Nicotine induces a long QT phenotype in Kcnq1-deficient mouse hearts.
We have previously shown that targeted disruption of the mouse Kcnq1 gene produces a long QT phenotype in vivo that requires extracardiac factors for manifestation (Casimiro et al., 2001). In the present study, we explore the hypothesis that autonomic neuroeffector transmission represents the "extra cardiac" stimulus that induces a long QT phenotype in mouse hearts lacking Kcnq1. Using the isolated perfused (Langendorff) mouse heart preparation, we challenged wild-type (Kcnq1+/+) and mutant (Kcnq1-/-) mouse hearts with nicotine, an autonomic stimulant. ECGs were recorded continuously, and QT intervals were compared at baseline and peak nicotine-induced heart rates. No significant differences in QT or any other ECG parameters were observed in Kcnq1+/+ versus Kcnq1-/- hearts at baseline. In the presence of nicotine, however, the JT, QT, and rate-corrected QT (QTc) intervals were significantly prolonged in Kcnq1-/- hearts relative to Kcnq1+/+ hearts (e.g., QTc = 92 +/- 11 ms versus 66 +/- 2 ms, respectively, p < 0.01). Similar findings were obtained when the hearts were challenged with either epinephrine or isoproterenol (0.1 microM each), thereby suggesting that sympathetic stimulation drives the long QT phenotype in Kcnq1-deficient hearts. This idea is supported by in vivo ECG data obtained from unrestrained conscious mice using radiotelemetry recording techniques. Again, no significant ECG differences were observed in Kcnq1-/- versus Kcnq1+/+ mice at baseline, but handling/injection stress led to significant QTc increases in Kcnq1-/- mice relative to wild-type controls (11 +/- 3 versus -1 +/- 1%, respectively, p < 0.05). These data suggest that sympathetic stimulation induces a long QT phenotype in Kcnq1-deficient mouse hearts.
Tosaka
Toshimasa
T
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057, USA.
Casimiro
Mathew C
MC
Rong
Qi
Q
Tella
Srihari
S
Oh
Michelle
M
Katchman
Alexander N
AN
Pezzullo
John C
JC
Pfeifer
Karl
K
Ebert
Steven N
SN
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009538:Nicotine / Q000009:adverse effects* / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000009:adverse effects* / Q000494:pharmacology; D010477:Perfusion; D010641:Phenotype; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496910:Kcnq1 protein, mouse; D018722:Nicotinic Agonists; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D009538:Nicotine