate-dependency may simply reflect the inverse relationship linking Inet to APD. In summary, reverse rate-dependency is an intrinsic property of cardioactive drug actions. 2. Beat-to-beat variability (short-term variability, SV) of APD is a good predictor of cardiac arrhythmias, however, the factors influencing its magnitude are not fully clarified. Since SV is an exponential function of APD itself, the term of relative SV (RSV) had to be introduced to eliminate the direct effect of APD changes. RSV is determined by normalizing the observed SV changes to concomitant changes in APD, and this ratio is compared to the exponential SV-APD relationship, obtained using inward and outward current injections. RSV is decreased by ion currents playing critical role in the negative feedback regulation of APD, such as ICa, IKs and IKr, therefore blocking of these currents may carry some proarrhythmic risk. Conversely, RSV was increased by INa, in line with the known antiarrhythmic effect of late INa blockade. RSV is modulated by several further parameters, like intracellular Ca2+ concentration, tissue redox potential, stimulation rate and temperature. 3. Adrenergic activation of L-type Ca2+ and various K+ currents is a crucial mechanism of cardiac adaptation, however, it carries substantial proarrhythmic risk. It was found that the isoproterenol (ISO)-induced activation of ICa precedes the enhancement of IKs and IKr. Since this temporal shift is differently affected by selective blockade of β1 and β2 adrenoceptors, and is reduced after inhibition of phosphodiesterases, different adrenergic signal transduction pathways and compartmentalization is likely involved. Audience Take Away: • Reverse rate-dependency is an intrinsic property of cardioactive drug actions and drug-induced changes in action potential duration increase with the baseline value of action potential duration. • Beat-to-beat variability of action potential duration, which is a good predictor of cardiac arrhythmias, changes together with baseline action potential duration, therefore, the term of relative variability had to be introduced to characterize drug actions on beat-to-beat variability. • The isoproterenol-induced activation of L-type Ca2+ current precedes the enhancement of K+ currents in canine ventricular myocytes, wich is likely related to differences in compartmentalization of the two systems. • These results of basic research may lead to better understanding the mechanisms of cardiac arrhythmias and the development of better antiarrhythmic strategies.
