leukotriene-e4 and Coronary-Disease

Topics: Animals; Cardiovascular System; Coronary Disease; Dogs; Guinea Pigs; Hemodynamics; Histamine; Humans; Inflammation; Leukotriene E4; Macaca; Rabbits; SRS-A

Excretion of leukotriene (LT) E4, the major urinary metabolite of cysteinyl leukotrienes in humans, is increased in patients with unstable angina and myocardial infarction, suggesting that cysteinyl leukotrienes are released into the circulation during episodes of myocardial ischaemia. Furthermore, leukotrienes are known to induce potent vasoconstrictive effects in human atherosclerotic coronary arteries and the saphenous vein. Accordingly, we measured urinary excretion of LTE4 in patients with stable coronary artery disease both before and after coronary artery bypass surgery, and in age-matched healthy controls, to study the relation between the systemic synthesis of cysteinyl leukotrienes and stable coronary artery disease, as well as the possible changes after bypass surgery.. LTE4 was isolated from urine samples by solid-phase extraction, purified by reverse-phase high-performance liquid chromatography, and subsequently quantified by radioimmunoassay.. In patients with coronary artery disease, preoperative urinary LTE4 levels were normally distributed on a log10 scale, with a genometric mean of 115 pmol/mmol creatinine (95% confidence interval 67-196) compared with 63.0 pmol/mmol creatinine (95% confidence interval 47.9-82.7) in healthy subjects (P < 0.05). Urinary LTE4 levels increased further in patients after coronary artery bypass surgery with levels peaking on the second day after surgery (266.2 pmol/mmol creatinine, 95% confidence interval 167.2-423.9) at significantly higher than preoperative levels (P < 0.02), and then decreasing by day 3.. Levels of cysteinyl leukotrienes are raised in coronary artery disease patients both before and after coronary artery bypass surgery. As these mediators are capable of inducing potent vasoconstrictive effects on atherosclerotic coronary arteries and the saphenous vein, our results could have important clinical and possibly therapeutic implications.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Coronary Artery Bypass; Coronary Disease; Humans; Leukotriene E4; Male; Middle Aged; Time Factors

Experimental cardiac ischemia in some animal models results in the activation of the enzyme 5-lipoxygenase and the subsequent production of leukotrienes, potent proinflammatory lipid mediators, by the affected myocardium. Furthermore, prototype antileukotriene drugs can show some beneficial effects on infarct size and cardiac function in these models. Accordingly, urinary excretion of leukotriene E4 (LTE4), the major urinary metabolite of peptide leukotrienes in humans, was measured in patients admitted to the hospital with evidence of acute myocardial ischemia to assess in vivo release of 5-lipoxygenase products during and after the ischemic episode.. Urinary leukotriene excretion was measured by reversed-phase high-performance liquid chromatography and specific radioimmunoassay on admission with acute chest pain and again on day 3 in the following patient groups: acute myocardial infarction (AMI), AMI and clinical evidence of early reperfusion after treatment with recombinant tissue-type plasminogen activator (rt-PA), diagnosis of unstable angina (UA) based on clinical history and coronary arteriography, controls with nonischemic chest pain who underwent coronary arteriography, and age-matched controls and normal hospital employees. In 16 patients with diagnosis of AMI, LTE4 excretion on admission (331 +/- 99 pg/mg creatinine sulfate; mean +/- SEM) was considerably higher than that measured on day 3 (195 +/- 59 pg/mg creatinine sulfate). In a subgroup of seven subjects treated with rt-PA resulting in early reperfusion, day 1 excretion was similar (215 +/- 50 pg/mg) but had significantly declined by day 3 (65 +/- 16 pg/mg; p less than 0.01). Urinary LTE4 excretion at admission for chest pain was also elevated in 14 patients having unstable angina (UA; 370 +/- 125 pg LTE4/mg creatinine sulfate). This had declined significantly (p less than 0.05) by day 3 (at which time chest pain had resolved) to 94 +/- 31 pg/mg creatinine sulfate, an excretion rate comparable with that measured in eight similarly aged subjects (64 +/- 12 pg/mg creatinine).. This study suggests that peptide leukotrienes are released during episodes of myocardial ischemia and provides clinical evidence for involvement of their biosynthetic enzyme, 5-lipoxygenase, during and after acute myocardial infarction and unstable angina attacks. Thus, potent and specific orally active leukotriene biosynthesis inhibitors may have therapeutic potential in limiting myocardial damage and functional abnormalities after acute ischemia.

Topics: Angina, Unstable; Arachidonate 5-Lipoxygenase; Chest Pain; Coronary Disease; Creatinine; Enzyme Activation; Female; Humans; Leukotriene E4; Leukotrienes; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Reference Values; SRS-A; Tissue Plasminogen Activator

Leukotriene (LT) E4, an important LT metabolite appearing in urine, can be rapidly separated from normal and pathological urines by automated reversed-phase HPLC after a simple sample-processing. The recoveries of LTE4 afforded by this system (86.4 +/- 6.5%, mean +/- SEM for 60 ng/L, 85.4 +/- 0.3% for 200 ng/L) are superior to those obtained by a manual extraction method. Consistency of results is similar. Highly reproducible retention times combined with a radioimmunoassay allow one to identify (based on co-elution) and quantify as little as 8 ng/L LTE4 in a 10-mL urine sample. LTE4 concentrations in urine from healthy persons approach this value (17 +/- 5 ng/L), whereas samples from patients with cardiac ischemia show a wider range of concentrations (8 to 388 ng/L), up to 50 times the detection limit. Thus this method is applicable to the noninvasive investigation of leukotriene involvement in a wide range of ischemic, inflammatory, and hypersensitive conditions.

Topics: Chromatography, High Pressure Liquid; Coronary Disease; Humans; Leukotriene E4; SRS-A

Leukotrienes are naturally occurring vasoactive metabolites of arachidonic acid that increase during inflammatory reactions and anaphylaxis. Coronary constriction and reduced myocardial contractility after leukotriene C4 and D4 administration were demonstrated in the isolated guinea pig heart. To explore the effects of leukotrienes in the in situ, blood-perfused heart, we administered leukotrienes C4, D4, and E4 into the coronary artery of the domestic pig. Increasing doses (0.1, 0.3, 1.0, and 3.0 micrograms) of leukotrienes C4, D4, and E4 were injected into the left anterior descending coronary artery of 8 open-chest domestic pigs. Significant dose-related reduction in coronary blood flow was observed after each leukotriene administration. Three micrograms of each leukotriene produced the following maximal decreases (mean +/- standard error); C4 = 80 +/- 9%, p less than 0.001; D4 = 81 +/- 3%, p less than 0.001; E4 = 64 +/- 12%, p less than 0.005. In several instances, surface electrograms recorded from the myocardial region exposed to leukotrienes showed signs of focal myocardial ischemia, sometimes accompanied by ventricular arrhythmia. Significant elevation of left ventricular end-diastolic pressure was observed after large doses (1 or 3 micrograms) of leukotrienes C4 and D4. Minimal (5 to 10%) decreases in mean arterial pressure and no change in heart rate were observed after leukotriene injection. We conclude that leukotrienes C4, D4, and E4 are extremely potent coronary constrictors in the in situ heart. The intensity of response and associated electrocardiographic signs of ischemia suggest that constriction is mainly due to a primary effect on vascular smooth muscle. However, coronary flow reduction may also reflect consequences of a primary negative inotropic action. Leukotrienes may play a significant role in the pathogenesis of a variety of cardiac disorders, particularly those associated with extensive inflammatory changes.

Topics: Animals; Coronary Circulation; Coronary Disease; Dose-Response Relationship, Drug; Guinea Pigs; Hemodynamics; Leukotriene E4; Myocardial Contraction; SRS-A; Vasoconstriction