Abstract
To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the β-adrenergic receptor agonist, isoproterenol (0.17 mg/kg, i.p.). Modest but significant increases in JT, QT, and rate-corrected QT (QTc) intervals were found in KO neonates relative to WT siblings during baseline ECG assessments (QTc = 57 ± 3 ms, n = 22 versus 49 ± 2 ms, n = 28, respectively, p < 0.05). Moreover, JT, QT, and QTc intervals significantly increased following isoproterenol challenge in the KO (p < 0.01) but not the WT group (p = 0.57). Furthermore, whole-cell patch-clamp recordings show that the slow delayed rectifier K+ current (IKs) was absent in KO but present in WT myocytes, where it was strongly enhanced by isoproterenol. This finding was confirmed by showing that the selective IKs inhibitor, L-735,821, blocked IKs and prolonged action potential duration in WT but not KO hearts. These data demonstrate that disruption of the Kcnq1 gene leads to loss of IKs, resulting in a long QT phenotype that is exacerbated by β-adrenergic stimulation. This phenotype closely reflects that observed in human LQT1 patients, suggesting that the neonatal mouse serves as a valid model for this condition. This idea is further supported by new RNA data showing that there is a high degree of homology (>88% amino acid identity) between the predominant human and mouse cardiac Kcnq1 isoforms.
Footnotes
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This research was supported by the Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation (to B.C.K.), the AHA (Grant SDG 0130285N to B.C.K.), the National Heart, Lung, and Blood Institute (Grants HL58743 to S.N.E. and HL071670 to B.C.K.), and the National Institute of Child Health and Human Development (to K.P.).
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DOI: 10.1124/jpet.103.063743.
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ABBREVIATIONS: LQT1, long QT 1 form of Long QT Syndrome; IKs, repolarizing K+ current; PKA, protein kinase A; ECG, electrocardiogram; QTc, rate-corrected QT interval; PCR, polymerase chain reaction; RT, reverse transcription; APD, action potential duration; WT, wild type; KO, knockout; bp, base pair(s); MAP, monophasic action potential.
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↵1 These authors contributed equally to the paper.
- Received December 2, 2003.
- Accepted February 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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