Amphipathic metabolites and membrane dysfunction in ischemic myocardium.

Corr, Peter B.; Gross, Richard W.; Sobel, Burton E.

doi:10.1161/01.res.55.2.135

Cited by 428 publications

(142 citation statements)

References 193 publications

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“…Increased free fatty acid levels have long been known to increase both susceptibility to arrhythmias and the severity of damage following ischaemia (Kurien & Oliver, 1966;deLeiris & Feuvray, 1977; Katz & Messineo, 1981;Neely & Feuvray, 1981;Corr et al, 1984). Mitochondrial P-oxidation of fatty acids is blocked during ischaemia resulting in accumulation of acyl-CoA in mitochondria and of acyl carnitines in the cytosol (Idell-Wenger et al, 1978;Liedtke et al, 1978; 'Present address (and correspondence): Syntex Research Centre, Research Park, Riccarton, Edinburgh EH 14 4AS 2Present address: Preclinical Research, Sandoz, CH-4002, Basle, Switzerland.…”

Section: Introductionmentioning

confidence: 99%

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Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Spedding¹,

Mir²

1987

British J Pharmacology

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Palmitoyl carnitine, a lipid metabolite which accumulates in cytoplasmic membranes during ischaemia, has been shown to resemble the Ca2+ channel activator, Bay K 8644, in K+‐depolarized smooth muscle. Palmitoyl carnitine caused concentration‐dependent (1–1000 μmol l−1) augmentations in the sensitivity to Ca2+ of K+‐depolarized taenia preparations from the guinea‐pig caecum. The (±)‐isomer was equieffective with the (–)‐isomer, whereas carnitine was ineffective and palmitic acid relaxed the tissues. The shift to the left of Ca2+ concentration‐response curves induced by palmitoyl carnitine (100 μmol l−1) was additive with that of Bay K 8644 (1 μmol l−1). The interactions of palmitoyl carnitine with the different classes of calcium‐antagonist were similar to those seen with Bay K 8644. Schild plots of the calcium‐antagonist effects of nifedipine were shifted to the right following preincubation of the taenia with palmitoyl carnitine (30–300 μmol l−1). The inhibitory effects of verapamil were especially sensitive to palmitoyl carnitine (100 μmol l−1). Whereas the potency of diltiazem as a calcium‐antagonist was reduced by palmitoyl carnitine (100 μmol l−1), the inhibitory effects of the lipophilic class III calcium‐antagonists, cinnarizine and flunarizine, were entirely resistant to palmitoyl carnitine (100 μmol l−1). Although palmitoyl carnitine has detergent properties in high concentrations and lyses red blood cells, these effects were not Ca2+‐dependent, nor were they modified by calcium‐antagonists. Other detergents did not have selective interactions with Ca2+ channels. Palmitoyl carnitine inhibited [3H]‐nitrendipine, [3H]‐verapamil and [3H]‐diltiazem binding to rat cortical membranes with IC50 values (μmol l−1) of 120 ± 1, 95 ± 17 and 120 ± 15 μmol l−1 respectively. The inhibition showed little temperature‐dependence, in contrast to that of Bay K 8644, except for a small reduction in the IC50 value for [3H]‐verapamil binding at 37°C (42 ± 5 μmol l−1). Palmitoyl carnitine interacted selectively with the Ca2+ channel, in that effects on ligand binding to α‐adrenoceptors, β‐adrenoceptors and 5‐HT1A receptors occurred only at 5–10 fold higher concentrations. It is concluded that palmitoyl carnitine, at concentrations which have previously been shown to occur in the cytoplasm during myocardial ischaemia, may interact directly with Ca2+ channels and may therefore be considered as an endogenous modulator of channel function. The site of action differs from that of other agents.

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Section: Introductionmentioning

confidence: 99%

“…Neely & Feuvray, 1981;Knabb et al, 1986). Acyl carnitines normally transport lipids into mitochondria but during ischaemia, cytosolic concentrations can reach up to 0.29 jmol g' dry weight or 75-200;Lmol 1` ( Idell-Wenger et al, 1978;Corr et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Spedding¹,

Mir²

1987

British J Pharmacology

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“…Thus, acyl CoA activation of the cardiac ryanodine receptor could represent a mechanism by which the sensitivity of the channel to myoplasmic Ca2' is controlled within cells. A deregulation of intracellular Ca2' during metabolic stresses in which fatty acid metabolites are elevated could also occur by this mechanism [7,20].…”

Section: Resultsmentioning

confidence: 99%

Removal of Mg²⁺ inhibition of cardiac ryanodine receptor by palmitoyl coenzyme A

et al. 1994

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45CaZ' fluxes and planar bilayer recordings indicated that the fatty acid metabolite palmitoyl coenzyme A, but not free coenzyme A or palmitic acid, stimulated the cardiac ryanodine receptor channel of pig heart sarcoplasmic reticulum. Palmitoyl CoA reactivated channels inhibited by concentrations of cytoplasmic free Mg2+ in the physiological range. Reactivation by palmitoyl CoA in the presence of Me was stimulated by myoplasmic free Ca" in the micromolar range. Acyl coenzyme A derivatives may be utilized by cardiac muscle cells to compensate for the severe Mg*+ inhibition of ryanodine receptors which would otherwise leave Ca*' stores unresponsive to Ca" and to other cytosohc ligands involved in signal transduction.

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“…Because of both hydrophilic and hydrophobic properties, LPC can easily exert deleterious effects on biological membrane systems and cause electrophysiological alterations and mechanical dysfunction (Corr et al, 1984;Das et al, 1986;Datorre et al, 1991;Hoque et al, 1995). Therefore, LPC has been suspected as one of the mediators of ischaemic injury.…”

Section: Introductionmentioning

confidence: 99%

Effects of β‐adrenoceptor antagonists on Ca²⁺‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes

Chen

Hashizume

Abiko

1996

British J Pharmacology

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1 The effects of fl-adrenoceptor antagonists including (-)-and (+)-propranolol, (-)-and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca2+ -overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat.2 Fura-2 was used for measurement of the intracellular calcium concentration ([Ca2+] 5 LPC markedly increased the release of creatine phosphokinase from 9 + 1 to 45 + 2% which could be significantly reduced by (-)-or (+)-propranolol but not by acebutolol or timolol. 6 The protective effects of (-)-and (+)-propranolol, (-)-and (+)-penbutolol against the Ca2+-overload induced by LPC were not associated with the fl-adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these fl-adrenoceptor antagonists against the Ca2+-overload induced by LPC.

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Amphipathic metabolites and membrane dysfunction in ischemic myocardium.

Cited by 428 publications

References 193 publications

Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Removal of Mg²⁺ inhibition of cardiac ryanodine receptor by palmitoyl coenzyme A

Effects of β‐adrenoceptor antagonists on Ca²⁺‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes

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Amphipathic metabolites and membrane dysfunction in ischemic myocardium.

Cited by 428 publications

References 193 publications

Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand

Direct activation of Ca2+ channels by palmitoyl carnitine, a putative endogenous ligand

Removal of Mg2+ inhibition of cardiac ryanodine receptor by palmitoyl coenzyme A

Effects of β‐adrenoceptor antagonists on Ca2+‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes

Contact Info

Product

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Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Direct activation of Ca²⁺ channels by palmitoyl carnitine, a putative endogenous ligand

Removal of Mg²⁺ inhibition of cardiac ryanodine receptor by palmitoyl coenzyme A

Effects of β‐adrenoceptor antagonists on Ca²⁺‐overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes