title: Phospholipid lysophosphatidylcholine as a metabolic trigger and HERG as an ionic pathway for extracellular K accumulation and "short QT syndrome" in acute myocardial ischemia.
abstract: 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.
authors.affiliation: Department of Pharmacology (State and Provincial Key Laboratory of China), Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Bai
authors.forename: Jingxiong
authors.initials: J
authors.lastname: Wang
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D007477:Ions / Q000737:chemistry / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D017202:Myocardial Ischemia / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D007477:Ions; D008244:Lysophosphatidylcholines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011188:Potassium