The long-term treatment with etomoxir improved functional capacity of pressure-overloaded left ventricle, which can be attributed to an enhanced myocardial performance. Chronic carnitine palmitoyltransferase-1 inhibition may thus represent a candidate approach for developing novel agents that are useful in the prevention of undesirable consequences of pressure overload-induced cardiac hypertrophy.

To define vascular effects of an enhanced dietary alpha-linolenic acid intake, 28 spontaneously hypertensive rats were fed a 3% sunflowerseed oil (44% linoleic acid) diet; in 3 groups (7 rats each), the diet was supplemented with 1, 2.5 or 5% linseed oil containing 62% alpha-linolenic acid. alpha-Linolenic acid was incorporated up to 12% in the aorta of the 5% linseed oil group. The eicosapentaenoic acid content was not significantly increased. The content of arachidonic acid and docosatetraenoic acid was moderately reduced in rats fed 5% linseed oil. The generation of 6-keto-PGF1 alpha (degradation product of prostacyclin) assessed by HPLC/electrochemical detection was, however, markedly increased (p < 0.05) in rats fed 2.5 and 5% linseed oil. The minor prostanoids TXB2, PGE2 and PGF2 alpha were not significantly altered. The high systolic and diastolic blood pressure of SHR monitored by radio telemetry was more effectively reduced (p < 0.05) in the light, i.e. sleep, cycle. An increased prostacyclin formation and lowered vascular arachidonic acid content associated with enhanced dietary alpha-linolenic acid intake would thus be expected to prove beneficial in the prevention of vascular disorders.

1 Etomoxir (2[6(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), an irreversible carnitine palmitoyltransferase 1 inhibitor, reduces the expression of the myocardial foetal gene programme and the functional deterioration during heart adaption to a pressure-overload. Etomoxir may, however, also improve the depressed myocardial function of hypertrophied ventricles after a prolonged pressure overload. 2 To test this hypothesis, we administered racemic etomoxir (15 mg kg 71 day 71 for 6 weeks) to rats with ascending aortic constriction beginning 6 weeks after imposing the pressure overload. 3 The right ventricular/body weight ratio increased (P50.05) by 20% in etomoxir treated rats (n=10) versus untreated rats with ascending aortic constriction (n=10). Left ventricular weight was increased (P50.05) by 8%. Etomoxir blunted the increase in left ventricular chamber volume. Etomoxir raised the proportion of V 1 isomyosin (35+4% versus 24+2%; P50.05) and decreased the percentage of V 3 isomyosin (36+4% versus 48+3%; P50.05). 4 Maximum isovolumically developed pressure was higher in etomoxir treated rats than in untreated pressure overloaded rats (371+22 versus 315+23 mmHg; P50.05). Maximum rates of ventricular pressure development (14,800+1310 versus 12,340+1030 mmHg s 71 ; P50.05) and decline (6440+750 versus 5040+710 mmHg s 71 ; P50.05) were increased as well. Transformation of pressure values to ventricular wall stress data revealed an improved myocardial function which could partially account for the enhanced function of the whole left ventricle. 5 The co-ordinated action of etomoxir on ventricular mass, geometry and myocardial phenotype enhanced thus the pressure generating capacity of hypertrophied pressure-overloaded left ventricles and delayed the deleterious dilative remodelling. Keywords: CPT-1 inhibitor; etomoxir; pressure overload; heart hypertrophy; heart failure; myosin isozymes; ventricular performanceAbbreviations: TDGA, 2-tetradecylglycidic acid; ACE, angiotensin converting enzyme; CPT-1, carnitine palmitoyltransferase I; POCA, clomoxir; P, left intraventricular pressure; V, left ventricular cavity volume; W, left ventricular wall volume; MHC, myosin heavy chains; +dP/dt max , maximal rate of intraventricular pressure rise and decline; 7ds/dt max , maximal rate of wall stress rise and decline; s, mean wall stress; C R , midwall circumference; +dP/ dt, rate of intraventricular pressure rise and decline; +ds/dt, rate of wall stress rise and decline

IntroductionThe precise mechanisms of the inflammatory responses after cerebral ischemia in vivo are difficult to elucidate because of the complex nature of multiple series of interactions between cells and molecules. This study explored temporal patterns of secretion of 30 cytokines and chemokines from Sprague Dawley rat astrocytes in primary culture in order to elucidate signaling pathways that are triggered by astrocytes during anoxia.MethodsPrimary cultures of rat brain astrocytes were incubated for periods of 2–24 hr in the absence of oxygen (anoxia) or under normal partial pressure of oxygen (controls). Simultaneous detection of 29 cytokines and chemokines in the samples was performed using a rat cytokine array panel, while the temporal pattern of angiopoietin‐1 (Ang‐1) secretion was determined separately using ELISA. Wilcoxon–Mann–Whitney test was used to compare normoxic and anoxic samples and the Hodge–Lehman estimator with exact 95% confidence intervals was computed to assess the size of differences in cytokine secretion. The obtained data were imported into the Core Analysis tool of Ingenuity Pathways Analysis software in order to relate changes in secretion of cytokines and chemokines from astrocytes during anoxia to potential molecular signal networks.ResultsWith the exception of Ang‐1, concentrations of all cytokines/chemokines in samples collected after anoxia exposure were either the same, or higher, than in control groups. No clear pattern of changes could be established for groups of cytokines with similar effects (i.e., pro‐ or anti‐inflammatory cytokines). The pattern of changes in cytokine secretion during anoxia was associated with the HIF‐1α‐mediated response, as well as cytokines IL‐1β and cathepsin S pathways, which are related to initiation of inflammation and antigen presentation, respectively, and to ciliary neurotrophic factor.ConclusionsThese in vitro findings suggest that astrocytes may play a role in triggering inflammation during anoxia/ischemia of the brain.