Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Due to their unique structure, lysophosphoglycerides (such as lysophosphatidylcholine, LPC), compounds known to accumulate in ischemic myocardium, form micelles at concentrations exceeding the critical micelle concentration (CMC). In this study, we found that sub-CMC levels of LPC exerted dose-dependent morphological changes on red blood cells and elicited dysrhythmia and contracture while increasing coronary artery resistance in isolated hearts. LPC at supra-CMC concentrations lysed red blood cells, elicited virtually instantaneous contracture in perfused hearts, and constricted isolated coronary arteries. Because bile salts form micelles also, effects of LPC were compared with those induced by selected concentrations of bile salts. At sub-CMC levels, bile salts did not affect red cell morphology appreciably and exerted only negative ino- and chronotropic effects in isolated hearts. However, at supra-CMC concentrations, bile salts lysed red blood cells and caused contracture in the hearts. Thus LPC exerts specific effects at sub-CMC levels independent of nonspecific detergent effects of micelles. These specific effects may contribute to the mechanical and electrical dysfunction associated with myocardial ischemia.
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PMID:Effects of amphiphiles on erythrocytes, coronary arteries, and perfused hearts. 746 19

1. Phospholipid metabolites lysophospholipids cause extracellular K(+) accumulation and action potential shortening with increased risk of arrhythmias during myocardial ischemia. Here we studied effects of several lysophospholipids with different lengths of hydrocarbon chains and charged headgroups on HERG K(+) currents (I(HERG)) expressed in HEK293 cells and the potential mechanisms using whole-cell patch-clamp techniques. 2. Only the lipids with 16 hydrocarbons such as 1-palmitoyl-lysophosphatidylcholine (LPC-16) and 1-palmitoyl-lysophosphatidylglycerol (LPG-16) were found to produce significant enhancement of I(HERG) and negative shifts of HERG activation, although the voltage dependence of the effects was different between LPC-16 and LPG-16 which have differently charged headgroups. The lipid with 18 hydrocarbons modestly increased I(HERG). The lipids with 6 or 24 hydrocarbons had no effect or slightly decreased I(HERG). 3. Inhibition or activation of protein kinase C did not alter the effects of LPC-16 and LPG-16. Participation of phosphatidylinositol-4,5-bisphosphate in I(HERG) enhancement by LPC-16/LPG-16 was also excluded. 4. Vitamin E augmented the effects of LPC-16/LPG-16 whereas xanthine/xanthine oxidase reduced I(HERG): indicating that LPC-16/LPG-16 produced dual effects on I(HERG): direct enhancement of I(HERG) and indirect suppression via production of superoxide anion. 5. We conclude that enhancement of HERG function by lysophospholipids is specific to the lipids with 16-hydrocarbon chain structure and the pattern of voltage dependence is determined by the polar headgroups. The increase in I(HERG) is best described by direct interactions between lipid molecules and HERG proteins, which is consistent with lack of effects via membrane destabilization or modulation by intracellular signaling pathways.
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PMID:Potential mechanisms for the enhancement of HERG K+ channel function by phospholipid metabolites. 1474 14

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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PMID:Phospholipid lysophosphatidylcholine as a metabolic trigger and HERG as an ionic pathway for extracellular K accumulation and "short QT syndrome" in acute myocardial ischemia. 1776 69

To determine whether ferilnic nirate (FLNT) can precondition the rat heart against myocardial ischemia/reperfusion (I/R) damage and its mechanism, two groups of experiments were conducted. In the first group of experiments, rats were divided among four treatment groups: sham group; solvent with I/R (I/R control group); FLNT pretreatment with I/R (I/R FLNT group); and late ischemic preconditioning group (LPC group). In the second group of experiments without I/R, rats were divided into two treatment groups: control group and FLNT group. The results indicated that myocardial infarct size and the levels of creatine kinase and lactate dehydrogenase in the sera of the I/R FLNT group were significantly lower and the level of nitric oxide molecule and Mn-containing superoxide dismutase were significantly elevated in the heart tissue compared with I/R control group. The protein expression ratio of Bcl-2/Bax in heart tissue was significantly elevated in the I/R FLNT group. These results demonstrate FLNT is able to precondition rat hearts against myocardial ischemia/reperfusion damage to a similar level as that achieved via the late phase of ischemic preconditioning. The mechanism may involve the up-regulation of nitric oxide and the strengthening of anti-oxidant and anti-apoptosis cellular functions.
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PMID:Ferilnic nirate produces delayed preconditioning against myocardial ischemia and reperfusion injury in rats. 2060 93