title: Effects of linoleic acid metabolites on electrical activity in adult rat ventricular myocytes.
abstract: Leukotoxin (Lx), an epoxide derivative of linoleic acid, has been suggested to be a toxic mediator of multiple organ failure in burn patients and of acute respiratory distress syndrome. Lx production was recently shown during myocardial ischemia/reperfusion. However, a recent study suggested that to be toxic Lx must be metabolized to Lx-diol. In the present study, isolated adult rat ventricular myocytes were studied with the whole-cell patch-clamp technique to determine the effects of these compounds on cardiac electrical activity. Measurements of action potentials showed that neither linoleic acid nor Lx (100 microM) caused any significant changes in action potential properties. However, Lx-diol in the range of 10-100 microM produced a dose dependent increase in duration and a decrease in overshoot of the action potential. Subsequent voltage clamp experiments isolating Na current (INa) and transient outward K current (Ito) revealed that Lx-diol inhibited INa and Ito by about 80% at 100 microM, while linoleic acid and Lx had no effect on these currents at the same concentration. While Lx-diol produced the same inhibition of INa and Ito at 100 microM, its effects were more potent on Ito with significant inhibition at 10 microM. Lx-diol also hastened the activation kinetics of Ito but not INa. The action of Lx-diol was rapid (reaching steady state in 3-5 min) and was reversible in 5-10 min following washout. Thus, Lx-diol could favor arrhythmias or cardiac arrest in intact heart and may be responsible for the cardiac problems seen in systemic inflammatory response syndrome. These results further support the suggestion that Lx is not toxic in the heart but rather must be metabolized to Lx-diol to produce toxic effects on cardiac muscle.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, 4301 W. Markham St., Slot 611, Little Rock, AR 72205, USA. stimersjosephr@exchange.uams.edu
authors.forename: J R
authors.initials: JR
authors.lastname: Stimers
authors.forename: M
authors.initials: M
authors.lastname: Dobretsov
authors.forename: S L
authors.initials: SL
authors.lastname: Hastings
authors.forename: A R
authors.initials: AR
authors.lastname: Jude
authors.forename: D F
authors.initials: DF
authors.lastname: Grant
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000737:chemistry / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects; D019787:Linoleic Acid / Q000378:metabolism* / Q000494:pharmacology; D013058:Mass Spectrometry; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000737:chemistry; D051381:Rats; D012964:Sodium / Q000737:chemistry; D013229:Stearic Acids / Q000378:metabolism / Q000494:pharmacology
chemical_list: C120038:9,10-dihydroxy-12-octadecenoic acid; D005098:Exotoxins; D013229:Stearic Acids; C018579:leukotoxin; D019787:Linoleic Acid; D012964:Sodium; D011188:Potassium