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Biomedical subjects

A Leaf

Publications and source records attributed to A Leaf.

At least 55 records · Page 3Linked to original sources
PubMed1997

Dietary n-3 fatty acids in the prevention of lethal cardiac arrhythmias.

It has been shown in animals and probably in humans that the n-3 polyunsaturated fatty acids are antiarrhythmic. We report recent studies on the mechanism(s) by which the polyunsaturated fatty acids exert their antiarrhythmic effects. The polyunsaturated fatty acids stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels, so that a stronger electrical stimulus is then required to elicit an action potential and a contraction of the myocyte. This appears at present to be the probable major antiarrhythmic mechanism of the polyunsaturated fatty acids.

Animals↗
PubMed1996

Polyunsaturated fatty acids modulate sodium and calcium currents in CA1 neurons.

Recent evidence indicates that long-chain polyunsaturated fatty acids (PUFAs) can prevent cardiac arrhythmias by a reduction of cardiomyocyte excitability. This was shown to be due to a modulation of the voltage-dependent inactivation of both sodium (INa) and calcium (ICa) currents. To establish whether PUFAs also regulate neuronal excitability, the effects of PUFAs on INa and ICa were assessed in CA1 neurons freshly isolated from the rat hippocampus. Extracellular application of PUFAs produced a concentration-dependent shift of the voltage dependence of inactivation of both INa and ICa to more hyperpolarized potentials. Consequently, they accelerated the inactivation and retarded the recovery from inactivation. The EC50 for the shift of the INa steady-state inactivation curve was 2.1 +/- 0.4 microM for docosahexaenoic acid (DHA) and 4 +/- 0.4 microM for eicosapentaenoic acid (EPA). The EC50 for the shift on the ICa inactivation curve was 2.1 +/- 0.4 for DHA and > 15 microM for EPA. Additionally, DHA and EPA suppressed both INa and ICa amplitude at concentrations > 10 microM. PUFAs did not affect the voltage dependence of activation. The monounsaturated oleic acid and the saturated palmitic acid were virtually ineffective. The combined effects of the PUFAs on INa and ICa may reduce neuronal excitability and may exert anticonvulsive effects in vivo.

Animals↗
PubMed1996

Long chain polyunsaturated fatty acids and visual function in preterm infants.

Electroretinograms (ERG) were recorded at 40 weeks post-conceptual age (PCA) in 18 infants born prematurely (25-32 weeks gestation). Fatty acid composition of plasma and red cell phospholipids was measured within 4 days of birth and at time of ERG testing, and detailed record was kept of dietary intake. Correlations were seen between percentage intake of breast milk and docosahexaenoic acid (DHA) in both plasma (r = 0.818, P < 0.0001) and red cells (r = 0.534, P = 0.035) and significant differences in fatty acid profiles were seen between infants receiving > 50% and < 50% breast milk. No difference was seen in retinal sensitivity between infants receiving > 50% or < 50% breast milk. A positive correlation was seen between scotopic (rod) b-wave implicit time on ERG and DHA in both plasma (r = 0.733, P = 0.001) and red cells (r = 0.502, P = 0.04). A positive correlation was seen between arachidonic acid and rod ERG amplitude (r = 0.565, P = 0.022) which may reflect the higher AA/DHA ratio in the developing retina. These data did not support our hypothesis that increased dietary DHA results in enhanced retinal maturation. Visual acuity measured at 40 weeks PCA and again 3 months later was similar between groups. While subtle relationships were demonstrated between long chain polyunsaturated fatty acids and visual function, all infants were felt to be within age-appropriate normal range at expected date of delivery and at 3 months corrected age.

Breast Feeding↗
PubMed1996

Evidence that free polyunsaturated fatty acids modify Na+ channels by directly binding to the channel proteins.

The effects of free polyunsaturated fatty acids (PUFA) on the binding of ligands to receptors on voltage-sensitive Na+ channels of neonatal rat cardiac myocytes were assessed. The radioligand was [benzoyl-2,5-(3)H] batrachotoxinin A 20alpha-benzoate ([(3)H]BTXB), a toxin that binds to the Na+ channel. The PUFA that have been shown to be antiarrhythmic, including eicosapentaenoic acid (EPA; C20:5n-3), docosahexaenoic acid (DHA; C22:6n-3), eicosatetraynoic acid (ETYA), linolenic acid (C18:3n-3), and linoleic acid (C18:2n-6), inhibited [(3)H]BTXB binding in a dose-dependent fashion with IC50 values of 28-35 microM, whereas those fatty acids that have no antiarrhythmic effects including saturated fatty acid (stearic acid, C18:0), monounsaturated fatty acid (oleic acid; C18:1n-9), and EPA methyl ester did not have a significant effect on [(3)H]BTXB binding. Enrichment of the myocyte membrane with cholesterol neither affected [(3)H]BTXB binding when compared with control cells nor altered the inhibitory effects of PUFA on [(3)H]BTXB binding. Scatchard analysis of [(3)H]BTXB binding showed that EPA reduced the maximal binding without altering the Kd for [(3)H]BTXB binding, indicating allosteric inhibition. The inhibition by EPA of [(3)H]BTXB binding was reversible (within 30 min) when delipidated bovine serum albumin was added. The binding of the PUFA to this site on the Na+ channel is reversible and structure-specific and occurs at concentrations close to those required for apparent antiarrhythmic effects and a blocking effect on the Na+ current, suggesting that binding of the PUFA at this site relates to their antiarrhythmic action.

Animals↗
PubMed1996

Protective effects of free polyunsaturated fatty acids on arrhythmias induced by lysophosphatidylcholine or palmitoylcarnitine in neonatal rat cardiac myocytes.

Cultured, spontaneously beating, neonatal rat cardiac myocytes were used to examine the effects of various free fatty acids added to the medium perfusing the cells on lysophosphatidylcholine (LPC)- or acylcarnitine-induced arrhythmias. Perfusion of the cells with LPC or palmitoylcarnitine (2-10 microM) induced sustained tachyrhythmia with episodes of spasmodic contractures and fibrillation. Free PUFA (10-15 microM) including eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), alpha-linolenic acid (18:3n-3), arachidonic acid (AA, 20:4n-6) and linoleic acid (18:2n-6) were able to effectively prevent as well as terminate the LPC or acylcarnitine-induced arrhythmias. In contrast, monounsaturated oleic acid (18:1n-9) and saturated stearic acid (18:0) did not have such effects. The protective effects of the polyunsaturated fatty acids (PUFA) could be reversed by cell perfusion with delipidated bovine serum albumin. To determine the potential primary action by which the PUFA exert the antiarrhythmic effects, measurements of intracellular Ca2+ levels and the response of the cells to electrical pacing in the absence or presence of the PUFA were performed and the effects of verapamil (a L-type Ca2+ channel blocker), tetrodotoxin (a Na+ channel blocker) and Ca2+ ionophore A23187 on the cell contraction and the cytosolic Ca2+ levels were compared with that of the PUFA. Results suggest that an inhibitory effect on the electrical automaticity/excitability of the cardiac myocyte rather than a reduction in cytosolic Ca2+ underlie the protective effects of PUFA. In conclusion, free PUFAs are able to effectively protect the cardiac myocytes against the arrhythmias induced by low concentrations of lysophosphatidylcholine or palmitoylcarnitine.

Animals↗
PubMed1996

Polyunsaturated fatty acids exert antiarrhythmic actions as free acids rather than in phospholipids.

Previous studies have shown that exogenous free n-3 polyunsaturated fatty acids (PUFA) can prevent tachyarrhythmias caused by specific agents in isolated cardiac myocytes. However, the question as to whether incorporation of the n-3 PUFA into membrane phospholipids has the same immediate protective effects remained to be answered. To answer this question, we increased the content of n-3 PUFA in the phospholipids of cultured neonatal rat myocytes by growing them 2-3 d in a culture to which eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) in 15 microM concentration was added. Analysis of the fatty acid composition of membrane phospholipids revealed a significantly higher level of EPA and DHA (from 0.2 to 7.6% and from 1.2 to 6.5%) in cells supplemented with EPA or DHA, respectively. The responses of the myocytes grown in normal media or in media enriched with the PUFA to arrhythmogenic agents were examined after free fatty acids were removed from the medium and the cells. The arrhythmogenic agents used were the beta-adrenergic agonist isoproterenol or an elevated extracellular concentration of calcium. The results showed that there was no significant difference in the induction of tachyarrhythmias by isoproterenol or by elevated [Ca2+]o in cells grown in media enriched with PUFA, as compared with cells grown in normal media in the absence of the free PUFA. Under the conditions of this study, only the unesterified PUFA were able to protect the cardiomyocytes against induced arrhythmias. There was no antiarrhythmic effect due to an increased fraction of EPA or DHA in membrane phospholipids.

Animals↗
PubMed1996

The cardiac antiarrhythmic effects of polyunsaturated fatty acid.

Each year in the United States alone some 250,000 persons die within one hour of an acute myocardial infarction. These deaths are largely due to ischemia-induced ventricular arrhythmias, primarily ventricular fibrillation (VF). Thus a safe, simple means of preventing such arrhythmias has considerable public health benefit potential. We have demonstrated that the intravenous infusion of n-3 polyunsaturated fatty acids (PUFA) from fish oils will prevent ischemia-induced VF in prepared, nonanesthetized, exercising dogs, confirming earlier feeding studies in rats. We show that this protective effect is due to an action of the free acidic form of the PUFA to alter the electrophysiology of individual cardiac myocyte so that the cells are electrically more stable. The electrophysiologic effects, in turn, result from direct and specific effects of the PUFA to block the fast voltage-dependent sodium channels. The binding of the free fatty acids is directly to the protein of the sodium channels and results in prolongation of the inactivated state of these channels. Other ion channels are also affected by the PUFA. Two clinical trials with n-3 PUFA are mentioned which inadvertently support the antiarrhythmic potential of PUFA ingestion.

Animals↗
PubMed1996

Prevention of cardiac sudden death by N-3 fatty acids: a review of the evidence.

The essential n-6 and n-3 polyunsaturated fatty acids can prevent ischaemia-induced ventricular fibrillation in rats, dogs and marmosets. In isolated neonatal rat cardiac myocytes, these have been shown to prevent tachyarrhythmias caused by elevated calcium concentrations, toxic levels of ouabain, a beta-adrenergic agent (isoproterenol), lysophosphatidylcholine and acylcarnitine. The antiarrhythmic effect is caused by a reduction in electrical excitability caused by partitioning of the free polyunsaturated fatty acids into the phospholipid cell membranes of the cardiac myocytes, which modulates membrane ion channels. Two clinical trials suggest they could prevent sudden cardiac death in humans.

Action Potentials↗
PubMed1995

Blocking effects of polyunsaturated fatty acids on Na+ channels of neonatal rat ventricular myocytes.

Recent evidence indicates that polyunsaturated long-chain fatty acids (PUFAs) prevent lethal ischemia-induced cardiac arrhythmias in animals and probably in humans. To increase understanding of the mechanism(s) of this phenomenon, the effects of PUFAs on Na+ currents were assessed by the whole-cell patch-clamp technique in cultured neonatal rat ventricular myocytes. Extracellular application of the free 5,8,11,14,17-eicosapentaenoic acid (EPA) produced a concentration-dependent suppression of ventricular, voltage-activated Na+ currents (INa). After cardiac myocytes were treated with 5 or 10 microM EPA, the peak INa (elicited by a single-step voltage change with pulses from -80 to -30 mV) was decreased by 51% +/- 8% (P < 0.01; n = 10) and 64% +/- 5% (P < 0.001; n = 21), respectively, within 2 min. Likewise, the same concentrations of 4,7,10,16,19-docosahexaenoic acid produced the same inhibition of INa. By contrast, 5 and 10 microM arachidonic acid (AA) caused less inhibition of INa, but both n - 6 and n - 3 PUFAs inhibited INa significantly. A monounsaturated fatty acid and a saturated fatty acid did not. After washing out EPA, INa returned to the control level. Raising the concentration of EPA to 40 microM completely blocked INa. The IC50 of EPA was 4.8 microM. The inhibition of this Na+ channel was found to be dose and time, but not use dependent. Also, the EPA-induced inhibition of INa was voltage dependent, since 10 microM EPA produced 83% +/- 7% and 29% +/- 5% inhibition of INa elicited by pulses from -80 to -30 mV and from -150 to -30 mV, respectively, in single-step voltage changes. A concentration of 10 microM EPA shifted the steady-state inactivation curve of INa by -19 +/- 3 mV (n = 7; P < 0.01). These effects of PUFAs on INa may be important for their antiarrhythmic effect in vivo.

Animals↗
PubMed1995

Free, long-chain, polyunsaturated fatty acids reduce membrane electrical excitability in neonatal rat cardiac myocytes.

Because previous studies showed that polyunsaturated fatty acids can reduce the contraction rate of spontaneously beating heart cells and have antiarrhythmic effects, we examined the effects of the fatty acids on the electrophysiology of the cardiac cycle in isolated neonatal rat cardiac myocytes. Exposure of cardiomyocytes to 10 microM eicosapentaenoic acid for 2-5 min markedly increased the strength of the depolarizing current required to elicit an action potential (from 18.0 +/- 2.4 pA to 26.8 +/- 2.7 pA, P < 0.01) and the cycle length of excitability (from 525 ms to 1225 ms, delta = 700 +/- 212, P < 0.05). These changes were due to an increase in the threshold for action potential (from -52 mV to -43 mV, delta = 9 +/- 3, P < 0.05) and a more negative resting membrane potential (from -52 mV to -57 mV, delta = 5 +/- 1, P < 0.05). There was a progressive prolongation of intervals between spontaneous action potentials and a slowed rate of phase 4 depolarization. Other polyunsaturated fatty acids--including docosahexaenoic acid, linolenic acid, linoleic acid, arachidonic acid, and its nonmetabolizable analog eicosatetraynoic acid, but neither the monounsaturated oleic acid nor the saturated stearic acid--had similar effects. The effects of the fatty acids could be reversed by washing with fatty acid-free bovine serum albumin. These results show that free polyunsaturated fatty acids can reduce membrane electrical excitability of heart cells and provide an electrophysiological basis for the antiarrhythmic effects of these fatty acids.

Action Potentials↗
PubMed1995

Prevention and termination of beta-adrenergic agonist-induced arrhythmias by free polyunsaturated fatty acids in neonatal rat cardiac myocytes.

Polyunsaturated omega-3 fatty acids, which have been shown to prevent ischemia-induced ventricular fibrillation in prepared dogs, were tested in cultured neonatal rat cardiac myocytes for their ability to prevent the tachyarrhythmias induced by isoproterenol, a beta-adrenergic agonist. We found that polyunsaturated fatty acids (5-10 microM), especially the fish oil omega-3 fatty acids, but not monouunsaturated and saturated fatty acids were able to effectively prevent and terminate the arrhythmias induced by isoproterenol (as well as by cAMP and cholera toxin) without affecting the cell contractility, and that their action was independent of their metabolites and incorporation into membrane phospholipid. These protective effects of the free fatty acids may contribute, at least in part, to their reported preventive effects on ischemia-induced ventricular fibrillation and sudden cardiac death.

Animals↗
PubMed1995

Protective effects of All-trans-retinoic acid against cardiac arrhythmias induced by isoproterenol, lysophosphatidylcholine or ischemia and reperfusion.

Previous studies have shown that free polyunsaturated fatty acids (PUFA) reduce the excitability of cardiac myocytes and exert antiarrhythmic effects. Therefore, we hypothesized that retinoic acid (RA, vitamin A acid), which has structural characteristics similar to those of PUFA, may have similar antiarrhythmic effects. To test this hypothesis, we used an isolated, spontaneously beating, neonatal rat cardiac myocyte preparation to examine the effects of RA, added to the perfusion solution, on the cell contraction and arrhythmias induced by isoproterenol (ISO) or lysophosphatidylcholine (LPC). All-trans-RA (10-20 microM) induced a marked and reversible reduction in the contraction rate of the cell in 2-5 min without changing the amplitude of the contractions. Superfusion of the myocytes with either ISO (3 microM) or LPC (5 microM) induced sustained tachyarrhythmias characterized by spasmodic contractures and fibrillation. Addition of 15-20 microM all-trans-RA to the perfusion solution effectively prevented as well as terminated the arrhythmias induced by ISO and LPC. Furthermore, in a whole-animal model of arrhythmia in which the left anterior descending coronary artery (LAD) of the anesthetized rat was occluded for 15 min followed by reperfusion, both the incidence and severity of ventricular tachycardia and fibrillation (VT, VF) were significantly reduced during the ischemic and reperfusion periods by intravenous infusion of all-trans-RA. In contrast, other analogues, including retinol and retinal, and other fat-soluble vitamins, including vitamin D, E, and K, did not have such effects. Our results demonstrate that all-trans-RA can produce antiarrhythmic effects similar to those of PUFA, suggesting a novel role of RA as a potential antiarrhythmic agent.

Animals↗
PubMed1995

Fatty acid composition of plasma and red cell phospholipids of preterm babies fed on breast milk and formulae.

UNLABELLED: Fatty acids of plasma and red cells of preterm babies, gestational age 28-33 weeks, weighing less than 2200 g were studied between birth and the expected date of delivery (EDD). Babies were fed either mothers' breast milk, or if they were unable, or chose not to breast-feed, randomly assigned to milk formula A or B. Milk B had 26% oleic acid, 0.5% docosahexaenoic acid (DHA) and 0.12% arachidonic (AA); A had 13% oleic acid, less than 0.05% AA and no DHA. The proportions of gamma linoleic and the other fatty acids, and the ratio of linoleic acid (LA)/alpha linolenic acid (ALA) were comparable in the two formulae. Diet and/or physiological adaptation seemed to be responsible for the significant changes in the proportions of certain fatty acids between birth and EDD. Incorporation of DHA in formula B increased its concentration in plasma and red cells, and reduced the conversion of LA to AA. With respect to maintenance of DHA status, milk B was superior to milk A but did not match breast milk. CONCLUSION: Fortification of formula with DHA without concomitant incorporation of AA may precipitate AA insufficiency and may have developmental implications.

Arachidonic Acids↗