Effects of potassium conductance inhibitors on spontaneous diastolic depolarization and abnormal automaticity in human atrial fibers

Abstract

The capability of generating spontaneous diastolic depolarization and automaticity was investigated in vitro by means of standard microelectrode techniques in 50 human atrial preparations. Samples were classified within two groups: group 1 was composed of 12 well-polarized preparations exhibiting action potentials that were fast responses (mean maximum diastolic potential: -75.5 mV and Vmax greater than 100 V/s); group 2 was composed of 38 partially-depolarized samples (mean maximum diastolic potential: -50.3 mV and Vmax less than 10 V/s) and was further divided into two subgroups. Subgroup 2A consisted of 20 spontaneously beating preparations and subgroup 2B consisted of 18 non-automatic partially-depolarized specimens. Highly-polarized fibers from group 1, although exhibiting a slight diastolic depolarization which was almost entirely suppressed by 2 mM caesium, never presented spontaneous activity under our experimental conditions. 90% of automatic fibers from subgroup 2A were sampled from dilated atria. In automatic preparations, diastolic depolarization was usually separated into two phases: an initial phase, also present in non-automatic fibers, and a late phase. Changes in the initial phase were not accompanied by concomitant changes in the spontaneous rate. Abnormal automaticity was clearly related to the late diastolic phase (absent in non-automatic fibers), the generation of which appeared to be a specific property of automatic fibers. The use of K conductance inhibitors (caesium, 4-aminopyridine, barium, low K solutions) provided indirect evidence that neither delayed outward ix current nor if type inward current are principally responsible for abnormal automaticity.

A slowly inactivating sodium current contributes to spontaneous diastolic depolarization of atrial myocytes

“…Thus late I Na is distinct from the Na ϩ window current, which is a steady-state, time-independent current that is present throughout the voltage range where the activation and inactivation relationships of I Na overlap (34). The potential for a role of late I Na in the genesis of DD lies in the fact that this inward current is present at voltages as negative as Ϫ70 mV in ventricular myocytes (33, 35) and Ϫ80 mV in Purkinje fibers (5); these membrane potentials are well within the reported voltage range for DD in atrial tissues (7,28,42). Because of its slow inactivation, late I Na may be activated during atrial DD, as suggested by the results of a previous study by .…”

“…The results of experiments on cat atrial myocytes showed that both T-type Ca 2ϩ current [I Ca(T) ] and Na ϩ -Ca 2ϩ exchange current (I Na-Ca ) are involved in DD and abnormal automaticity (14), whereas the results of a study of human atrial fibers suggest a role for the pacemaker current I f in DD (7). On the other hand, a study of human atrial fibers (28) found that tetrodotoxin (TTX) markedly decreased the slope of DD, suggesting that a TTX-inhibited, slowly inactivating Na ϩ current (I Na ) may play a role in the development of atrial DD.…”

“…DIASTOLIC DEPOLARIZATION (DD) that may lead to rapid action potential (AP) firing is often observed in cardiac atrial preparations, including atrial fibers excised from human hearts (7,28,42), and in multicellular (13,31,32,49) or single cell (14,50) preparations from various animal species. Although the increased automaticity caused by DD has been recognized as one of the major mechanisms to initiate atrial fibrillation (29,41), the ionic basis underlying DD of atrial myocytes is not fully understood.…”

Functional role of cholinoceptors and purinoceptors in human isolated atrial and ventricular heart muscle

“…Several authors have related the great variability of results obtained in human atrial heart muscle (shape of the action potential, partial depolarization) to disease (Hordof et al, 1976;Ten Eick & Singer, 1979;Mary-Rabine et al, 1983;Escande et al, 1986;1987;Lee, 1986) or age (Escande et al, 1985) of the patients. In our hands, however, the quality of electrophysiological experiments seemed to be mainly determined by the procedure of isolation and further handling of the preparations.…”

Two differential mechanisms of automaticity in diseased human atrial fibers.

“…The precise ionic mechanism responsible for generation of the slow-type AAPs (CL > 2.0 s) in group 1 remains uncertain (EsCANDE et al, 1986). However, the slow activation of 'Ca' probably coupled with the deactivation of delayed rectifying K current (Ix, IMANISHI and SURAWICZ, 1976;KATZUNG and MORGENSTERN, 1977) seems to contribute to the development of the slow AAPs for the following reasons.…”