We have previously shown that chronic rapid atrial activation (400 bpm) reduces atrial conduction velocity in dogs, contributing to the development of a substrate supporting sustained atrial fibrillation (AF). However, the cellular and ionic mechanisms underlying these functional changes have not been defined. We applied whole-cell patch-clamp techniques to atrial myocytes from dogs subjected to atrial pacing at 400 bpm for 7 days (P7, n = 6) and 42 days (P42, n = 5) and compared the results with those from sham-operated dogs similarly instrumented but without pacemaker activation (P0, n = 6). Rapid atrial pacing allowed for the induction of sustained AF in 67% and 100% of dogs paced for 7 and 42 days, respectively, and significantly decreased conduction velocity under P7 and P42 conditions. In dogs paced for 7 days, Na+ current (INa) density was reduced by 28% at -40 mV (P < .0001, n = 59 cells). INa changes were even more decreased under P42 conditions, by approximately 52% at -40 mV (P < .0001): from -78.7 +/- 4.6 pA/pF (P0, n = 28 cells) to -37.7 +/- 3.0 pA/pF (P42, n = 43 cells). INa was significantly reduced at all voltages ranging from -65 to -10 mV. Voltage-dependent activation and inactivation properties, activation kinetics, and recovery from inactivation were not altered by rapid atrial pacing; however, inactivation kinetics were slowed. AF duration was related to mean INa in each dog (r2 = .573, P < .001). We conclude that rapid atrial activation significantly reduces both conduction velocity and INa density. Since INa is a major determinant of conduction velocity, our data point to INa reduction as a potentially important mechanism contributing to the substrate for AF in this model.

In adult rat atrial myocytes, three kinetically distinct Ca¥-independent depolarizationactivated outward K¤ currents, IK,fast, IK,slow and Iss, have been separated and characterized. 2. To test directly the hypothesis that different voltage-dependent K¤ channel (Kv channel) á subunits underlie rat atrial IK,fast, IK,slow and Iss, the effects of antisense oligodeoxynucleotides (AsODNs) targeted against the translation start sites of the Kv á subunits Kv1.2, Kv1.5, Kv4.2, Kv4.3, Kv2.1 and KvLQT1 were examined. 3. Control experiments on heterologously expressed Kv á subunits revealed that each AsODN is selective for the subunit against which it was targeted. 4. Peak outward K¤ currents were attenuated significantly in rat atrial myocytes exposed to AsODNs targeted against Kv4.2, Kv1.2 and Kv1.5, whereas AsODNs targeted against Kv2.1, Kv4.3 and KvLQT1 were without effects. 5. No measurable effects on inwardly rectifying K¤ currents (IK1) were observed in atrial cells exposed to any of the Kv á subunit AsODNs. 6. Kinetic analysis of the currents evoked during long (10 s) depolarizing voltage steps revealed that AsODNs targeted against Kv4.2, Kv1.2 and Kv1.5 selectively attenuate rat atrial IK,fast, IK,slow and Iss, respectively, thus demonstrating that the molecular correlates of rat atrial IK,fast, IK,slow and Iss are distinct. 7. The lack of effect of the Kv4.3 AsODNs on peak outward K¤ currents reveals that Kv4.2 and Kv4.3 do not heteromultimerize in rat atria in vivo. In addition, the finding that Kv1.2 and Kv1.5 contribute to distinct K¤ currents in rat atrial myocytes demonstrates that Kv1.2 and Kv1.5 also do not associate in rat atria in vivo.

Voltage‐clamp studies on atrial myocytes isolated from adult and postnatal day 15 (P15) C57BL6 mice demonstrate the presence of three kinetically distinct Ca2+‐independent, depolarization‐activated outward K+ currents: a fast, transient outward current (Ito,f), a rapidly activating, slowly inactivating current (IK,s) and a non‐inactivating, steady‐state current (Iss). The time‐ and voltage‐dependent properties of Ito,f, IK,s and Iss in adult and P15 atrial cells are indistinguishable. Pharmacological experiments reveal the presence of two components of IK,s: one that is blocked selectively by 50 μM 4‐aminopyridine (4‐AP), and a 4‐AP‐insensitive component that is blocked by 25 mM TEA; Iss is also partially attenuated by 25 mM TEA. There are also two components of IK,s recovery from steady‐state inactivation. To explore the molecular correlates of mouse atrial IK,s and Iss, whole‐cell voltage‐clamp recordings were obtained from P15 and adult atrial cells isolated from transgenic mice expressing a mutant Kv2.1 α subunit (Kv2.1N216Flag) that functions as a dominant negative, and from P15 atrial myocytes exposed to (1 μM) antisense oligodeoxynucleotides (AsODNs) targeted against Kv1.5 or Kv2.1. Peak outward K+ current densities are attenuated significantly in atrial myocytes isolated from P15 and adult Kv2.1N216Flag‐expressing animals and in P15 cells exposed to AsODNs targeted against either Kv1.5 or Kv2.1. Analysis of the decay phases of the outward currents evoked during long (5 s) depolarizing voltage steps revealed that IK,s is selectively attenuated in cells exposed to the Kv1.5 AsODN, whereas both IK,s and Iss are attenuated in the presence of the Kv2.1 AsODN. In P15 and adult Kv2.1N216Flag‐expressing atrial cells, mean ± s.e.m. IK,s and Iss densities are also significantly lower than in non‐transgenic atrial cells. In addition, pharmacological experiments reveal that the TEA‐sensitive component IK,s is selectively eliminated in P15 and adult Kv2.1N216Flag‐expressing atrial cells. Taken together, the results presented here reveal that both Kv1.5 and Kv2.1 contribute to mouse atrial IK,s, consistent with the presence of two molecularly distinct components of IK,s. In addition, Kv2.1 contributes to mouse atrial Iss.

Despite a genetic inability to produce Cx43 and a developmental history that culminates in marked gross cardiac morphologic abnormalities, premature death, and myocardial inexcitability ex vivo, cardiac Na+ channel distribution and function appear to be normal in Cx43 null hearts. Although intimate structural and functional interrelationships have been described between ion channels and gap junction channels, expression and function of Na+ channels is not affected by the absence of Cx43.

Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel-blocking drugs.

Alkalinization antagonizes the INa-blocking action of imipramine by promoting unbinding from the receptor. Intracellular alkalosis has a particularly important effect related to the activated-state interaction. The lipid-soluble, uncharged moiety appears to be a critical determinant of imipramine's ability to dissociate from the Na+ channel receptor.

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