8-11-14-eicosatrienoic-acid and Chronic-Disease

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Arachidonic Acid; Chronic Disease; Fatty Acid Desaturases; Fatty Acids, Omega-6; Humans; Inflammation

Atypical antipsychotics such as olanzapine cause metabolic side effects leading to obesity and insulin resistance. The underlying mechanisms remain elusive. In this study we investigated the effects of chronic treatment of olanzapine on the fatty acid composition of plasma in mice.. Twenty 8-week female Balb/c mice were randomly assigned to two groups: the OLA group and the control group. After treatment with olanzapine (10 mg/kg/day) or vehicle intraperitoneally for 8 weeks, fasting glucose, insulin levels and oral glucose tolerance test were determined. Effects on plasma fatty acid profile and plasma indices of D5 desaturase, D6 desaturase and SCD1 activity were also investigated.. Chronic administration of olanzapine significantly elevated fasting glucose and insulin levels, impaired glucose tolerance, but did not increase body weight. Total saturated fatty acids and n-6 polyunsaturated fatty acids were significantly increased and total monounsaturated fatty acids were significantly decreased, while total n-3 polyunsaturated fatty acids showed no prominent changes. Chronic olanzapine treatment significantly up-regulated D6 desaturase activity while down-regulating D5 desaturase activity. Palmitic acid (C16:0), dihomo-γ-linolenic acid (C20:3n-6) and D6 desaturase were associated with an increase probability of insulin resistance, whereas nervonic acid (C24:1) and SCD1 were significantly associated with a lower insulin resistance probability.. All results indicated that such drug-induced effects on fatty acid profile in plasma were relevant for the metabolic adverse effects associated with olanzapine and possibly other antipsychotics. Further studies are needed to investigate geneticand other mechanisms to explain how plasma fatty acids regulate glucose metabolism and affect the risk of insulin resistance.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antipsychotic Agents; Area Under Curve; Benzodiazepines; Blood Glucose; Chronic Disease; Fatty Acid Desaturases; Fatty Acids; Female; Glucose Tolerance Test; Insulin; Insulin Resistance; Mice; Mice, Inbred BALB C; Olanzapine; Palmitic Acid; Random Allocation

Cardiorenal syndromes were defined and classified recently, but the mechanism of chronic renocardiac syndrome remains disputed. Theories about chronic renocardiac syndrome cannot offer a convincing explanation for it. As a result, the current therapies of chronic renocardiac syndrome do not contribute to a satisfied prognosis. Epoxyeicosatrienoic acids, the products of arachidonic acid metabolized by cytochrome P450 enzymes, play an important role in the maintenance of renal hemodynamics, and regulation of renal, cardiac, and vascular function with antihypertensive and anti-inflammatory properties. It is well documented that down-regulation of epoxyeicosatrienoic acids might be involved in alterations in various pathophysiological states, including hypertension, uremia and hepatorenal syndrome. Likewise, epoxyeicosatrienoic acids were reduced in heart failure and renal dysfunction. This leads to the proposed hypothesis that epoxyeicosatrienoic acids down-regulation may be the novel mechanism of chronic renocardiac syndrome. These findings suggest that manipulation of epoxyeicosatrienoic acid levels could be a novel pharmacological therapy strategy for chronic renocardiac syndrome.

Topics: 8,11,14-Eicosatrienoic Acid; Chronic Disease; Heart Diseases; Humans; Kidney Diseases; Syndrome

The systemic vasculature exhibits attenuated vasoconstriction following chronic hypoxia (CH) that is associated with endothelium-dependent vascular smooth muscle (VSM) cell hyperpolarization. We hypothesized that increased production of arachidonic acid metabolites such as the cyclooxygenase product prostacyclin or cytochrome p-450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) contributes to VSM cell hyperpolarization following CH. VSM cell resting membrane potential (Em) was measured in superior mesenteric artery strips isolated from rats with control barometric pressure (Pb, congruent with 630 Torr) and CH (Pb, 380 Torr for 48 h). VSM cell Em was normalized between groups following administration of the CYP inhibitors 17-octadecynoic acid and SKF-525A. VSM cell hyperpolarization after CH was not altered by cyclooxygenase inhibition, whereas the selective CYP2C9 inhibitor sulfaphenazole normalized VSM cell Em between groups. Iberiotoxin also normalized VSM cell Em, which suggests that large-conductance, Ca2+-activated K+ (BKCa) channel activity is increased after CH. Sulfaphenazole administration restored phenylephrine-induced and myogenic vasoconstriction and Ca2+ responses of mesenteric resistance arteries isolated from CH rats to control levels. Western blot experiments demonstrated that CYP2C9 protein levels were greater in mesenteric arteries from CH rats. In addition, 11,12-EET levels were elevated in endothelial cells from CH rats compared with controls. We conclude that enhanced CYP2C9 expression and 11,12-EET production following CH contributes to BKCa channel-dependent VSM cell hyperpolarization and attenuated vasoreactivity.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Aryl Hydrocarbon Hydroxylases; Blotting, Western; Calcium Channel Blockers; Cell Membrane; Chronic Disease; Cyclooxygenase Inhibitors; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Fatty Acids, Unsaturated; Hypoxia; In Vitro Techniques; Male; Membrane Potentials; Mesenteric Arteries; Muscle, Smooth, Vascular; Oxygenases; Potassium Channels, Calcium-Activated; Proadifen; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Vasoconstriction

Topics: 8,11,14-Eicosatrienoic Acid; Acute Disease; Chronic Disease; Eicosanoids; Endothelium, Vascular; Hemorheology; Humans; Myocardial Infarction; Myocardial Ischemia; Platelet Activation; Stress, Mechanical