Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously reported in working swine hearts a preferred use of fatty acids during early myocardial reperfusion. The purpose of these studies was to test whether this pattern of substrate oxidation was the result of excess energy demands during mechanical recovery. Two groups of pig hearts (n = 15) were compared. Both received Intralipid with heparin (serum fatty acids, 1.02 +/- 0.05 mumol/ml) to ensure preferred substrate availability and both received [2-14C]pyruvate to monitor myocardial use of a carbohydrate substrate. In one group (n = 8) oxfenicine was administered to suppress fatty acid utilization. Left anterior descending (LAD) coronary flow was maintained at aerobic levels for 30 min, reduced by 60% for 45 min, and restored to aerobic levels for a final 50 min. Ischemia caused the expected decreased in global and regional mechanical performance. Recovery in motion during reflow was less in oxfenicine-treated hearts (73 vs. 32% decrease in systolic shortening from aerobic values in treated and control hearts, P less than or equal to 0.01 and P less than or equal to 0.05, respectively). Pyruvate oxidation declined dramatically in both groups during ischemia but recovered disparately. In control hearts CO2 production remained depressed during reperfusion (NS from ischemic values), whereas in treated hearts it increased 5.5-fold (but did not exceed aerobic values). Tissue levels of acetyl CoA and acetylcarnitine were not statistically different between perfusion beds (aerobic vs. reperfusion) within groups. Oxfenicine reduced levels of acetyl carnitine in both perfusion beds.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of substrate preference for oxidative metabolism during early myocardial reperfusion. 238 16

Two fatty acid blocking agents, oxfenicine (33 mg/kg) and 4-bromocrotonic acid (0.34 mg/kg/min for 70 min), were used to selectively adjust levels of long-chain acyl CoA and carnitine in aerobic and ischemic myocardium. The purpose of the study was to test whether the shift in these amphiphiles was associated with alterations of mechanical function in intact myocardium. The extracorporeally perfused swine heart preparation was used. Hearts were perfused at aerobic levels for 40 min following which flow to the anterior descending (LAD) circulation was reduced by 50% for the final 30 min of perfusion. All hearts were perfused with excess fatty acids to raise serum levels to 1.37 +/- 0.16 mumol/mol throughout the studies. Oxfenicine and 4-bromocrotonic acid affected a 20% (P less than 0.05 and P less than 0.05, respectively) further decline in 14CO2 production from labelled palmitate as compared with placebo hearts during regional ischemia. Accompanying this were downward shifts in acyl carnitine (-27 delta %, NS in aerobic tissue; -70 delta %, P less than 0.001 in ischemic tissue) and acyl CoA (-13 delta %, NS in aerobic tissue; -33 delta %, P less than 0.01 in ischemic tissue) for oxfenicine and upward shifts of acyl carnitine (+212 delta %, P less than 0.001 in aerobic tissue; -9 delta %, NS in ischemic tissue) and acyl CoA (+78 delta %, P less than 0.001 in aerobic tissue; +29 delta %, P less than 0.025 in ischemic tissue) for 4-bromocrotonic acid. These adjustments in amphiphiles were further associated with improved function (+55 delta % increase in max LV dP/dt, P less than 0.05) in oxfenicine-treated hearts and depressed function (+87 delta % increase in LVEDP, P less than 0.05) in 4-bromocrotonic acid-treated hearts. Thus, at comparable conditions of coronary flow, left ventricular pressure, and fatty acid availability and oxidation between treatments, depletion or build-up of CoA and carnitine esters as affected by selective inhibitors of fatty acid metabolism were causally linked to improved or impaired cardiac performance in intact hearts.
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PMID:Effects of the fatty acid blocking agents, oxfenicine and 4-bromocrotonic acid, on performance in aerobic and ischemic myocardium. 362 84

A new model using isolated rabbit hearts perfused at constant flow in the Langendorff mode with the sinus node destroyed and under constant (2 Hz) pacing is described. Ventricular ischemia (24 min) was induced by ligation of the left ventricular branch of the coronary artery (LVB), followed by reperfusion (15 min). The programmed electrical stimulation (PES) technique was used to induce arrhythmias in the ischemic zone (IZ). Three agents with different mechanisms of action were tested to validate this model: dl-sotalol (10(-6) and 10(-5) M), oxfenicine (10(-6) M), and lidocaine (10(-5) M). These compounds were administered 15 min before the ligature and maintained until the end of the experiment. Ventricular effective refractory period (VERP), PES-induced ventricular fibrillation (VF), and coronary perfusion pressure (CPP) were monitored. PES-induced VF was only observed in ischemic tissue. Sotalol slightly reduced VF incidence only during reperfusion. Oxfenicine prevented PES-induced VF during the ischemia, but not during reperfusion, while lidocaine prevented VF during ischemia and throughout the reperfusion period. In conclusion, the rabbit heart model where PES is applied to normal and ischemic myocardium, appears useful to discern different mechanisms involved in ventricular arrhythmias. In addition, this model is considerably cheaper than equivalent dog models.
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PMID:An in vitro method for the evaluation of antiarrhythmic and antiischemic agents by using programmed electrical stimulation of rabbit heart. 818 42

Perhexiline is a potent prophylactic anti-anginal agent that has been shown to inhibit myocardial utilization of long-chain fatty acids and to inhibit the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1. We compared the hemodynamic and biochemical effects of perhexiline (0.5 and 2.0 microM) and of another CPT-1 inhibitor, oxfenicine (0.5 mM), in Langendorff-perfused rat hearts subjected to 60 min of low-flow ischemia (95% flow reduction) followed by 30 min of reperfusion. Both perhexiline (2 microM only) and oxfenicine attenuated (p < 0.003, p < 0.0002, respectively) increases in diastolic tension during ischemia, without significant effects on developed tension, or on cardiac function during reperfusion. Myocardial concentrations of long-chain acylcarnitines (LCAC), products of CPT-1 action, were decreased (p < 0.05) by oxfenicine, unaffected by 2 microM perhexiline, and increased slightly by 0.5 microM perhexiline. Perhexiline, but not the active metabolite of oxfenicine, also inhibited cardiac CPT-2 with similar IC50 and Emax, although lower Hill slope, compared with CPT-1. Oxfenicine, but not perhexiline, reduced concentrations of the endogenous CPT-1 inhibitor, malonyl-CoA. Perhexiline, but not oxfenicine, inhibited myocardial release of lactate during normal flow. We conclude that (a) perhexiline protects against diastolic dysfunction during ischemia in this model, independent of major changes in LCAC accumulation and (b) this may result from simultaneous effects of perhexiline on myocardial CPT-1 and CPT-2.
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PMID:Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. 1111 81