Scn3b knockout mice exhibit abnormal ventricular electrophysiological properties.
We report for the first time abnormalities in cardiac ventricular electrophysiology in a genetically modified murine model lacking the Scn3b gene (Scn3b(-/-)). Scn3b(-/-) mice were created by homologous recombination in embryonic stem (ES) cells. RT-PCR analysis confirmed that Scn3b mRNA was expressed in the ventricles of wild-type (WT) hearts but was absent in the Scn3b(-/-) hearts. These hearts also showed increased expression levels of Scn1b mRNA in both ventricles and Scn5a mRNA in the right ventricles compared to findings in WT hearts. Scn1b and Scn5a mRNA was expressed at higher levels in the left than in the right ventricles of both Scn3b(-/-) and WT hearts. Bipolar electrogram and monophasic action potential recordings from the ventricles of Langendorff-perfused Scn3b(-/-) hearts demonstrated significantly shorter ventricular effective refractory periods (VERPs), larger ratios of electrogram duration obtained at the shortest and longest S(1)-S(2) intervals, and ventricular tachycardias (VTs) induced by programmed electrical stimulation. Such arrhythmogenesis took the form of either monomorphic or polymorphic VT. Despite shorter action potential durations (APDs) in both the endocardium and epicardium, Scn3b(-/-) hearts showed DeltaAPD(90) values that remained similar to those shown in WT hearts. The whole-cell patch-clamp technique applied to ventricular myocytes isolated from Scn3b(-/-) hearts demonstrated reduced peak Na(+) current densities and inactivation curves that were shifted in the negative direction, relative to those shown in WT myocytes. Together, these findings associate the lack of the Scn3b gene with arrhythmic tendencies in intact perfused hearts and electrophysiological features similar to those in Scn5a(+/-) hearts.
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, United Kingdom.
Parvez
P
Hakim
Iman S
IS
Gurung
Thomas H
TH
Pedersen
Rosemary
R
Thresher
Nicola
N
Brice
Jason
J
Lawrence
Andrew A
AA
Grace
Christopher L-H
CL
Huang
D000200:Action Potentials; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010477:Perfusion; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D018754:Ventricular Dysfunction / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*
D017931:DNA Primers; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; C568321:Scn5a protein, mouse; D015222:Sodium Channels