Targeted Expression of a Dominant-Negative K v 4.2 K + Channel Subunit in the Mouse Heart

Publisher Website
Google Scholar
Abstract
—Action potential duration is prolonged in many forms of heart disease, often as a result of reductions in Ca2+-independent transient outward K+ currents (ie, Ito). To examine the effects of a primary reduction in Ito current in the heart, transgenic mice were generated that express a dominant-negative N-terminal fragment of the Kv4.2 pore-forming potassium channel subunit under the control of the mouse α-myosin heavy chain promoter. Two of 6 founders died suddenly, and only 1 mouse successfully transmitted the transgene in mendelian fashion. Electrophysiological analysis at 2 to 4 weeks of age demonstrated that Ito density was specifically reduced and action potential durations were prolonged in a subset of transgenic myocytes. The heterogeneous reduction in Ito was accompanied by significant prolongation of monophasic action potentials. In vivo hemodynamic studies at this age revealed significant elevations in the mean arterial pressure, peak systolic ventricular pressures, and ±dP/dt, indicativ...