Inhibition of platelet aggregation by prostacyclin is attenuated after exercise in patients with angina pectoris.

We tested whether alteration of platelet sensitivity to prostacyclin (PGI2) is involved in the activation of platelets induced by exercise in patients with stable angina. Twenty patients and 20 control subjects underwent treadmill testing. Blood samples were obtained before and immediately after exercise for plasma thromboxane B2 (TXB2) and 6-keto-PGF1 alpha (6kP) assays and platelet aggregation studies. Dose-response curves for platelet aggregation to collagen were obtained in the presence and absence of 1 nmol/L PGI2 to quantify the antiaggregation effects of PGI2. At rest, platelet aggregation by collagen was enhanced in the patients. However, platelets were more sensitive to exogenous PGI2, apparently associated with lower plasma 6kP levels in the patients. After exercise, plasma TXB2 levels increased in the patients but not in the control subjects. Plasma 6kP levels remained unchanged and platelet sensitivity to PGI2 decreased in the patients whereas these values increased in the control subjects. The exercise-induced changes in platelet sensitivity to PGI2 correlated with those of platelet adenylate cyclase activity in response to 1 nmol/L PGI2 (r = 0.787, p less than 0.01). Thus impaired sensitivity of platelets to PGI2, in addition to the reduced response of prostanoid secretion, might be relevant to the platelet activation associated with exercise in patients with stable angina.     

Effect of OKY-046, a thromboxane A2 synthetase inhibitor, on arachidonate-induced platelet aggregation: possible role of "prostaglandin H2 steal" mechanism

To clarify the mode of action of a selective thromboxane A2 (TXA2) blockade in platelet reactivity, we examined the effect of (E)-3-[4-(1-imidazolylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a potent TXA2 synthetase inhibitor, on human platelet aggregation induced by arachidonic acid (1 mM) in the absence and presence of aspirin-treated aortic microsomes containing prostacyclin (PGI2) synthetase activity ex vivo. The production of TXA2 and PGI2 in platelet rich plasma was determined by the amounts of their stable catabolites, TXB2 and 6-keto-PGF1 alpha respectively, measured by radioimmunoassay. In the absence of aortic microsomes, OKY-046 (greater than 10(-5) M) produced more than 90% inhibition of TXA2 production, whereas platelet aggregation was less inhibited, about 40% inhibition over control, by OKY-046 in that concentration. In the presence of aortic microsomes, the inhibitory effect of OKY-046 on platelet aggregation was markedly augmented in a dose-dependent manner in proportion to the increment of PGI2 production, which paralleled the OKY-046-induced inhibition of TXA2. These results suggest that a selective TXA2 blockade produces effects on platelet aggregation mainly in dual fashion in the presence of PGI2 synthetase: one is due to mere inhibition of TXA2 synthetase and the other is due to the enhancement of PGI2 production probably involving "prostaglandin H2 (PGH2) steal" mechanism, in which PGH2 accumulated in platelets is partly converted to a substrate of PGI2 synthetase in aortic microsomes to produce PGI2.     

Reduction of prostacyclin synthesis as a possible cause of transient flow reduction in a partially constricted canine coronary artery

Coronary blood flow decreases cyclically in a partially occluded coronary artery of anesthetized dogs. Spontaneous aggregation and deaggregation of platelet plugs in the constricted artery have been indicated to be responsible for this phenomenon. A current hypothesis is that platelet aggregation may be determined by a balance between proaggregatory platelet product, thromboxane A2 (TXA2), and antiaggregatory substance, prostacyclin (PGI2). To elucidate the relationship between the cyclical reduction of coronary flow (CRCF) and metabolic alterations of TXA2 and PGI2, we attempted to determine the plasma levels of their stable catabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the coronary circulation of 69 dogs. Of 40 cases, 20 cases exhibited CRCF accompanying a significant increase in TXB2 in the coronary sinus (CS) (P less than 0.05) and constant levels of 6-keto-PGF1 alpha in the CS and aorta (Ao). Another 20 cases did not exhibit CRCF that accompanied a marked increase in 6-keto-PGF1 alpha (P less than 0.05) with virtually no change in TXB2 in the CS and Ao. A higher dose of indomethacin (10 mg/kg, i.v.) was capable of evoking CRCF in cases not exhibiting CRCF spontaneously. Under these conditions, a significant decrease in 6-keto-PGF1 alpha was seen both in the CS and Ao compared with lower doses of indomethacin (1 to 3 mg/kg, P less than 0.01), that produced less pronounced reduction of 6-keto-PGF1 alpha without CRCF. Intravenous infusion of PGI2 (0.1 microgram/kg/min.) completely abolished spontaneously and indomethacin-induced CRCF with a marked elevation of 6-keto-PGF1 alpha in the CS and Ao. Although OKY-1580, a TXA2 synthetase inhibitor, relieved spontaneously-evoked CRCF with a marked increase in 6-keto-PGF1 alpha and a slight reduction of TXB2, indomethacin-induced CRCF was not abolished by this agent. These results are consistent with the hypothesis that the reduction of endogenous PGI2 synthesis in the vascular wall is related to the occurrence of CRCF after partial constriction of coronary artery and indomethacin.     

Exercise-induced myocardial ischemia in patients with coronary artery disease: lack of evidence for platelet activation or fibrin formation in peripheral venous blood

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.     

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep

We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.     

Effects of treadmill exercise on platelet functions and blood coagulating activities in healthy men

The effects of treadmill exercise (up to 85% of the predicted maximum heart rate) on platelet functions and coagulating activities were studied in 26 normal men. Blood sampling for the measurements were performed from the antecubital vein at rest, at 3, 6, 9, and 12 min during exercise, immediately postexercise, and at 6 and 30 min after exercise. Measurements for blood analysis included the following: platelet sensitivity and percent aggregation to ADP, platelet counts, plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels, plasma epinephrine and norepinephrine levels, plasma fibrinogen level, activity of plasma antithrombin III, and of plasma factors VIII, IX, XI, and XII. No significant changes were induced by dynamic leg exercise in platelet sensitivities and the maximum and 3-min percent aggregation. The platelet counts increased during exercise in platelet-rich plasma without a significant change in that in whole blood. During exercise, plasma thromboxane B2 levels showed a tendency to increase, while plasma 6-keto-prostaglandin F1 alpha levels to decrease. Plasma epinephrine levels showed a tendency to increase and norepinephrine levels increased during exercise. Among coagulating factors, factor VIII activities and fibrinogen levels increased without altering activities of factors IX, XI, and XII. Antithrombin III activities also increased during exercise. In spite of significant changes in several coagulating factors, prothrombin time and partial thromboplastin time were not influenced by exercise. In conclusion, dynamic leg exercise of a moderate to high intensity produced a significantly elevated plasma level of factor VIII, fibrinogen, antithrombin III, and catecholamines without affecting the hemostatic balance in normal subjects.     

Serial studies of platelet factor 4 and beta thromboglobulin during exercise in patients with coronary artery disease

In vivo activation of platelets can be accurately measured by radioimmunoassays of platelet factor 4 (PF4) and beta thromboglobulin (beta TG). Studies that attempt to correlate increases in PF4 and beta TG levels with exercise-induced myocardial ischemia have yielded conflicting results. To further examine the natural history of release of PF4 and beta TG we used a method of serial samplings of these proteins during and after exercise in nine normal subjects and 24 patients with coronary artery disease (CAD). Mean values for PF4 and beta TG at rest, during each stage, and immediately after treadmill exercise were the same for normal subjects and for patients with positive and negative responses to exercise-tolerance tests (ETTs). However, nonparametric analysis and regression equations disclosed differences in trends of PF4 level during exercise; PF4 levels increased in normal subjects during exercise, while patients with positive ETTs had no change in PF4 levels and patients with negative ETTs actually showed a decrease in PF4. This investigation confirmed that exercise-induced myocardial ischemia is not associated with platelet aggregation as manifested by the release of the platelet-specific proteins PF4 and beta TG. Statistical analysis suggested that prior reports of elevated levels of PF4 during exercise could have been caused by technical and methodologic difficulties that were associated with the collection and handling of the samples.     

Whole blood aggregation, thromboxane release and the lyso derivative of platelet activating factor in myocardial infarction and unstable angina

To investigate the pathophysiology of intracoronary thrombus formation we measured whole blood aggregation in response to ADP, platelet activating factor (PAF) and collagen, along with thromboxane B2 (TXB2) production during collagen induced aggregation, plasma TXB2 and plasma levels of lyso-PAF, in 38 subjects with and without ischaemic heart disease (12 with acute myocardial infarction, 9 with prolonged ischaemic chest pain without infarction and 17 normals). Lyso-PAF was measured, after in vitro acetylation to active PAF, by bioassay using 14C-serotonin labelled rabbit platelets. TXB2 was measured by radioimmunoassay. Plasma TXB2 was elevated at presentation only in patients with myocardial infarction (p less than 0.01). While impedance aggregation was similar in the three groups, aggregation to collagen resulted in greater release of TXB2 in subjects with myocardial infarction (p less than 0.01), an abnormality persisting 2-4 months later. Plasma lyso-PAF levels were significantly depressed throughout the first week in subjects with infarction (p less than 0.002), but after 2 to 4 months the level was greater than in normal subjects (p less than 0.001), changes presently unexplained. It is possible that the disorder of platelet function preceded and predisposed to coronary thrombosis. The findings strengthen the grounds for aspirin therapy in acute myocardial infarction.     

Augmented platelet reactivity and thromboxane A2 production possible aggravating factors in unstable angina

We examined platelet aggregation and plasma levels of thromboxane B2, a stable metabolite of thromboxane A2, in patients with unstable angina and correlated these platelet indices with the response to antianginal conventional therapy such as isosorbide dinitrate and calcium channel blocker. Eight of 36 patients exhibited anginal attacks more than 5 times/week in spite of the therapy, designated refractory unstable angina, associated with augmented platelet aggregation induced by arachidonate (0.3 mM, 71 +/- 3%, mean +/- SEM) and collagen (2 micrograms/ml, 72 +/- 5%), and elevated plasma levels of thromboxane B2 (350 +/- 19 pg/ml). In the remainder of the patients whose anginal attacks were effectively subsided by the therapy, platelet aggregation was much lower (arachidonate: 34 +/- 9%, collagen: 31 +/- 8%, p less than 0.01) and plasma levels of thromboxane B2 were also lower (295 +/- 12 pg/ml, p less than 0.05). To evaluate the effect of selective thromboxane A2 blockade on clinical findings and platelet reactivity in refractory unstable angina, OKY-046 (600 mg/day, p.o.) was administered to another 14 patients with refractory unstable angina in addition to the conventional therapy. We found that platelet aggregation induced by arachidonate (71 +/- 4%) and collagen 65 +/- 8%) was markedly reduced (44 +/- 7% and 24 +/- 3%, respectively, p less than 0.01) and plasma levels of thromboxane B2 (358 +/- 31 pg/ml) and thromboxane B2 production in serum (29 +/- 5 ng/ml) were also significantly reduced after OKY-046 treatment (262 +/- 21 pg/ml, p less than 0.05, and 1.4 +/- 0.2 ng/ml, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostanoid synthesis by cultured gastric and duodenal mucosa: Possible role in the pathogenesis of duodenal ulcer

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.     

Follow-up of prostaglandin plasma levels after acute myocardial infarction

Prostaglandin plasma levels are elevated in patients with transient myocardial ischemia. We measured 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane (B2(TXB2) in venous blood of 32 patients with myocardial infarction on the first, third, and seventh days. TXB2 and 6-keto-PGF1 alpha levels in these patients (up to 117 +/- 237 pg/ml and 96 +/- 105 pg/ml mean +/- SD, respectively) differed significantly from levels in normal control subjects (10 +/- 12 pg/ml and 4 +/- 7 pg/ml mean +/- SD, respectively) (p less than 0.01). Prostaglandin values remained elevated from day 1 through day 7. In most patients, 6-keto-PGF1 alpha levels prevailed over those of TXB2. In a subgroup suffering from cardiac arrhythmias, the ratio of 6-keto-PGF1 alpha/TXB2 was inverse. It is concluded that prostaglandin generation is increased for at least 7 days after myocardial infarction. A disturbed ratio of 6-keto-PGF1 alpha/TXB2 in favor of the latter might be associated with cardiac arrhythmias in myocardial infarction.     

Thromboxane B2, 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 plasma levels in arteriosclerosis obliterans: relationship to clinical manifestations, risk factors, and arterial pathoanatomy

Current concepts of atherogenesis based on animal and human investigations indicate prostaglandins as a key factor in atherosclerotic lesions. The plasma profiles of thromboxane B2 (TXB2), 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 were investigated by means of a sensitive radioimmunoassay technique in 40 patients with arteriosclerosis obliterans and in 30 healthy control subjects. Abnormally high levels of TXB2 and PGE2 (222.97 +/- 320.86 pg/ml, mean +/- SD, vs 20 +/- 2.1 and 352.66 +/- 235.54 vs 24.4 +/- 3, p less than 0.01) were detected in arteriosclerosis obliterans patients. The ratio between TXB2 and 6-keto-PGF1 alpha was increased from 1.2 in control subjects to 6.0 in patients. In arteriosclerosis obliterans TXB2 increased in relation to clinical manifestations and to the extension of the vascular damage. In addition, TXB2 was positively related to serum triglyceride content (r = 0.562, p less than 0.05) and inversely related to platelet count (r = 0.727, p less than 0.001). The marked imbalance between the stable metabolites of thromboxane and prostacyclin in arteriosclerosis obliterans patients provides biologic evidence which fits well with the thrombogenic theory of atherosclerosis. These results further support the theory that prostaglandins may be heavily involved in atherosclerosis.     

Selective thromboxane A2 synthetase inhibition in vasospastic angina pectoris

To investigate whether thromboxane A2 is responsible for the initiation of vasospastic angina pectoris, thromboxane B2 levels were measured in the great cardiac vein and the arterial blood of 12 patients with clinically and angiographically proved vasospastic angina and therapeutic trials were performed with selective thromboxane A2 synthetase inhibitor OKY-046, an imidazole derivative. During ergonovine-provoked (11 cases) and spontaneous (1 case) anginal attacks, great cardiac vein thromboxane B2 increased from 121 +/- 27 to 430 +/- 382 pg/ml (p less than 0.05, n = 12), arterial thromboxane B2 increased from 93 +/- 18 to 122 +/- 33 pg/ml (NS, n = 12) and thromboxane B2 production increased from 3.18 +/- 1.88 to 25.16 +/- 22.32 ng/min (p less than 0.05, n = 6). Subsequently, OKY-046, 400 mg/day orally, was administered to 7 of the 12 patients, while a continuous electrocardiogram was recorded on a dual channel Holter monitor during a 3 day placebo period and the 3 day OKY-046 regimen. Although peripheral plasma thromboxane B2 levels decreased significantly from 98 +/- 15 to 12 +/- 8 and 28 +/- 10 pg/ml (1 and 6 hours after ingestion, respectively) (p less than 0.05 for both), 6-keto-prostaglandin F1 alpha production in serum increased significantly from 0.48 +/- 0.22 to 2.3 +/- 0.72 (1 hour) and 1.8 +/- 0.46 ng/ml (6 hours) (p less than 0.05 for both) during OKY-046 administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral microcirculatory changes after cerebral embolization induced by glass bead injection in rabbits.

The authors investigated microcirculatory changes in cerebral embolization induced by an injection of glass beads (mesh size 20/400, 15 mg/body) using intravital microscopy and reflectance spectrophotometry in normal rabbits. Cerebral embolization with the glass bead injection reduced the inner diameter of cerebral arterioles, the index of cerebral hemoglobin concentration (IHb), and the index of oxygen saturation (ISO2). Moreover, platelet aggregation rates and plasma levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) appreciably increased. During observation of the pial vasculature, "white bodies" became visible at the entrance of arteriolar branchings two to three minutes after the glass bead injection. After indomethacin administration (3 mg/kg, IV), they could not observe white bodies, and platelet aggregation rates were significantly reduced. The plasma levels of TXB2 and 6-keto-PGF1 alpha were also significantly reduced. These findings suggest that glass beads do injury to the microvascular endothelial cells leading to development of white bodies, ie, "flying thrombi." Therefore, the cerebral microvascular embolization induced by the glass bead injection appears to be an experimental model for evaluating efficacy of remedies for the cerebral microcirculatory disorders.     

Comparison of platelet function during exercise in normal subjects and coronary artery disease patients: Potential role of platelet activation in myocardial ischemia

Platelet function parameters as influenced by exercise stress were evaluated in 22 patients with coronary artery disease (CAD) and in 13 normal subjects. Upon exercise stress, 14 CAD patients exhibited positive tests and eight exhibited negative tests. Platelet counts during exercise increased similarly in normal and CAD patients. Platelet aggregation response to ADP was unaffected by exercise both in normal and CAD patients. Platelets from 7 of the 14 CAD patients with positive stress tests had increased sensitivity to endoperoxide analog (U-46619) defined as less than 200 ng/ml U-46619 required for 50% platelet aggregation. Resting plasma beta-thromboglobulin (B-TG) levels, an index of in vivo platelet activation, were significantly higher in CAD patients compared to normal subjects (74 +/- 7 and 41 +/- 5 ng/ml, respectively; p less than 0.02). During exercise plasma B-TG levels increased in normal subjects to 60 +/- 5 ng/ml. In contrast, B-TG levels increased to 102 +/- 14 ng/ml in CAD patients (p less than 0.01 compared to normal subjects). These increases were transient and B-TG declined to preexercise values soon after exercise. Eleven of the 12 CAD patients with positive exercise stress tests had increases in plasma B-TG levels, whereas only three of the eight CAD patients with negative stress tests had any increase. These observations of increased platelet activation in certain CAD patients during exercise may be related to exercise-induced myocardial ischemia.     

肌氨肽苷对冠心病患者血管内皮功能的影响及其与血小板功能的关系

目的　评价肌氨肽苷注射液对冠心病患者血管内皮功能及血小板功能的影响及二者之间的相互关系。方法　将 14 6例冠心病患者分为肌氨酞苷治疗组与常规治疗组 ,各组又分别分为急性心肌梗死 (AMI)、陈旧性心肌梗死 (OMI)、不稳定型心绞痛 (UA)及稳定型心绞痛 (SA) 4个亚组。对照组 2 0例。分别测定各组治疗前后的血浆内皮素 (ET)、一氧化氮 (NO)及血小板最大聚集率 (PAGTmax)、血栓素B2 (TXB2 )的变化。结果　 1.治疗前 ,各AMI组与UA组的血浆ET、PAGTmax及TXB2 较对照组显著增高 ,NO与对照组比较显著降低 ;OMI及SA组各参数均无显著性差异。 2 .肌氨肽苷治疗后AMI组与UA组的血浆ET、PAGTmax及TXB2 较治疗前显著降低 ,NO呈显著性增高(P <0 .0 5 ,P <0 .0 1) ,与对照组比较差异无显著性 (P >0 .0 5 ) ;ET下降值分别与PAGTmax、TXB2 的变化呈显著性正相关关系。而常规治疗组治疗后各值与治疗前比较虽有变化 ,但均无显著性差异。结论　肌氨肽苷注射液可通过降低血浆ET水平和增加NO浓度来改善血管内皮功能及进一步发挥抑制血小板聚集及血栓形成的作用     

Exercise-induced left bundle branch block and its relation to coronary artery disease

The records of 2,584 consecutive patients who underwent both treadmill exercise testing and coronary cineangiography were reviewed to determine the relation between exercise-induced, acceleration-dependent left bundle branch block (LBBB) and the presence of coronary artery disease (CAD). Rate-dependent LBBB during exercise was identified in 28 patients (1.1%), who were categorized according to their presenting symptoms: classic angina pectoris, atypical chest pain, symptomatic cardiac arrhythmia and asymptomatic. Asymptomatic patients underwent a screening exercise test. CAD was present in 7 of 10 patients who presented with classic angina pectoris, but 12 of 13 patients presenting with atypical chest pain had normal coronary arteries. All 10 patients in whom LBBB developed at a heart rate of 125 beats/min or higher were free of CAD, whereas 9 of 18 patients in whom LBBB developed at a heart rate of less than 125 beats/min had CAD. Normal coronary arteries were present in 3 patients who presented with angina and in whom both chest pain and LBBB developed during exercise. It is concluded that patients who present with atypical chest pain in whom rate-dependent LBBB develops on the treadmill are significantly less likely to have CAD than patients who present with classic angina; the onset of LBBB at a heart rate of 125 beats/min or higher is highly correlated with the presence of normal coronary arteries, regardless of patient presentation; and patients with angina in whom both chest pain and LBBB develop during exercise may have normal coronary arteries.     

Effects of exercise and ethanol ingestion on platelet thromboxane release in healthy men

We studied the effects of repeated bicycle exercises and ethanol ingestion (1.5 g/kg) on platelet aggregation and thromboxane (TxB2) release in 10 healthy male volunteers. After a bicycle exercise performed in the morning, the adenosine diphosphate (ADP)-induced platelet aggregation and the aggregation-associated thromboxane release were found to be decreased in fasting men. In contrast, after ingestion of fruit juice and a second exercise at noon, platelet aggregation and thromboxane release were increased. These latter changes were negligible when ethanol was ingested together with fruit juice. A third exercise, performed in the evening, again caused a decrease in the aggregation and associated thromboxane release during the control session, but provoked an increase during the ethanol session. Exercise increased the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha. Changes in the plasma arachidonic acid (AA) concentration probably influenced the platelet thromboxane release. The results suggest that both physical exercise and ingestion of ethanol in fruit juice influence the ADP-stimulated platelet thromboxane release.     

Sudden death induced by intracoronary platelet aggregation

Sodium arachidonate (AA, 1.5 mg/kg) was injected into the coronary arteries in 16 rabbits. Arrhythmia, marked ST-T depression and apnea appeared in all cases, and 7 cases died within 10 min after the AA. Before the injection, the thromboxane B2 (TXB2) value was 1.2 +/- 0.2 ng/ml (mean +/- SE) and the 6-keto-PGF1 alpha value was 2.1 +/- 0.4 ng/ml. Three minutes after the AA, TXB2 values were 5.0 +/- 1.1 in the surviving cases and 17.9 +/- 6.5 ng/ml in the cases which died. 6-keto-PGF1 alpha values were 47.7 +/- 4.6 in the surviving cases and 248.5 +/- 69.3 ng/ml in the cases which died. There occurred no deaths in 7 cases pretreated with aspirin (ASA) and in 11 cases pretreated with OKY-046 and 1581, which are specific inhibitors of TXA2 synthetase. TXB2 values did not change in the ASA and OKY groups after the AA injection. 6-keto-PGF1 alpha values did not change in the ASA group and increased in the OKY group after the AA injection. Histological findings of the heart showed more remarkable ischemic changes in the non-pretreated group than in the ASA and OKY groups. These results suggest a role for TXA2 in sudden death. PGI2 production was extremely enhanced, suggesting the presence of a protective mechanism against thrombogenesis in vivo.     

Thromboxane A2 could be involved in bronchial hyperresponsiveness to methacholine in asthmatic subjects but not in bronchitic subjects

To determine whether the involvement of thromboxane A2 in bronchial hyperresponsiveness is specific to asthma, we examined the effects of a selective thromboxane synthetase inhibitor (OKY-046) and a cyclooxygenase inhibitor (indomethacin) on bronchial responsiveness to methacholine in patients with bronchial asthma and chronic bronchitis. The provocative concentration of methacholine producing a 20% fall in forced expiratory volume in one second (PC20-FEV1) was measured before and after oral administration of OKY-046 and indomethacin in eight asthmatic and 10 bronchitic subjects. Baseline FEV1 value was not altered by OKY-046 or indomethacin. The geometric mean value of PC20-FEV1 increased significantly (p less than 0.005) from 1.78 to 4.27 mg/ml after OKY-046 in asthmatic subjects, but not in bronchitic subjects. On the other hand, PC20-FEV1 was not altered by indomethacin in all subjects. It was concluded that the involvement of thromboxane A2 in bronchial hyperresponsiveness may be specific to asthma.