Dominant-negative suppression of IK1 in the mouse heart leads to altered cardiac excitability

Sodium channel Scn1b null mice exhibit prolonged QT and RR intervals

“…Single ventricular myocytes were extracted from P17-19 Scn1b null and wildtype male mice as described [14,15]. Minor modifications included addition of 0.33 mg/ml heparin to the anesthetic, 50 μM EGTA to solution A, and 25 mg/ml bovine serum albumin to solution C. Only rod-shaped, quiescent cells with smooth striations were selected for examination.…”

“…Standard 3-lead surface ECGs of P17 Scn1b null, heterozygous, and wildtype male mice were recorded as described [15]. Acquisition was performed 8-10 min following anesthesia and data collected for 8 consecutive min at a sampling rate of 5 kHz using a DP304 differential amplifier (Warner Instruments Corp., Hamden, CT).…”

“…The first investigator (Investigator 1) calculated parameters for each individual animal from averages of 20-40 consecutive traces using homemade software (Delphi 5, Borland Int.) [15]. Data were then combined from the averaged measurements for each individual mouse to yield an averaged value for each genotype.…”

IK1 and cardiac hypoxia: After the long and short QT syndromes, what else can go wrong with the inward rectifier K+ currents?

“…In a study using in vivo adenoviral-mediated expression of a dominant-negative Kir2.1 mutant channels in guinea pig hearts, Miake et al demonstrated that suppression of I K1 decelerates the AP repolarization, prolongs AP duration (APD), and depolarizes the resting membrane potential [7]. Transgenic mice with suppressed I K1 show significant changes in surface ECG, including prolongation of QRS complexes and QT intervals [8]. Electrophysiologic study performed in an ATS patient suggests that reduced Kir2.1 current contributes to the development of delayed afterdepolarizations (DAD) and ventricular arrhythmias [18].…”

“…important roles of I K1 in cardiac physiology have long been documented, its roles in cardiac arrhythmia generation have only been increasingly recognized recently [6][7][8][9][10][11][12] and indeed, have "lagged" behind other K + channels, e.g., KvLQT1 (encoded by KCNQ1 gene) and HERG (encoded by KCNH2 gene) which have been linked to several types of inherited cardiac arrhythmias and drug-induced long QT syndrome [13,14]. The article by Piao et al, in this issue of the Journal provides compelling evidence for yet another role of I K1 , namely as a "first responder" during cardiac ischemia and hypoxia [15].…”