Key result
In a rabbit model of acute myocardial ischemia, LPC-16 accumulation and HERG enhancement triggered extracellular K+ accumulation and QT shortening, which were prevented by dofetilide.
Why the study?
Does dofetilide prevent extracellular K+ accumulation and QT shortening induced by LPC-16 or ischemia in a rabbit model?
Does dofetilide prevent extracellular K+ accumulation and QT shortening induced by LPC-16 or ischemia in a rabbit model?
LPC-16 accumulation and HERG enhancement represent a novel ionic mechanism for ischemic extracellular K+ accumulation and QT shortening, which can be prevented by dofetilide.
May link LPC-16/HERG to ischemic QT shortening; leaves open therapeutic targeting in patients.
The most profound abnormalities during acute myocardial ischemia are extracellular K(+) accumulation ([K(+)](o)- upward arrow) and shortening of action potential duration or QT interval (APD- downward arrow or QT- downward arrow), which are pivotal in the genesis of ischemic arrhythmias and sudden cardiac death. The ionic mechanisms however remained obscured. We performed studies in a rabbit model of acute global myocardial ischemia in order to explore ionic and metabolic mechanisms for ischemic [K(+)](o)- upward arrow and QT- downward arrow. Exogenous 1-palmitoyl-lysophosphatidylcholine (LPC-16) mimicked the low-perfusion ischemia to produce significant [K(+)](o)- upward arrow and QT- downward arrow. The [K(+)](o)- upward arrow and QT- downward arrow induced by either LPC-16 or ischemia were prevented by dofetilide, a blocker of rapid delayed rectifier K(+) current (I(Kr)), but not by blockers for other K(+) channels. Consistently, dofetilide efficiently abolished the ventricular tachy-arrhythmias induced by ischemia or LPC-16. LPC-16 remarkably shortened APD and enhanced the function of I(Kr) and HERG (the pore-forming subunit of I(Kr)). The effects of LPC-16 manifested with shorter APD (faster repolarization rate) and at more negative potential (membrane repolarization). Dofetilide abolished the I(Kr)/HERG enhancing and APD shortening effects of LPC-16. Our results suggest that LPC-16 accumulation/HERG enhancement may be a link between metabolic trigger and ionic pathway for ischemic [K(+)](o)- upward arrow and QTc- downward arrow. This represents the first documentation of I(Kr)/HERG as the ionic mechanism in ischemic [K(+)](o)- upward arrow and QTc- downward arrow. Inhibition of LPC-16 production and accumulation and/or of I(Kr)/HERG may be a promising therapeutic strategy to attenuate the incidence of lethal arrhythmias associated with ischemic heart disease.
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Bai et al. (2007) studied Acute myocardial ischemia. 1-palmitoyl-lysophosphatidylcholine (LPC-16) and Dofetilide was evaluated on Extracellular K+ accumulation and shortening of action potential duration or QT interval. In a rabbit model of acute myocardial ischemia, LPC-16 accumulation and HERG enhancement triggered extracellular K+ accumulation and QT shortening, which were prevented by dofetilide.
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