Beta-oxidation Of Free Fatty Acids Research Articles

Dietary L-carnitine supplementation modifies blood parameters of mid-lactating dairy cows during standardized lipopolysaccharide-induced inflammation.

L-carnitine, available as feed additive, is essential for the beta-oxidation of free fatty acids in the mitochondrial matrix. It provides energy to immune cells and may positively impact the functionality of leukocytes during the acute phase response, a situation of high energy demand. To test this hypothesis, German Holstein cows were assigned to a control group (CON, n = 26) and an L-carnitine supplemented group (CAR, n = 27, rumen-protected L-carnitine product: 125 g/cow/d, corresponded to total L-carnitine intake: 25 g/cow/d, supplied with concentrate) and received an intravenous bolus injection of lipopolysaccharides (LPS, 0.5 µg/kg body weight, E. coli) on day 111 postpartum as a model of standardized systemic inflammation. Blood samples were collected from day 1 ante injectionem until day 14 post injectionem (pi), with frequent sampling through an indwelling venous catheter from 0.5 h pi to 12 h pi. All parameters of the white blood cell count responded significantly to LPS, while only a few parameters were affected by L-carnitine supplementation. The mean eosinophil count, as well as the percentage of basophils were significantly higher in CAR than in CON over time, which may be due to an increased membrane stability. However, phagocytosis and production of reactive oxygen species by leukocytes remained unchanged following L-carnitine supplementation. In conclusion, although supplementation with 25 g L-carnitine per cow and day resulted in increased proportions of specific leukocyte populations, it had only minor effects on the functional parameters studied in mid-lactating dairy cows during LPS-induced inflammation, and there was no evidence of direct improvement of immune functionality.

Hepatoprotective Effects of Rheum turkestanicum Janisch on High-fat Diet-induced Non-alcoholic Fatty Liver Disease in Mice

Background:: Consumption of a high-fat diet (HFD) is one of the main causes of nonalcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. background: Consumption of a high-fat diet (HFD) is one of the main causes of non-alcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on which the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. Objective:: This study aimed to evaluate the effect of Rheum turkestanicum Janisch extract (RTE) on HFD-induced NAFLD in BALB/c mice. Materials and Methods:: The study was performed with two models of prevention and therapeutic effect of RTE. Serum biochemical markers, histopathology, oxidative stress indicators, and qRTPCR were measured to evaluate the effects of RTE on lipid metabolism disorders in mice feeding with HFD. Results:: In the prevention model, compared to the HFD group, RTE treatment decreased the levels of glucose, triglyceride, and cholesterol and improved liver profile markers, oxidative stress, and expression of genes involved in lipid metabolism. Conclusion:: The results of this study suggest that RTE has hepatoprotective effects against HFDinduced liver damage by reducing oxidative stress, lipogenesis, and increasing beta-oxidation of free fatty acids.

Fasting ketone levels vary by age: implications for differentiating physiologic from pathologic ketotic hypoglycemia.

Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical aspart of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is tomeasure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast. Children≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast. Data from 94 participants (mean 8.3±5.7 years, 54 % male, 46 % female, were analyzed. Children≤3 years of age (19) have significantly higher mean (0.40±0.06 mmol/L) and median (0.4, IQR 0.2-0.6 mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21±0.02 mmol/L) and median BHB (0.1, IQR 0.1-0.2 mmol/L) (p<0.0001). Fasting BHB levels of >1.0 mmol/L was rare (2 %, N=2) and 74 % (N=70) of participants had BHB levels <0.3 mmol/L. BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0 mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.

The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.

Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma.

Dynamic changes in chromatin accessibility, altered adipogenic gene expression, and total versus de novo fatty acid synthesis in subcutaneous adipose stem cells of normal-weight polycystic ovary syndrome (PCOS) women during adipogenesis: evidence of cellular programming

BackgroundNormal-weight polycystic ovary syndrome (PCOS) women exhibit adipose resistance in vivo accompanied by enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with accelerated lipid accumulation per cell in vitro. The present study examines chromatin accessibility, RNA expression and fatty acid (FA) synthesis during SC abdominal ASC differentiation into adipocytes in vitro of normal-weight PCOS versus age- and body mass index-matched normoandrogenic ovulatory (control) women to study epigenetic/genetic characteristics as well as functional alterations of PCOS and control ASCs during adipogenesis.ResultsSC abdominal ASCs from PCOS women versus controls exhibited dynamic chromatin accessibility during adipogenesis, from significantly less chromatin accessibility at day 0 to greater chromatin accessibility by day 12, with enrichment of binding motifs for transcription factors (TFs) of the AP-1 subfamily at days 0, 3, and 12. In PCOS versus control cells, expression of genes governing adipocyte differentiation (PPARγ, CEBPα, AGPAT2) and function (ADIPOQ, FABP4, LPL, PLIN1, SLC2A4) was increased two–sixfold at days 3, 7, and 12, while that involving Wnt signaling (FZD1, SFRP1, and WNT10B) was decreased. Differential gene expression in PCOS cells at these time points involved triacylglycerol synthesis, lipid oxidation, free fatty acid beta-oxidation, and oxidative phosphorylation of the TCA cycle, with TGFB1 as a significant upstream regulator. There was a broad correspondence between increased chromatin accessibility and increased RNA expression of those 12 genes involved in adipocyte differentiation and function, Wnt signaling, as well as genes involved in the triacylglycerol synthesis functional group at day 12 of adipogenesis. Total content and de novo synthesis of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1), and oleic (C18:1) acid increased from day 7 to day 12 in all cells, with total content and de novo synthesis of FAs significantly greater in PCOS than controls cells at day 12.ConclusionsIn normal-weight PCOS women, dynamic chromatin remodeling of SC abdominal ASCs during adipogenesis may enhance adipogenic gene expression as a programmed mechanism to promote greater fat storage.

'Targeting the feast of a sleeping beast': Nutrient and mineral dependencies of encysted Acanthamoeba castellanii.

Acanthamoeba spp. cause a corneal infection, Acanthamoeba keratitis (AK), and a cerebral infection, granulomatous amoebic encephalitis (GAE). Though aggressive chemotherapy has been able to kill the active trophozoite form of Acanthamoeba, the encysted form of this parasite has remained problematic to resist physiological concentrations of drugs. The emergence of encysted amoeba into active trophozoite form poses a challenge to eradicate this parasite. Acanthamoeba trophozoites have active metabolic machinery that furnishes energy in the form of ATPs by subjecting carbohydrates and lipids to undergo pathways including glycolysis and beta-oxidation of free fatty acids, respectively. However, very little is known about the metabolic preferences and dependencies of an encysted trophozoite on minerals or potential nutrients that it consumes to live in an encysted state. Here, we investigate the metabolic and nutrient preferences of the encysted trophozoite of Acanthamoeba castellanii and the possibility to target them by drugs that act on calcium ion dependencies of the encysted amoeba. The experimental assays, immunostaining coupled with bioinformatics tools show that the encysted Acanthamoeba uses diverse nutrient pathways to obtain energy in the quiescent encysted state. These findings highlight potential pathways that can be targeted in eradicating amoebae cysts successfully.

OR20-03 Transcriptional Changes in Lipid Metabolism of Adipocytes Derived from Subcutaneous Abdominal Adipose Stem Cells of Normal-Weight Polycystic Ovary Syndrome Women

Normal-weight polycystic ovary syndrome (PCOS) women exhibit increased adipose insulin resistance in vivo (1) accompanying enhanced subcutaneous (SC) abdominal adipose stem cell (ASC) development to adipocytes with greater lipid accumulation per cell in vitro (2). To determine whether this phenomenon is associated with abnormal adipogenic gene transcription during ASC differentiation into adipocytes, SC abdominal ASCs isolated from three non-Hispanic Caucasian normal-weight PCOS women and three age- and BMI-matched controls were cultured in adipogenic differentiation medium for 3–12 days. After RNA isolation, gene expression levels were determined by RNA sequencing at days 3, 7, and 12. Differentially expressed genes were filtered for significance (padj<0.05) and fold change (>2-fold); upstream regulator genes and gene ontology (GO) functions were determined using Ingenuity Pathway Analysis. Gene set enrichment analysis (GSEA) also was used to identify enriched cellular processes (3). Differentially expressed genes in PCOS vs. control cells were either upregulated (466, 768 and 441 genes on days 3, 7 and 12, respectively) or downregulated (742, 974 and 605 genes on days 3, 7 and 12, respectively) over time, with critical genes governing adipocyte cell differentiation in PCOS cells increased 2–6 fold at days 3, 7 and 12 (PPARγ, CEBPα, ADIPOQ, AGPAT2, FABP4, LPL, PLIN1). The predicted upstream regulator genes TGFβ1 (an adipogenic inhibitor) and TNF (a pro-inflammatory adipokine) were significantly reduced in PCOS relative to control cells at all time points. The GO functions lipid oxidation and free fatty acid (FFA) beta-oxidation were enriched amongst upregulated genes in PCOS cells across all time points, while acylglycerol synthesis was increased at days 7 and 12 alone (z>2, p<0.05, all GO functions). In parallel, GSEA showed in PCOS cells significantly increased transcripts related to oxidative phosphorylation, peroxisome activity and adipogenesis at all time points (p<0.05). Thus, adipocytes derived from SC abdominal ASCs of normal-weight PCOS women exhibit early activation of adipogenic genes, potentially underlying their exaggerated lipid accumulation in vitro, as previously described (2). These PCOS-related changes in gene expression involve an increase in both oxidative phosphorylation and FFA beta oxidation, which could disrupt the balance between energy production and lipid storage, particularly when caloric intake exceeds energy utilization.

Gene expression in the liver of the rat induced in synthetic torpor

Torpor/hibernation is a survival strategy used by several mammals in periods of unfavorable environmental conditions, such as food shortage and low ambient temperature. It is characterized by an active reduction in metabolic rate followed by a decrease in body temperature. The decrease of metabolism and therefore in oxygen demand could be beneficial in many clinical conditions, such as, but not only, transplant and stroke. Recently, rats (non‐hibernating mammals) were successfully induced in a torpor‐mimicking state called synthetic torpor (Cerri, Annu Rev Physiol., 2017) by central inhibition of Raphe Pallidus (RPa), a key brainstem area involved in thermoregulation (Cerri et al., J Neurosci., 2013). Even though this model is very promising, it is still not known how this condition of induced etherotermy acts on a cellular level on a non‐hibernating mammal.Eight male Sprague‐Dawley rats, adapted to a standard Light‐Dark cycle of 12h‐12h (Light: 07 AM–07 PM), were used. Under general anesthesia (Diazepam, 5mg/kg, i.m., Ketamine, 100 mg/kg, i.p.), animals were implanted with a hypothalamic thermistor and a microcannula within the RPa. After recovery from surgery, starting at 7 AM, rats were divided in two groups: i) animals induced in a state of synthetic torpor by the repeated microinjections of the GABA‐A agonist muscimol (1mM, 120nl), within the RPa for 9 hours (Synthetic torpor, n=4); ii) homeothermic animals, injected with artificial cerebrospinal fluid (aCSF) within the RPa (Control, n =4), for 9 hours. At 4 PM, rats were euthanized and the liver was dissected and processed for gene expression analysis by RNA‐Seq.Analysis of the Differential Expression (DE) shows that in synthetic torpor a total of 1107 mRNA sequences were significantly up‐regulated, among which genes involved in the metabolic switch to beta‐oxidation of free fatty acids (fatty acid binding proteins (FABP), Peroxisome proliferator‐activated receptor (PPAR) family, Pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK4), Carnitine Palmitoyltransferase 1α (CPT1α)) and 1337 significantly down‐regulated.In a preliminary analysis, we report that several upregulated genes in synthetic torpor are known to be upregulated in hibernation as well. These preliminary findings suggest that the specific adaptation observed in natural torpor may be replicated also in non hibernators. Significantly upregulated mRNA expression of genes involved in fatty acid metabolism, in rats induced in synthetic torpor (Synthetic torpor, n=4) vs normothermic ones (Control, n=4) expressed in values of log2FC (FC=fold change). On the right side, their corresponding known function, and a list of hibernating species where a significant upregulation of the genes has been observed in literature. mRNA log2FC Function Upregulated in Fatty‐acid binding proteins (FABP) Facilitation of β‐oxidation in mitochondria Myotis lucifugus (Eddy&amp; Storey, 2004) Ictidomys tridecemlineatus (Epperson et al., 2010) FABP5 1.05 FABP9 1.65 FABP12 1.42 Peroxisome proliferator‐activated receptor (PPAR) family Safe deposition and consumption of fatty acid, avoiding the associated inflammatory risks (Nunn et al. 2007). Linked to the integration of nutritional information and circadian rhythms (Kohsaka &amp; Bass, 2007; Green et al. 2008). Spermophilus tridecemlineatus (Eddy et al., 2004) Myotis lucifugus (Eddy&amp; Storey, 2004) PPARGC1a 3.40 PPARGC1b 1.80 Pyruvate dehydrogenase lipoamide kinase isozyme 4 Shift away from the oxidation of carbohydrates and toward the combustion of stored fatty acids as the primary source of energy during torpor (Buck et al., 2002) Ictidomys Tridecemlineatus (Buck et al., 2002) PDK4 4.03 Carnitine Palmitoyltransferase 1α Fatty acid catabolism Urocitellus parryii (Williams et al., 2011) CPT1α 1.08

L-Carnitine Does Not Reduce Cytotoxicity from Induction Chemotherapy for Acute Lymphoblastic Leukemia

IntroductionOff-target effects of induction therapy to treat Acute Lymphoblastic Leukemia (ALL) can lead to hepatotoxicity, cardiotoxicity, and neuropathy, particularly in patients with previous co-morbidities. Incorporation of pegylated L-asparaginase (L-ASP) into pediatric and adult ALL induction regimens has increased remission rate but results in severe hepatotoxicity. Levocarnitine (L-carnitine), a small amino-acid derivative, has been reported in small case series in children and adults with ALL to reduce asparaginase-induced hepatotoxicity. L-carnitine functions as a transport molecule and facilitates long-chain free fatty acid beta-oxidation; exogenous supplementation with L-carnitine may therefore protect hepatocytes through facilitation of fatty acid transport and maintenance of antioxidant balance in mitochondria. However, the effects of L-carnitine on ALL cell survival and possible contributions of L-carnitine to chemotherapy resistance in ALL are not known. Given the ability of L-carnitine to enhance energy production, we sought to investigate whether L-carnitine could compromise the efficacy of common induction chemotherapy agents against ALL cells.MethodsHuman ALL cells, BV173 and RS4;11 were treated with L-carnitine and either daunorubicin (DNR) or vincristine (VCR) for 72 hours (n=4-6). RS4;11 cells were additionally treated with L-ASP (n=4), and current testing to assess dexamethasone in RS4;11 is in progress. Experiments were performed in 96-well culture plates with a seeding density of 90,000-120,000 cells/well (~5 x105 cells/mL). Growth media (RPMI 1640, 1% sodium pyruvate, 1% glutamine, 10% fetal bovine serum) was supplemented to physiologic (50 μM) and supraphysiologic (100-200 μM) levels of L-carnitine (normal reference range: 25-70 μM). Chemotherapy doses were chosen to represent ~EC90 concentrations (BV173: 2 nM VCR and 25 nM DNR; RS4;11: 2 nM VCR, 20 nM DNR, and 0.1 IU/mL L-ASP). After 72 hours, cell viability was measured by trypan blue exclusion and confirmed with spectrophotometric analysis with the Alamar Blue cell viability assay. Data were analyzed using one-way analysis of variance (ANOVA) with significance defined as p<0.05.ResultsAddition of L-carnitine did not significantly affect cytotoxicity of VCR or DNR in BV173 (n=6) or cytotoxicity of VCR, DNR, or L-ASP in RS4;11 (n=4) as measured by trypan blue exclusion at 72 hours (Figure 1A). L-carnitine also did not affect cell viability assessed using Alamar Blue colorimetric assay, presented as the difference in reduction of resazurin (resorufin) compared to untreated RS4;11 or BV173 cells (Figure 1B).ConclusionOur data show L-carnitine has no significant effect on the cytotoxicity of VCR, L-ASP, or DNR in two human ALL cell lines. For providers incorporating L-carnitine into induction therapy to reduce asparaginase-induced hepatotoxicity, this data supports its use without compromising the efficacy of induction therapy. Further investigation is necessary to determine whether L-carnitine alters efficacy of glucocorticoid drugs, particularly dexamethasone, and other chemotherapies used in the treatment of ALL and across other ALL subtypes. DisclosuresNo relevant conflicts of interest to declare.

The role of point-of-care 3-hydroxybutyrate testing in patients with type 2 diabetes undergoing coronary angiography

PurposeKetone bodies, 3-hydroxybutyrate (3BOHB), and acetoacetate derive from increased free fatty acid beta-oxidation, thus reflecting marked insulin deprivation with or without decompensated diabetes. Objectives of this study were (1) to determine circulating levels of 3BOHB in patients with and without type 2 diabetes (T2DM), before and after an elective coronary angiography; (2) to detect 3BOHB modification during the procedure; (3) to study possible associations between 3BOHB and clinical parameters/outcomes.MethodsSixteen T2DM (72 ± 11 years) and 22 matched controls (71 ± 12 years) undergoing elective coronary angiography were enrolled. In all subjects, biohumoral parameters were determined at hospital admission. Point-of-care determinations of 3BOHB, glucose, and creatinine were performed, at 7 a.m, immediately before and after the procedure. The duration of the fasting period and of the procedure was recorded.ResultsT2DM had significantly higher fasting (0.538 ± 0.320 vs 0.255 ± 0.197 mM/l; p = 0.005) and pre-procedural (0.725 ± 0.429 vs 0.314 ± 0.205; p = 0.002) 3BOHB concentrations than controls. Similarly, absolute increment of 3BOHB from the morning value was significantly greater in T2DM (0.369 ± 0.252 vs 0.127 ± 0.135 in controls; p = 0.002). Significant correlations were observed between pre-procedure 3BOHB and glucose levels (r = 0.586; p < 0.0001) and between pre-procedure 3BOHB and fasting creatinine concentrations (r = 0.364; p = 0.029).ConclusionsAn overnight fasting period and a concomitantly stressful condition induce inappropriate 3BOHB increase in T2DM. Point-of-care capillary 3BOHB may be useful before any procedural/surgical intervention in these patients.

Evidence for a beneficial effect of glucose–insulin–potassium in patients with acute coronary syndromes. Did the IMMEDIATE trial solve an unanswered question?

Evaulation of: Selker HP, Beshansky JR, Sheehan PR et al. Out-of-hospital administration of intravenous glucose–insulin–potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 9(307), 1925–1933 (2012).Catecholamine release in conjunction with an acute coronary syndrome induces metabolic changes that impair the situation for the ischemic myocardium. Attempts have been made to improve the prognosis in patients with acute coronary syndrome by means of infusing glucose–insulin–potassium in order to improve glucose metabolism and decrease beta-oxidation of free fatty acids. A trial, IMMEDIATE, tested this concept in a new way by initiating glucose–insulin–potassium during transportation to hospital, is discussed in this article.

Chronic Activation of Peroxisome Proliferator-Activated Receptor-α with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure

Severe heart failure (HF) is characterized by profound alterations in cardiac metabolic phenotype, with down-regulation of the free fatty acid (FFA) oxidative pathway and marked increase in glucose oxidation. We tested whether fenofibrate, a pharmacological agonist of peroxisome proliferator-activated receptor-alpha, the nuclear receptor that activates the expression of enzymes involved in FFA oxidation, can prevent metabolic alterations and modify the progression of HF. We administered 6.5 mg/kg/day p.o. fenofibrate to eight chronically instrumented dogs over the entire period of high-frequency left ventricular pacing (HF + Feno). Eight additional HF dogs were not treated, and eight normal dogs were used as a control. [3H]Oleate and [14C]Glucose were infused intravenously to measure the rate of substrate oxidation. At 21 days of pacing, left ventricular end-diastolic pressure was significantly lower in HF + Feno (14.1 +/- 1.6 mm Hg) compared with HF (18.7 +/- 1.3 mm Hg), but it increased up to 25 +/- 2 mm Hg, indicating end-stage failure, in both groups after 29 +/- 2 days of pacing. FFA oxidation was reduced by 40%, and glucose oxidation was increased by 150% in HF compared with control, changes that were prevented by fenofibrate. Consistently, the activity of myocardial medium chain acyl-CoA dehydrogenase, a marker enzyme of the FFA beta-oxidation pathway, was reduced in HF versus control (1.46 +/- 0.25 versus 2.42 +/- 0.24 micromol/min/gram wet weight (gww); p < 0.05) but not in HF + Feno (1.85 +/- 0.18 micromol/min/gww; N.S. versus control). Thus, preventing changes in myocardial substrate metabolism in the failing heart causes a modest improvement of cardiac function during the progression of the disease, with no effects on the onset of decompensation.

Effects of procainamide and disopyramide on long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic heart.

Though the efficacies of procainamide and disopyramide in treating arrhythmias are well established, their precise mechanisms of antiarrhythmic action remain unclear. Arrhythmias which occur during acute myocardial ischemia can be explained partly on a metabolic basis. The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acids has been suggested as a cause of serious arrhythmias. The purpose of this study was to investigate changes in free carnitine, long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic canine heart following the administration of procainamide and disopyramide. The coronary artery was occluded for 40 min and myocardial samples were prepared from both nonischemic and ischemic areas. Procainamide and disopyramide prevented the accumulation of long chain acyl carnitine and long chain acyl CoA in the ischemic myocardium. The results showed that procainamide and disopyramide had beneficial effects on fatty acid metabolism. It was suggested that one of the antiarrhythmic mechanisms of these drugs might be the prevention of the accumulation of fatty acyl derivatives in the ischemic myocardium.

Antiarrhythmic and myocardial metabolic effects of verapamil during coronary artery reperfusion.

The accumulation of metabolic intermediates subsequent to impaired beta-oxidation of free fatty acids has been suggested to be a cause of cellular damage and ventricular arrhythmias in the ischemic heart. The effects of verapamil on ventricular arrhythmias and free fatty acids metabolism during coronary artery reperfusion in experimental dogs were evaluated over a period of 40 minutes and followed by reperfusion for 15 minutes. One tenth mg/kg/min of verapamil was administered for 5 minutes before occlusion and followed by an infusion of 0.01 mg/kg/min to the end of the experiment. Myocardial samples were obtained from both the non-ischemic and ischemic areas after coronary artery reperfusion and then ATP, free carnitine, long chain acyl carnitine and long chain acyl CoA were measured. In the control group, 3 dogs (27%) had ventricular fibrillation and 2 dogs (18%) had ventricular tachycardia during coronary occlusion. In addition, 2 dogs (25%) developed ventricular fibrillation after reperfusion. On the other hand, all 6 dogs treated with verapamil had neither ventricular fibrillation nor tachycardia during both coronary artery occlusion and reperfusion. ATP and free carnitine levels in the ischemic area were significantly higher in the verapamil group than in the control group (ATP: p less than 0.01, free carnitine: p less than 0.05), while long chain acyl carnitine levels in the ischemic area were significantly lower in the verapamil group than in the control group (p less than 0.01). However, there was no significant change in long chain acyl CoA levels between the control and verapamil groups.(ABSTRACT TRUNCATED AT 250 WORDS)