6-ketoprostaglandin-f1-alpha and Myocardial-Infarction

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Coronary Disease; Diet, Atherogenic; Myocardial Contraction; Myocardial Infarction; Nucleotides, Cyclic; Prostaglandins; Rabbits; Thiophenes; Thromboxane A2; Ticlopidine

Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infarction, but the underlying mechanisms are unclear. The effects of binge drinking on the hemostatic system and its circadian variation have not been investigated. We investigated the effects of an acute intake of a large dose of alcohol (1.5 g/kg).. Twelve healthy, nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit juice alone and, lying in a supine position, were followed up for 12 to 24 hours. The treatments were randomized and separated from each other by a 1-week washout period. Blood and urine were collected for hemostatic measurements.. The urinary excretion of the platelet thromboxane A(2) metabolite 2, 3-dinor-thromboxane B(2) was significantly (P<0.05) greater during the night after an evening intake of alcohol than during the control night. A smaller increase was observed during the daytime after an intake of alcohol in the morning. The effects on the endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F(1alpha) excretion were negligible. A 7-fold increase in plasminogen activator inhibitor 1 activity was observed after both morning (P<0. 05) and evening (P<0.01) intakes of alcohol.. This is the first study to suggest that acute ingestion of a relatively large but tolerable dose of alcohol transiently enhances thromboxane-mediated platelet activation. The observations also demonstrate alcohol-induced changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of alcohol.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adult; Alcoholic Intoxication; Biomarkers; Circadian Rhythm; Creatinine; Cross-Over Studies; Disease Susceptibility; Drug Administration Schedule; Ethanol; Fibrinolysis; Hemorheology; Hemostasis; Humans; Male; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Platelet Activation; Platelet Aggregation; Stroke; Supine Position; Thromboxane B2

To investigate the effects of bepridil on silent myocardial ischemia and on eicosanoid metabolism, 10 patients with chronic stable angina underwent exercise treadmill testing and 48-hour ambulatory electrocardiographic monitoring both before and after 4 weeks of bepridil administration (150 mg/day). Fasting venous levels of thromboxane B2, 6-keto-prostaglandin F1 alpha, and leukotriene C4 were measured by radioimmunoassay. Bepridil decreased heart rate responses to daily activities during ambulatory monitoring, and significantly (p < 0.05) reduced the median frequency and duration of silent myocardial ischemic episodes (from 5.5 to 0 events/48 hours and from 86 to 0 minutes/48 hours respectively). Bepridil significantly decreased the blood pressure heart rate product at peak exercise and significantly prolonged the mean exercise tolerance time (from 456.6 to 527.0 second). Bepridil also significantly decreased the plasma levels of thromboxane B2 and leukotriene C4 at rest. These results suggest that bepridil may reduce silent myocardial ischemic episodes either by the reduction of cardiac oxygen demand during daily activities and exercise stress, or by controlling coronary and systemic vasomotor tone. The drug also has a salutary effect on eicosanoid metabolism, to which its efficacy on silent myocardial ischemic episodes may be related.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Arachidonic Acids; Bepridil; Chronic Disease; Electrocardiography, Ambulatory; Exercise Test; Female; Heart Rate; Humans; Leukotriene C4; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Radioimmunoassay; Single-Blind Method; Thromboxane B2

Several recent observations suggest that atrial natriuretic peptides (ANP) can modulate steroidogenesis in isolated rat Leydig cells and in young men. Other observations suggest that catechol estrogen can inhibit prostaglandin (PGI2) release in the endothelium, and we had found that androgen can relieve angina pectoris and improve myocardial ischemia in elderly men with coronary heart disease (CHD), possibly through relieving coronary artery smooth muscle spasm. Because ANP and PGI2 are vasoactive peptides which regulate vasomotion, there must be an interaction between steroidogenesis hormones and vasoactive peptides. We evaluated the effects of androgen (Sustanon 250) administration on plasma ANP, PGI2 and thromboxane (TXA2) levels in elderly men with CHD. Thirty 60-75-year-old men with CHD received 250 mg (1 ml) Sustanon 250 injection, and 30 age- and sex-matched CHD patients received 1 ml saline. Plasma ANP, PGI2, TXA2, estradiol (E2) and testosterone (T) were determined before injection and 3 weeks thereafter. The results showed that Sustanon 250 administration increased plasma ANP levels, decreased TXA2 and increased PGI2 levels significantly, and thereby improved the TXA2/PGI2 imbalance in CHD patients (all P < 0.01). Meanwhile, serum T levels rose (P < 0.01), but E2 levels remained unchanged, and thus the E2/T ratio decreased (P < 0.05). Our findings demonstrate that androgen exerts its regulatory role by altering plasma ANP levels and the TXA2/PGI2 ratio.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Atrial Natriuretic Factor; Delayed-Action Preparations; Drug Combinations; Estradiol; Humans; Male; Middle Aged; Myocardial Infarction; Testosterone; Thromboxane B2

Forty two patients with acute myocardial infarction (AMI) were randomly distributed to the following groups: (1) the non-aspirin-treated group; (2) the daily-aspirin-treated group (aspirin, 300mg, once everyday); (3) the intermittent-aspirin-treated group (aspirin, 300mg, once every three days). In addition to the three groups, a group of normal subjects was selected. Blood was taken by venipuncture of the antecubital vein in patients on the first, second, seventh, fourteenth and twenty-first hospitalized days. The plasma levels of 6-keto-prostaglandin F1 alpha(6-keto-PGF1 alpha) and thromboxane B2(TXB2) were measured respectively by the scintillation counting of radioimmunoassay. The ratio of 6-keto-PGF1 alpha to TXB2 (K/T ratio) was also calculated. Conclusions were as follows: (1) Intermittent treatment with low-dose aspirin is superior to daily treatment in improving the PGI2/TXA2 balance in patients with AMI. (2) Daily low-dose aspirin has cumulative inhibitory effects on PGI2 and TXA2 synthesis in AMI patients. While intermittent treatment has the same cumulative inhibitory effect on TXA2 synthesis as daily treatment, but no cumulative inhibitory effect on PGI2 synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Aspirin; Female; Humans; Male; Middle Aged; Myocardial Infarction; Thromboxane B2

To assess the appropriate dose of aspirin in the treatment of patients with acute myocardial infarction (AMI), 60 cases of AMI were randomized into 2 groups, 30 cases each; one with conventional therapy, another with conventional therapy combined with daily oral aspirin 100mg. The second group was further divided into subgroup I with serum peak CK < 1000 U/L and subgroup II with serum peak CK > 1000U/L. The parameters of platelet function including plasma TXB2, TXB2/6-keto-PGF1 alpha, platelet aggregation induced by 5-HT and epinephrine were studied on different days for 3 weeks. The results revealed that there was a successful inhibition of platelet function as assessed by significant decrease of plasma TXB2 and TXB2/6-keto-PGF1 alpha ratio and inhibition of platelet aggregation in the subgroup I, but little effect on subgroup II. It is shown that in the treatment of AMI, a daily dose of 100mg of aspirin is insufficient for severe cases, and according to the observation in ISIS-2 study, a daily dose of aspirin around 160mg may be appropriate.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aspirin; Blood Platelets; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Function Tests; Thromboxane B2

The prostaglandin-thromboxane system, platelet hemostasis and central hemodynamics were evaluated in 51 patients with heart failure-complicated acute myocardial infarction during aspirin, roxicam and basic (nitrates + cardiac glycosides + diuretics) therapies. The new non-steroidal antiinflammatory agent roxicam was shown to selectively inhibit thromboxane, without affecting prostacyclin levels. The agent may be regarded as the drug of choice in using antiaggregatory therapy in patients with myocardial infarction concurrent with heart failure.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiac Glycosides; Diuretics; Epoprostenol; Heart Failure; Humans; Myocardial Infarction; Nitrates; Piroxicam; Thromboxane A2; Thromboxane B2; Thromboxanes

Previous studies have found that Panax quinquefolius saponins (PQS) combined with dual antiplatelet therapy (DAPT) of aspirin and clopidogrel enhances antithrombotic effects while reducing gastric mucosal injury induced by DAPT. We investigated the effects of the combined drug therapy (PQS+DAPT) through the COX/PG pathways.. Acute myocardial infarction (AMI) was induced in Wistar rats by ligation of the left anterior descending (LAD) coronary artery, and the animals were randomly divided into Model, DAPT, and PQS+DAPT groups. Rats in the sham group did not undergo artery ligation. They were intragastrically treated for 14 days. Myocardial infarct size; myocardial pathology; platelet aggregation rate, CD62p activation, concentrations of thromboxane B2 (TXB2), 6-keto-PGF1α, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI), the TXB2/6-keto-PGF1α ratio were measured. The ultrastructure of the gastric mucosa was observed by scanning electron microscopy. The expression of PGE2 and 6-keto-PGF1α in gastric mucosa was measured by radioimmunoassay, and levels of COX-1, COX-2, and VEGF in gastric mucosa were assessed using immunohistochemistry.. The addition of Panax quinquefolius saponins (PQS+DAPT) to standard DAPT therapy significantly decreased the myocardial infarct area, degree of myocardial lesions, TXB2 and PAI levels, and the TXB2/6-keto-PGF1α ratio, while increasing 6-keto-PGF1α and t-PA levels and reducing the degree of gastric mucosal injury. Expression of PGE2, 6-keto-PGF1α, COX-2, and VEGF in the gastric mucosa was upregulated in the PQS+DAPT group compared with the standard DAPT group.. PQS increases the degree of DAPT inhibition of myocardial necrosis and antiplatelet effects in AMI rats, as well as reducing damage to the gastric mucosa caused by DAPT. The mechanism may be related to inhibition of TXB2 and PAI activity and elevation of 6-keto-PGF1α and t-PA levels in blood, and may be associated with upregulated expression of COX-2, PGE2, PGI2, and VEGF in gastric tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Clopidogrel; Cyclooxygenase 2; Gastric Mucosa; Male; Myocardial Infarction; Myocardium; Panax; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Saponins; Thromboxane B2; Ticlopidine; Tissue Plasminogen Activator; Vascular Endothelial Growth Factor A

To examine the microvascular pathological characteristics and changes in related injury\ factors in a rat model of acute blood stasis.. A total of 75 Sprague-Dawley rats were divided randomly and equally into a control group\ and four experimental groups assessed at different times after the induction of stasis (0, 1, 3 or 6 h after\ stasis) (n = 15). The acute blood stasis model was established through rat tail-vein injection of\ high-molecular-weight dextran. After Electrocardiograph (ECG) detection at predetermined times (0,\ 1, 3 and 6 h after induction of stasis), the rats were sacrificed and blood and cardiac samples were harvested\ for analysis. Hematoxylin-eosin (HE) staining and transmission electron microscopy were used\ for histopathological detection; an enzyme linked immunosorbent assay (ELISA) was used to detect\ thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-Keto-PGF1α) concentrations; a real-time\ polymerase chain reaction (PCR) reaction system was used to detect intercellular adhesion molecule\ 1 (ICAM-1) and vascular cell adhesion molecule1 (VCAM-1) mRNA expression; western blotting was\ used to detect vascular endothelial cadherin (VE-cadherin) protein expression.. The ST segment in the ECG showed gradual elevation after induction of stasis and continued\ elevation at a high level at 3 and 6 h. The HE staining showed changes in myocardial cell necrosis\ and tissue dissociation after the induction of stasis, along with inflammatory infiltration. Results of\ transmission electron microscopy showed immediate changes in blood stasis and lumen occlusion in\ the microvasculature, along with endothelial cell swelling. After the induction of stasis, TXB2 concentrations\ gradually increased while 6-Keto-PGF(1α) concentrations were immediately significantly reduced.\ The TXB(2)/6-Keto-PGF(1α) ratio was maintained at a high level. ICAM-1 mRNA expression showed\ an unstable elevation while VCAM-1 mRNA expression was significantly reduced after the induction\ of stasis. Compared with the control group, VE-cadherin protein expression increased at 0 and 3 h after\ the induction of stasis, while no change occurred at 1 and 6 h.. The pathological manifestations of acute blood stasis are microvascular blood retention,\ lumen stenosis and even occlusion. The condition is also called "blood coagulation and weep" in\ Traditional Chinese Medicine. The blood stasis model resulted in the injury and necrosis of endothelial\ cells and cardiomyocytes, along with the presence of an imbalance of vasomotor factor levels, platelet\ activation, and increases in the expression of adhesion molecules and endothelial barrier dysfunction,\ which corresponds to "blood failed to nourish" in Traditional Chinese Medicine.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Adhesion Molecules; Disease Models, Animal; Electrocardiography; Heart; Humans; Intercellular Adhesion Molecule-1; Male; Microvessels; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Thromboxane B2; Vascular Cell Adhesion Molecule-1

A genetic variant (rs20417) of the PTGS2 gene, encoding for COX-2, has been associated with decreased COX-2 activity and a decreased risk of cardiovascular disease (CVD). However, this genetic association and the role of COX-2 in CVD remain controversial.. The association of rs20417 with CVD was prospectively explored in 49 232 subjects (ACTIVE-A, CURE, epiDREAM/DREAM, ONTARGET, RE-LY, and WGHS) and the effect of potentially modifiable risk factors on the genetic association was further explored in 9363 INTERHEART participants. The effect of rs20417 on urinary thromboxane and prostacyclin metabolite concentrations was measured in 117 healthy individuals. Carriage of the rs20417 minor allele was associated with a decreased risk of major CVD outcomes (OR = 0.78, 95% CI: 0.70-0.87; P = 1.2 × 10(-5)). The genetic effect was significantly stronger in aspirin users (OR: 0.74, 95% CI: 0.64-0.84; P = 1.20 × 10(-5)) than non-users (OR: 0.87, 95% CI: 0.72-1.06; P = 0.16) (interaction P-value: 0.0041). Among patients with previous coronary artery disease (CAD), rs20417 carriers had a stronger protective effect on risk of major adverse events when compared with individuals without previous CAD (interaction P-value: 0.015). Carriers had significantly lower urinary levels of thromboxane (P = 0.01) and prostacyclin (P = 0.01) metabolites when compared with non-carriers.. The rs20417 polymorphism is associated with a reduced risk of major cardiovascular events and lower levels of thromboxane and prostacyclin. Our results suggest that a genetic decrease in COX-2 activity may be beneficial with respect to CVD risk, especially, in higher risk patients on aspirin.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aspirin; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Female; Heterozygote; Humans; Male; Multicenter Studies as Topic; Myocardial Infarction; Polymorphism, Genetic; Prospective Studies; Randomized Controlled Trials as Topic; Stroke; Thromboxane B2

In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y12-receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia-reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS).. Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A2A/A1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation.. Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Animals; Aspirin; Cardiotonic Agents; Clopidogrel; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Drug Evaluation, Preclinical; Enzyme Induction; Lipoxins; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Nitric Oxide Synthase Type III; Pyrazoles; Quinazolines; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A1; Receptor, Adenosine A2A; Ticagrelor; Ticlopidine; Triazoles; Up-Regulation

Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA2 and COX2, and increases myocardial 6-keto-PGF1alpha levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS-/- and iNOS-/- mice. Male C57BL/6 wild-type (WT), eNOS-/-, and iNOS-/- mice received 10 mg.kg(-1).day(-1) Pio (Pio+) or water alone (Pio-) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4+/-1.4% vs. 39.0+/-1.1%; P<0.001), as well as in the eNOS-/- (32.0+/-1.6% vs. 44.2+/-1.9%; P<0.001) and iNOS-/- (18.0+/-1.2% vs. 45.5+/-2.3%; P<0.001) mice. The protective effect of Pio in eNOS-/- mice was smaller than in the WT (P<0.001) and iNOS-/- (P<0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS-/- mice. iNOS was undetectable in all six groups. Pio increased cPLA2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS-/- and iNOS-/-, mice. Pio increased the myocardial 6-keto-PGF1alpha levels and cPLA2 and COX2 activity in the WT, eNOS-/-, and iNOS-/- mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cardiovascular Agents; Cyclooxygenase 2; Cytochrome P-450 Enzyme System; Disease Models, Animal; Immunoblotting; Intramolecular Oxidoreductases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phospholipases A2, Cytosolic; Phosphorylation; Pioglitazone; Polymerase Chain Reaction; RNA, Messenger; Thiazolidinediones

To investigate the association between the polymorphism of the prostacyclin synthase gene and Uigur patients with myocardial infarction in Xinjiang.. Three hundred and ten patients with myocardial infarction (MI) and 306 healthy control subjects were detected by polymerase chain reaction and restriction fragment length polymorphism. The serum 6-keto-PGF(1alpha ) was detected with radioimmunoassay kit in all subjects.. The genotype distributions of the control group and MI group were in the Hardy-Weinberg equilibrium(chi (2)= 0.442, 1.867, P> 0.05). The frequencies of CC, CA and AA were 0.70, 0.26 and 0.03 in the MI group and 0.62, 0.32 and 0.06 in the controls. There was significant difference in frequencies of CC genotype and C allele but no difference in frequencies of CA and AA genotypes between the controls and the MI cases. There was significant difference in serum 6-keto-PGF(1alpha ) level between the MI group and control group (P< 0.05), as well as among the three genotypes (P< 0.05). In the cases with CC genotype the serum 6-keto-PGF(1alpha ) level was lower than that of others (P< 0.05).. The CC genotype and C allele of the prostacyclin synthase gene might be a risk factor of MI in Uigur population in Xinjiang, which may lead to the decreased serum 6-keto-PGF(1alpha ) level.

Topics: 6-Ketoprostaglandin F1 alpha; Asian People; Base Sequence; Case-Control Studies; Cytochrome P-450 Enzyme System; Ethnicity; Exons; Female; Gene Frequency; Genotype; Humans; Intramolecular Oxidoreductases; Logistic Models; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic

Statins reduce infarct size by upregulating nitric oxide synthases and PGI2 production. In this article, the infarct size-limiting effect of low-dose simvastatin + ezetimibe, ezetimibe, and high-dose statins were compared. Rats received 3-day water, atorvastatin (10 mg/kg/d), simvastatin (10 mg/kg/d), simvastatin (2 mg/kg/d), simvastatin (2 mg/kg/d) + ezetimibe (1 mg/kg/d), or ezetimibe. Rats underwent 30-minute coronary artery occlusion and 4-hour reperfusion. Atorvastatin and simvastatin 10 reduced infarct size, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. Atorvastatin and simvastatin 10 increased nitric oxide synthases activity, whereas simvastatin-2, ezetimibe, and simvastatin-2 + ezetimibe had only a small effect. Atorvastatin and simvastatin 10 significantly increased myocardial 6-ketoprostaglandin F(1 alpha) levels, whereas simvastatin 2, ezetimibe, and simvastatin 2 + ezetimibe had no effect. High-dose statin is required to decrease infarct size, upregulate myocardial nitric oxide synthases activities, and increase 6-keto prostaglandin F(1 alpha) levels. Combination of ezetimibe and low-dose statin is ineffective in modulating myocardial biochemical changes associated with cardioprotection.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticholesteremic Agents; Atorvastatin; Azetidines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Ezetimibe; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Nitric Oxide Synthase; Pyrroles; Rats; Rats, Sprague-Dawley; Simvastatin; Up-Regulation

Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS(-/-) and iNOS(-/-) mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-kappaB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS(-/-) and iNOS(-/-) mice received ATV (10 mg.kg(-1).day(-1); ATV(+)) or water alone (ATV(-)) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-kappaB in WT mice. It also increased myocardial COX2 activity. In eNOS(-/-) mice, ATV increased COX2 expression but not COX2 activity or iNOS expression. NF-kappaB was not activated by ATV in the eNOS(-/-) mice. In the iNOS(-/-) mice, eNOS and p-eNOS levels were increased but not iNOS and COX2 levels; however, NF-kappaB was activated. In conclusion, both eNOS and iNOS are essential for the IS-limiting effect of ATV. The expression of COX2 by ATV is iNOS, but not eNOS or NF-kappaB, dependent. Activation of COX2 is dependent on iNOS.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Atorvastatin; Cyclooxygenase 2; Disease Models, Animal; Electrophoretic Mobility Shift Assay; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunoblotting; Janus Kinases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; NF-kappa B; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Peptides; Phosphorylation; Protein Kinase Inhibitors; Pyrroles; Time Factors; Tyrphostins; Up-Regulation

We assessed whether aspirin (acetylsalicylic acid, ASA), administered before reperfusion, abrogates the infarct size (IS)-limiting effect of atorvastatin (ATV). Statins reduce IS. This dose-dependent effect is mediated by upregulation of cycloxygenase-2 (COX2) and PGI(2) production. Administration of selective COX2-inhibitors either with ATV for 3 days or immediately before coronary occlusion blocks the IS-limiting effect of ATV. Sprague-Dawley rats received 3-day ATV (10 mg x kg(-1) x day(-1)) or water alone. Rats underwent 30 min coronary artery occlusion and 4 h reperfusion (IS protocol, n=8 in each group), or rats underwent 30 min coronary artery occlusion and 10 min reperfusion (enzyme expression and activity protocol, n=4 in each group). Immediately before reperfusion rats received intravenous ASA (5, 10, or 20 mg/kg) or saline. Area-at-risk (AR) was assessed by blue dye and IS by triphenyltetrazolium chloride. ATV reduced IS (10.1 +/- 1.4% of the AR) compared with controls (31.0 +/- 2.2%). Intravenous ASA alone did not affect IS (29.0 +/- 2.6%); however, ASA dose dependently (5, 10, and 20 mg/kg) attenuated the protective effect of ATV on IS (15.8 +/- 0.9%, 22.0 +/- 1.6%, and 23.7 +/- 3.8%, respectively). ASA dose dependently blocked the upregulation of COX2 by ATV. COX2 activity was as follows: control, 8.93 +/- 0.90 pg/mg; ATV, 75.85 +/- 1.08 pg/mg; ATV + ASA5, 34.39 +/- 1.48 pg/mg; ATV + ASA10, 19.87 +/- 1.10 pg/mg; and ATV + ASA20, 9.36 +/- 0.94 pg/mg. ASA, administered before reperfusion in doses comparable to those used in the clinical setting, abrogates the IS-limiting effect of ATV in a model with mechanical occlusion of the coronary artery. This potential adverse interaction should be further investigated in the clinical setting of acute coronary syndromes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Atorvastatin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Membrane Proteins; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Pyrroles; Rats; Rats, Sprague-Dawley

Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been shown to be mediators of cardioprotection induced by ischemic preconditioning and opioids. However, it is not known whether COX-2 is involved in morphine-induced cardioprotection accompanied with iNOS. Therefore, we investigated the role of COX-2 in morphine-induced cardioprotection and the effect of iNOS on COX-2. Myocardial ischemia was induced by a 45-min coronary artery occlusion in mice. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by triphenyltetrazolium chloride staining. The COX-2-selective inhibitor NS-398 was used to investigate the role of COX-2. Expression of COX-2 was assessed by Western blotting, and the myocardial prostaglandin (PG)E2 and 6-keto-PGF(1alpha) contents were measured using enzyme immunoassays. The iNOS-selective inhibitor SMT and iNOS gene-knockout mice were used to investigate the effect of iNOS on COX-2. IS/AAR was reduced significantly 1 and 24 h after morphine preconditioning. The infarct-sparing effect 24 h after morphine administration, but not the cardioprotection 1 h later, was completely abolished by NS-398. Marked enhancement of myocardial COX-2 expression was measured 24 h after morphine preconditioning associated with up-regulation of myocardial contents of PGE2 and 6-keto-PGF(1alpha). Neither the level of COX-2 nor the contents of PGE2 and 6-keto-PGF(1alpha) were enhanced 1 h later. Administration of SMT and targeted abrogation of iNOS gene blocked the enhancement of myocardial PGE2 and 6-keto-PGF(1alpha) 24 h after morphine administration but did not inhibit the up-regulation of COX-2 expression. We concluded that COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cardiotonic Agents; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Heart; Ischemic Preconditioning, Myocardial; Isothiuronium; Male; Mice; Mice, Inbred Strains; Mice, Knockout; Morphine; Myocardial Infarction; Myocardium; Nitric Oxide Synthase Type II; Nitrobenzenes; Sulfonamides; Up-Regulation

To study the therapeutic effects of the series of Muskone (the Muskone includes Slender Dutchmanspipe Root, Tumuxiang, and not Slender Dutchmanspipe Root) on experimental myocardial infarct and pain in rats.. Coronary artery ligation was applied for the model of myocardial infarct. Therapeutic effects were evaluated by measuring parameters of histomorphometry, blood plasm of ET, 6- keto-PGF1alpha and TXB2. Intraperitoneal injection acetic was applied for the model of ache, the frequency and eclipse period of writhing were evaluated its effect of resisting pain.. The Muskone including Radix Aristolociae, the Muskone including Radix Inulae and the Muskone without Radix Aucklandiae all can decrease the area of myocardial infarction in rats, the level of TXB2, ET, and the frequency of writhing significantly. Also it can increase the level 6-keto-PGF1alpha, the ratio of 6-keto-PGF1alpha and TXB2. Single Radix Aristolociae or Radix Inulae only relieved pain.. The Muskone including Radix Aristolociae, the Muskone including Radix Inulae and the Muskone without Radix Aucklandiae all have significant therapeutic effect on both myocardial infarction and pain, while single Radix Aristolociae or Radix Inulae only can relieve pain.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aristolochia; Cycloparaffins; Drug Combinations; Drugs, Chinese Herbal; Endothelins; Female; Inula; Male; Mice; Mice, Inbred ICR; Myocardial Infarction; Pain; Plants, Medicinal; Rats; Rats, Wistar; Thromboxane B2

To observe the effects of the series of Muskone (the Muskone includes Slender Dutchmanspipe Root, Tumuxiang, and not Slender Dutchmanspipe Root) on myocardial ischemia, myocardial infarction and hematological index in experimental canines, and to explain the pharmacological action and characteristic of its therapeutic effect on ischemic heart disease.. The range and degree of myocardial ischemia was evaluated by epicardial electrogram mapping, and the range extent of myocardial infarction was determined by quantitate histology (N-BT staining method). Meanwhile, the changes of ET, TXB2, 6-Keto-PGF1alpha were determined to study the effects of the series of Muskone on myocardial ischemia, myocardial infarction and hematological index in experimental canines.. The series of Muskone can improve myocardial ischemia and infarction in experimental canines, and relieve significantly the degree of myocardial ischemia (Sigma-ST) determined by epicardial electrogram mapping, decrease the range of myocardial ischemia (N-ST) determined by epicardial electrogram mapping and decrease infarction zone determined by N-BT staining method. And it has a significant inhibition on activity of ET induced by myocardial ischemia and infarction, and increases 6-Keto-PGF1alpha and 6-Keto-PGF1alpha/TXB2 induced by myocardial ischemia.. The series of Muskone has significant therapeutic effect on myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aristolochia; Cycloparaffins; Dogs; Drug Combinations; Drugs, Chinese Herbal; Endothelins; Female; Inula; Male; Myocardial Infarction; Myocardium; Plants, Medicinal; Thromboxane B2

We sought to investigate the time course of morphine-induced delayed cardioprotection and examine the role of cyclooxygenase (COX) in this cardioprotective effect.. Cyclooxygenase-2 has been shown to be essential for the delayed cardioprotection induced by ischemic preconditioning and delta-opioid agonists.. Male mice were subjected to 45 min of coronary artery occlusion followed by 120 min of reperfusion. Expressions of COX-2 and COX-1 were assessed by Western blotting, and the myocardial prostaglandin (PG)E2 and 6-keto-PGF(1-alpha) contents were measured using enzyme immunoassays.. A powerful infarct-sparing effect appeared 24 and 48 h after morphine preconditioning and faded after 72 h. After 24 h, the anti-infarct effect was associated with enhanced myocardial levels of COX-2, PGE2, and 6-keto-PGF(1-alpha), and no changes in COX-1 protein levels were found. Cardioprotection and increases in PGE2 and 6-keto-PGF(1-alpha) were completely abolished by the COX-2-selective inhibitor NS-398 and the non-selective COX inhibitor indomethacin, whereas the COX-1-selective inhibitor SC-560 had no effect. After 48 h, up-regulation of myocardial PGE2 and 6-keto-PGF(1-alpha) was also observed, and COX-1 expression was enhanced markedly, but only a slight increase in COX-2 expression was apparent. Cardioprotection and the increases in PGE2 and 6-keto-PGF(1-alpha) 48 h after morphine administration were abrogated only by indomethacin, and not by SC-560 or NS-398.. Morphine confers delayed cardioprotection via a COX-dependent pathway; COX-2 is essential for the cardioprotection observed in the initial stage (24 h), whereas, in the final stage (48 h), cardioprotection is mediated by COX-1 in concert with COX-2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cardiotonic Agents; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Indomethacin; Ischemic Preconditioning, Myocardial; Male; Membrane Proteins; Mice; Mice, Inbred Strains; Morphine; Myocardial Infarction; Myocardium; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides; Time Factors; Up-Regulation

Cyclooxygenase-2 (COX-2) mediates the late phase of ischemic preconditioning (IPC), but whether this enzyme modulates early IPC, anesthetic-induced preconditioning (APC), or other forms of pharmacologic preconditioning (PPC) is unknown. The authors tested the hypothesis that COX-2 is an essential mediator of IPC, APC, and PPC in vivo.. Barbiturate-anesthetized dogs (n = 91) were instrumented for measurement of hemodynamics and randomly assigned to receive IPC (four 5-min coronary occlusions interspersed with 5-min reperfusions), APC (1.0 minimum alveolar concentration of isoflurane for 30 min), or PPC (selective mitochondrial K(ATP) channel opener diazoxide, 2.5 mg/kg intravenous) in the presence or absence of pretreatment with oral aspirin (650 mg), the selective COX-2 inhibitor celecoxib (200 mg), or acetaminophen (500 mg) administered 24, 12, and 2 h before experimentation in 12 separate experimental groups. All dogs were subjected to a 60-min coronary artery occlusion followed by 3 h of reperfusion. Myocardial infarct size and coronary collateral blood flow were quantified with triphenyltetrazolium staining and radioactive microspheres, respectively. Myocardial 6-keto-prostaglandin F1alpha, a stable metabolite of prostacyclin, was measured (enzyme immunoassay) in separate experiments (n = 8) before and after isoflurane administration, in the presence or absence of celecoxib.. No significant differences in baseline hemodynamics or the left ventricular area at risk for infarction were observed between groups. IPC, isoflurane, and diazoxide all decreased myocardial infarct size (9 +/- 1, 12 +/- 2, and 11 +/- 1%, respectively) as compared with control (30 +/- 1%). Celecoxib alone had no effect on infarct size (26 +/- 3%) but abolished IPC (30 +/-3%), APC (30 +/- 3%), and PPC (26 +/- 1%). Aspirin (24 +/- 3%) and acetaminophen alone (29 +/- 2%) did not alter infarct size or abolish APC-induced protection (18 +/- 1 and 19 +/- 1%, respectively). Isoflurane increased myocardial 6-keto-prostaglandin F1alpha to 463 +/- 267% of baseline in the absence but not in the presence (94 +/- 13%) of celecoxib.. The results indicate that COX-2 is a critical mediator of IPC, APC, and PPC in dogs. The role of cyclooxygenase enzymes as obligatory mediators of myocardial protection produced by diverse preconditioning stimuli may have implications for the clinical use of COX-2 inhibitors.

Topics: 6-Ketoprostaglandin F1 alpha; Acetaminophen; Anesthetics, Inhalation; Animals; Aspirin; Celecoxib; Coronary Circulation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diazoxide; Dogs; Hemodynamics; Ischemic Preconditioning, Myocardial; Isoenzymes; Isoflurane; Membrane Proteins; Myocardial Infarction; Myocardium; Potassium Channels; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Sulfonamides

Although activation of delta-opioid receptors is known to induce both early and late preconditioning (PC) against myocardial infarction, the mechanisms for this salubrious effect are unclear. Furthermore, it is unknown whether delta-opioid receptors can also induce late PC against myocardial stunning. By using conscious rabbits (n = 120) in this study, we found that the delta-opioid receptor agonist (+/-)-4-[(alpha-R*)-alpha-[(2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl]-N,N-diethylbenzamide (BW-373U86) induced late PC against myocardial stunning 24 h after treatment and that this effect was abolished by the selective cyclooxygenase-2 (COX-2) inhibitors N-[2-(cyclohexyloxy)4-nitrophenyl]methanesulfonamide (NS-398) and celecoxib. This protective effect was also abrogated by the selective delta(1)-opioid receptor antagonist 7-benzylidenenaltrexone, indicating that the delta(1)-opioid receptor is necessary for BW-373U86-induced late PC. BW-373U86 did not induce early PC against stunning. In addition, BW-373U86 induced late PC against infarction, which was blocked by NS-398. At 24 h after BW-373U86 administration, myocardial COX-2 protein expression and PGE(2) and 6-keto-PGF(1alpha) levels were significantly increased. These results demonstrate that activation of delta-opioid receptors induces late PC against both stunning and infarction via a COX-2-dependent mechanism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzamides; Benzylidene Compounds; Celecoxib; Consciousness; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Heart Rate; Ischemic Preconditioning, Myocardial; Isoenzymes; Male; Myocardial Infarction; Myocardial Stunning; Myocardium; Naltrexone; Narcotic Antagonists; Nitrobenzenes; Piperazines; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rabbits; Receptors, Opioid, delta; Sulfonamides

8-iso-prostaglandin F(2 alpha)(8-iso-PGF(2 alpha)), a representative isoprostane, has been reported to be a reliable marker for oxidant stress in vivo. To examine if 8-iso-PGF(2 alpha)is generated in patients with acute myocardial infarction (AMI), we measured the level of immunoreactive 8-iso PGF(2 alpha)in the great cardiac vein as well as classical eicosanoids, 6-keto-prostaglandin F(1 alpha)(6-keto-PGF(1 alpha)) and thromboxane B(2)(TXB(2)) in the process of urgent coronary balloon angioplasty. Fourteen patients with anterior AMI were divided into two groups: the totally occluded (n=7) and the already perfused groups (n=7). In the former, transient elevation of 8-iso-PGF(2 alpha)was observed immediately after the angioplasty, i.e. the ratio of post-angioplasty level to pre-level was approximately 2.4 for 8-iso-PGF(2 alpha), 14 for 6-keto-PGF(1 alpha), and 5 for TXB(2). In the already perfused group, the levels of these eicosanoids were unchanged. In the totally occluded group, peak creatine phosphokinase in a peripheral vein was correlated with the level of 8-iso-PGF(2 alpha)(r(2)=0.841, P<0.01), but not with those of the other two eicosanoids. In conclusion, transcardiac 8-iso-PGF(2 alpha)generation is a reliable marker for the size of myocardium exposed to oxidant stress.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angioplasty, Balloon, Coronary; Creatine Kinase; Dinoprost; F2-Isoprostanes; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Oxidative Stress; Oxygen; Reperfusion; Thromboxane B2; Time Factors

Several attempts have been made to replace aspirin with compounds without gastric toxicity; a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, and a nitric oxide-aspirin, NCX-4016, have been developed for this purpose. This paper compares effects of celecoxib, NCX-4016 and aspirin on production of prostacyclin (PGI2) and thromboxane A2 (TXA2) and activation of the inducible form of nitric oxide synthase (iNOS) in infarcted heart in situ. Aspirin was most effective in reducing myocardial PGI2 synthesis and formation of TXA2. Myocardial effects of celecoxib resemble those of NCX-4016, although the two compounds have different modes of action.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Epoprostenol; Heart; Isoenzymes; Male; Myocardial Infarction; Myocardium; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Platelet Aggregation Inhibitors; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rabbits; Sulfonamides; Thromboxane A2

A new family of nitroderivatives of conventional non-steroidal anti-inflammatory drugs capable of releasing nitric oxide has been synthesized. Among these compounds, a nitroderivative of aspirin (NCX 4016), which displays antiplatelet and vasodilating activities, appears to have clinical potential in cardiac pathology related to coronary insufficiency.. In this study the beneficial effects of NCX 4016 and aspirin were evaluated in vitro in a model of myocardial ischemia-reperfusion of the rabbit and in vivo in a model of acute myocardial infarction of the same animal species.. The NCX 4016 (from 1 x 10(-5) M to 3 x 10(-4) M) caused dose-dependent cardiac protection in isolated rabbit hearts subjected to low flow ischemia-reperfusion. Inhibition of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) generation and proportional reduction of creatine kinase (CK) activity at reperfusion was observed. Aspirin (1 x 10(-4)M) markedly worsened the post-ischemic ventricular dysfunction and this event was paralleled by a 63% increase in CK activity and abolition of 6-keto-PGF1alpha formation. Perfusion of the hearts with NG-monomethyl-L-arginine (1 x 10(-5) M) worsened the ischemia-reperfusion damage in perfused hearts. This event was prevented by prior treatment with NCX 4016 (1 x 10(-4) M) but not with aspirin (1 x 10(-4) M). Ligation of the first antero-lateral branch of the left coronary artery in rabbits resulted in acute myocardial infarction with a mortality rate of 60% at 24 hours. NCX 4016 (0.5 mg/kg/min for 2 hours) significantly reduced the mortality rate by 10%, protected the rabbits against electrocardiogram derangement and almost abolished CK activity in plasma and myeloperoxidase activity in cardiac tissue. Aspirin was devoid of any protective activity.. In the rabbit NCX 4016 appears to exert a relevant cardioprotection likely mediated by nitric oxide donation. These results suggest that this nitroderivative of aspirin may lead to innovative therapy in myocardial ischemia and infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Aspirin; Creatine Kinase; Dose-Response Relationship, Drug; Electrocardiography; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Peroxidase; Rabbits; Vasoconstrictor Agents; Ventricular Function, Left

A comparative analysis of the content of the soluble form of cell adhesion protein P-selectin in the blood plasma of patients with acute myocardial infarction (AMI), massive atherosclerosis (MA) and primary pulmonary hypertension (PPH), investigation of the relationship between plasma content of P-selectin and known markers of platelets and endothelial cells activation, preliminary assessment of the prognostic value of P-selectin determination.. This study included 16 patients with AMI, 20 patients with MA, 21 patients with PPH and 18 healthy donors. The follow-up was 1-5 years. End-points in the group of patients with AMI were recurrent acute coronary syndrome and coronary artery by-pass operation, in the group with MA--thrombotic complications (acute coronary syndrome, ischemic stroke) and in the group with PPH--death. P-selectin was measured by ELISA and platelet factor 4 (PF4), thromboxane B2 (TXB2), endothelin-I and stable prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) by means of commercial ELISA kits.. Mean level of P-selectin in blood plasma of patients with AMI (1 day) (361 +/- 18 ng/ml), MA (410 +/- 31 ng/ml) and PPH (627 +/- 83 ng/ml) was increased in comparison with the group of healthy donors (269 +/- 12 ng/ml) (everywhere p < 0.001). In AMI, P-selectin was increased on day 1 only, on days 2, 3 and 10-14 of the disease the level of P-selectin was significantly lower than on day 1 and did not differ from the control level in the group of donors. In patients with MA a significant correlation was detected between plasma content of P-selectin and platelet activation marker PF4 (r = 0.606, P = 0.007) and in patients with PPH between the content of P-selectin and another platelet activation marker TXB2 (r = 0.622, p = 0.013). However, no correlation was found in PPH patients between the content of P-selectin and markers of endothelial activation and/or damage (endothelin-1 and 6-keto-PGF1 alpha). Difference in the concentration of P-selectin in patients with or without end-points during the follow-up period was detected in patients with AMI (353 +/- 14 ng/ml and 451 +/- 24 ng/ml, p = 0.009) and PPH (477 +/- 58 ng/ml and 927 +/- 184 ng/ml, p = 0.017) but not with MA (426 +/- 37 ng/ml and 361 +/- 24 ng/ml, p = 0.295).. The level of P-selectin in plasma was increased in patients with acute thrombosis (AMI, 1 day) as well as in patients without clinical signs of thrombosis but with a massive injury of the vasculature (MA and PPH). The increase of P-selectin was, presumably, caused by its secretion from activated platelets since its concentration in plasma correlated with platelet concentration but not endothelial activation markers. Preliminary data indicate that blood plasma soluble P-selectin may be considered as a potential prognostic marker in AMI and PPH.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; Biomarkers; Blood Coagulation; Blood Vessels; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Myocardial Infarction; P-Selectin; Platelet Activation; Platelet Factor 4; Prognosis; Solubility; Thromboxane B2

We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E(2) and 6-keto-PGF(1alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGI(2) as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Gene Expression Regulation, Enzymologic; Ischemic Preconditioning; Isoenzymes; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Stunning; Myocardium; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pyrazoles; Rabbits; Sulfonamides; Transcription, Genetic

Nitric oxide (NO) donors are heterogeneous substances which release NO, a biologically active compound. NO released by nitric oxide donors has important effects on the circulation by causing vasodilation, diminishing myocardial contractile force, inhibiting platelet aggregation, and counteracting the effects of thromboxane A2. In the infarcted heart, activation of the inducible form of nitric oxide synthase (iNOS) and the formation of prostacyclin and thromboxane A2 by cyclooxygenase (COX) were increased. Myocardial infarction also resulted in increased myocardial NO production. Aspirin (acetylsalicylic acid. ASA) at low concentration (35 mg/kg/day) fails to change iNOS production, in contrast to higher dose (150 mg/kg/day) which, as previously shown, inhibits iNOS activity. ASA at all doses also suppresses myocardial prostanoid formation because of inhibition of COX. Recently, two NO donors have been synthesized: NCX 4016 and Diethylenetriamine/NO (DETA/NO). NCX 4016 combines an NO-releasing moiety with a carboxylic residue via an esteric bond. We describe here that NCX 4016 (65 mg/kg/day) increased prostacyclin and thromboxane A2 production in the infarcted heart muscle, overcoming the inhibitory effects of ASA. As a result of nitric oxide release, oxidation products of NO (NO2- and NO3-; NOx) in arterial blood rose following administration of NCX 4016. On oral administration, NCX 4016 did not change systemic arterial pressure. The effects of a single NO donor, DETA/NO (1.0 mg/kg/day) on the infarcted heart were also investigated On intravenous administration, the compound increased NO concentration in arterial blood slightly but to a lesser degree than NCX 4016. Like NCX 4016, it raised myocardial production of prostacyclin and thromboxane A2 in the infarcted heart. However, it caused a severe fall in blood pressure. These findings demonstrate that newly-synthesized NO donors release nitric oxide in situ and increase myocardial production of prostanoids. NCX 4016 has therapeutic potential because it can be orally administered, lacks hypotensive effects, increases blood levels of nitric oxide and myocardial prostacyclin production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Cyclooxygenase Inhibitors; Drug Interactions; Enzyme Activation; Heart Rate; Male; Myocardial Infarction; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rabbits; Thromboxane A2; Triazenes; Ventricular Pressure

The production of prostacyclin (PGI2) and thromboxane A2 (TXA2) in infarcted and noninfarcted portions of the rabbit heart was studied prior to and following administration of acetylsalicylic acid (aspirin). Aspirin was administered intravenously (iv) as water-soluble Aspisol, d-lysinmono (acetylsalicylate) (Bayer, Leverkusen, Germany) into an ear vein. A branch of the left circumflex coronary artery was ligated. The animals were divided into three groups. The first group received 150 mg/kg/day of aspirin (75 mg/kg of aspirin every 12 h, n = 10). The first administration of aspirin was 1 h after ligation of the coronary artery and the last injection was 1 h before euthanasia. The second group received 5 mg/kg/day of aspirin (every 24 h, n = 10). A separate group of rabbits not receiving aspirin served as controls (n = 12). Two days following onset of ischemia, inducible form of nitric oxide synthase (iNOS) was measured in heart muscle and the oxidation products of nitric oxide (nitrite, NO-2 plus nitrate, NO-3: their sum referred to as NOx) were determined in arterial and coronary venous blood. Concentrations of both PGI2 and TXA2 were elevated in the infarcted portions of the heart compared to the noninfarcted regions. Formation of prostanoids was accompanied by increased activation of iNOS. Both doses of aspirin diminished the concentrations of PGI2 and TXA2 in infarcted heart muscle; in contrast, small doses of aspirin failed to influence myocardial iNOS activity. Apparently small doses of aspirin changed the relationship of iNOS to cyclooxygenase (COX). Coronary arterial-venous difference of NOx and myocardial iNOS activity showed parallel increases. Diminution of prostacyclin by aspirin can damage gastric mucosa and interfere with vasodilatation. Since NO counters these deficiencies, a combination of aspirin with a nitric oxide donor may be advantageous.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Coronary Vessels; Enzyme Activation; Epoprostenol; Heart; Myocardial Infarction; Myocardium; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Prostaglandins; Rabbits; Thromboxane A2; Thromboxane B2

Nitric oxide (NO) and prostacyclin (PGI2) are putative cardioprotective agents. Evidence indicates that there may be a reciprocal relationship involved in the synthesis of NO and PGI2, so that inhibiting the release of one mediator may promote the synthesis of the other. Therefore, we investigated the effects of concomitantly inhibiting NO and PGI2 synthesis, using NG-nitro-L-arginine (L-NOARG) or indomethacin, respectively, on infarct size. Langendorff-perfused rabbit hearts were assigned randomly to one of five treatment groups of n=6: control L-NOARG 100 micromol/l; indomethacin 3 micromol/l L-NOARG 100 micromol/l + indomethacin 3 micromol/l; or L-NOARG 100 micromol/l + L-arginine 1 mmol/l. After 30 min regional ischaemia and 120 min reperfusion, infarct size was assessed by tetrazolium staining. Infarct size was reduced significantly in hearts treated with L-NOARG (20.8+/-1.3%) compared to control hearts (34.7+/-0.4%). This reduction in infarct size was abolished by co-perfusing with a 10-fold excess of L-arginine (30.7+/-1.7%). While indomethacin alone had no effect (33.4+/-2.3%), perfusion with both L-NOARG and indomethacin resulted in a significant increase in infarct size (44.0+/-1.9%) compared to controls. Treatment with L-NOARG alone increased 6-keto PGF1alpha in coronary effluent prior to ischaemia (30.5+/-1.2 vs 16.6+/-1.3 pg/min/g in controls, P<0.05). This effect was reversed by co-perfusion with either L-arginine or indomethacin. These results indicate that the reduction in infarct size by L-NOARG may be due to increased PGI2 release. Concomitant administration of indomethacin negated this effect and revealed an adverse effect of NO synthase inhibition on infarct size.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arginine; Cyclic GMP; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Hemodynamics; In Vitro Techniques; Indomethacin; Male; Myocardial Infarction; Myocardial Reperfusion; Nitric Oxide Synthase; Nitroarginine; Rabbits

The role of prostanoids in patients with ischemic heart disease including acute myocardial infarction (AMI) has been recognized. However, there is very limited knowledge of the baseline TXB2 and 6-keto-PGF1a plasma levels in patients with AMI before therapy has been administered. We compared plasma levels of TXB2 and 6-keto-PGF1a by enzyme immunoassay in 18 AMI patients before thrombolysis, with those of 13 healthy controls. Plasma levels of TXB2 (319.78+/-16.50 pg/ml) and 6-keto-PGF1a (536.72+/-56.71 pg/ml) were heterogeneous, but significantly higher in the AMI patients than in controls (175.92+/-17.29 pg/ml and 192.08+/-26.11 pg/ml, respectively). In some patients, long-term aspirin therapy mildly inhibits baseline prostanoid levels, however, limited data prevents us from further speculations on this issue. Although, the contributions by prostanoids to the pathogenesis of AMI have been well proposed, their plasma concentrations are not uniformly elevated, and it is still unclear whether the resultant changes are indicative of clinically meaningful effects.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aspirin; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Myocardial Infarction; Reference Values; Thromboxane B2

The key role of prostanoids has been recognized in patients with ischemic heart disease. However, serial changes of thromboxane and prostacyclin during both brief and prolonged ischemia-reperfusion are poorly known. These plasma prostanoids were measured during myocardial stunning (MS) and acute myocardial infarction (AMI). The effects of magnesium (Mg), diltiazem, and a Mac-1 inhibitor on the level of the stable metabolites of thromboxane (TXB2) and prostacyclin (6-keto-PGF1 alpha) were elucidated. Forty-nine swine underwent brief (8 min) or prolonged (50 min) coronary artery occlusion followed by reperfusion. The occlusion phase was associated with a decline of plasma prostanoids, followed by a significant increase during reperfusion. Mg and diltiazem similarly affected plasma prostanoids by reducing TXB2 release at 1 h of reperfusion. There was, however, no effect on plasma 6-keto-PGF1 alpha. The Mac-1 inhibition was associated with stabilization of both antagonistic prostanoids as well. Ability of Mg, diltiazem, and leumedins to favorably modulate plasma prostanoid levels have direct clinical implications for the use of these agents in patients with coronary artery disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diltiazem; Enzyme-Linked Immunosorbent Assay; Female; Leucine; Macrophage-1 Antigen; Magnesium; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardial Stunning; Prostaglandins; Swine; Thromboxane B2

Abnormalities of arachidonic acid metabolism are implicated in spasm and thrombosis in coronary arteries. Therefore, arachidonic acid metabolites were examined in patients with acute myocardial infarction (AMI). Plasma levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6KPGF1 alpha), leukotriene B4 (LTB4), and slow reacting substance of anaphylaxis (SRS-A) composed of leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), were measured in 19 AMI patients. Plasma levels of TXB2, LTB4, and SRS-A in systemic artery blood were significantly elevated during the acute stage (within twenty-four hours after the onset of chest pain) of AMI (TXB2, 0.36 ng/mL; LTB4, 0.75 ng/mL; and SRS-A [LTC4+LTD4+LTE4], 0.96 ng/mL compared with those of normal controls (TXB2, 0.18 ng/mL; LTB4, 0.44 ng/mL; and SRS-A (LTC4+LTD4+LTE4], 0.31 ng/mL). These values decreased to near-normal control levels by one month after the AMI attack. The findings in this study suggest that abnormalities of arachidonic acid metabolism accompany, and may play a role in the pathogenesis of, AMI.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arachidonic Acid; Female; Humans; Leukotriene B4; Male; Middle Aged; Myocardial Infarction; SRS-A; Thromboxane B2

Thirty-two patients with acute myocardial infarction performed an exercise stress test one month after hospital discharge. The in vivo formation of thromboxane and prostacyclin formation before and during the exercise stress test was analyzed with gas chromatography-mass spectrometry of the in vivo formed metabolites 2,3-dinor-TxB2 and 2,3-dinor-6-keto-PGF1 alpha. Patients with a significant increase in thromboxane formation (> 30%) during exercise (P < 0.0001) had a worse prognosis, with a 60% incidence of coronary events during the three years following the index infarction as compared to only 8% in the group without such an increase in thromboxane formation during exercise (P = 0.008). The group with coronary events and increased thromboxane formation included patients not detected by classical risk factors. Our findings suggest that exercise-induced thromboxane formation in survivors of an acute myocardial infarction may include prognostic information not defined by other risk indicators.

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic beta-Antagonists; Adult; Aged; Aspirin; Epoprostenol; Exercise; Exercise Test; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Cyclooxygenase Inhibitors; Humans; Myocardial Infarction; Thromboxane B2

A study was carried out on the effect of aspirin 175 mg/day on the plasma levels of 6 keto PGF 1 alpha and TXB2 in patients with acute myocardial infarction and in patients subjected to coronary artery bypass surgery. Our results showed a fall in the levels of both the prostagladins from day one to day seven and further from seven to day nine in patients with myocardial infarction treated with aspirin 175 mg/day. In patients with myocardial infarction accompanied by arrhythmias the TXB2 levels dominated over the 6 Keto PGF 1 alpha levels. In the group of patients subjected to coronary bypass surgery but after treatment with aspirin 175 mg/day for a period of five days both 6 keto PGF 1 alpha and TXB2 levels fell significantly.

Topics: 6-Ketoprostaglandin F1 alpha; Arrhythmias, Cardiac; Aspirin; Case-Control Studies; Coronary Artery Bypass; Cyclooxygenase Inhibitors; Humans; Myocardial Infarction; Postoperative Care; Thromboxane B2; Time Factors

A study was carried out on the plasma levels of 6 Keto PGF1 alpha and Thromboxane B2 (TXB2) in patients with acute myocardial infarction. Our results showed a generalized increase in the levels after acute myocardial infarction. The 6 Keto PGF1 alpha levels increased twice as compared to control values while the TXB2 levels increased nine times as compared to control values. The prostaglandin levels were found to increase from day 1 to day 3 and further from day 3 to day 7. In most of the patients with uncomplicated myocardial infarction the 6 Keto PGF1 alpha levels were higher than the TXB2 levels. In patients with myocardial infarction accompanied by arrhythmias the TXB2 levels dominated over the 6 Keto PGF1 alpha levels.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arrhythmias, Cardiac; Female; Humans; Male; Middle Aged; Myocardial Infarction; Radioimmunoassay; Thromboxane B2

Effects of methylflavonolamine (MFA) on TXA2 and PGI2 plasma levels in rabbits of myocardial infarction were investigated. It was found that TXB2 levels were inhibited by MFA 2.5 or 5.0 mg.kg-1 i.v. while 6-keto-PGF1 alpha levels were only slightly inhibited after repeated doses of 5.0 mg.kg-1 i.v. within 6 h. This result indicates that MFA exhibit stronger inhibition on cyclo-oxygenase in platelets than in endothelial cells. In addition, the myocardial injury and the size of myocardial infarction were much less in the MFA treated groups than in the control.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Flavonoids; Flavonols; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Rabbits; Thromboxane B2

Several attempts have been undertaken to reduce the severity of ischemic myocardial injury by exogenous administration of eicosanoids and by modification of endogenous eicosanoid production. The present study investigates whether defibrotide, a compound that stimulates endogenous prostacyclin (PGI2), has a beneficial effect in experimental ischemic myocardial injury. Anesthetized, open-chest minipigs were subjected to 1 h of coronary artery occlusion, followed by 3 h of reperfusion. Defibrotide (32 mg/kg x h) or its vehicle were infused i.v. throughout the experiment. Defibrotide increased cardiac PGI2 formation 3- to 4-fold greater than control (P < .05). Thromboxane levels remained unchanged. Irreversible ischemic injury, as identified by negative tetrazolium staining, amounted to 44 +/- 6% of the area at risk in pigs receiving vehicle but was reduced to 23 +/- 4% by defibrotide (P < .05). This reduced tissue injury in defibrotide-treated pigs was associated with improved functional recovery (left ventricular pressure, + dP/dtmax), during early reperfusion. Recovery did not occur in vehicle-treated pigs. Collagen (2 micrograms/ml)-induced platelet aggregation ex vivo was increased in vehicle-treated pigs during ischemia and reperfusion, but not in animals treated with defibrotide. Polymorphonuclear neutrophil leukocyte accumulation in the ischemic border zone was reduced from 59 +/- 17 cells/mm2 in vehicle-treated pigs to 17 +/- 9 cells/mm2 by defibrotide (P < .05). Pretreatment of the animals with indomethacin (3 mg/kg) prevented the reduction of infarct size and polymorphonuclear neutrophil leukocyte infiltration by defibrotide. Indomethacin increased infarct size in vehicle- and defibrotide-treated pigs by 71 and 59%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Cyclooxygenase Inhibitors; Disease Models, Animal; Epoprostenol; Female; Granulocytes; Indomethacin; Leukocyte Count; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Platelet Count; Polydeoxyribonucleotides; Prostaglandins; Stimulation, Chemical; Swine; Swine, Miniature; Thromboxane A2; Ventricular Function, Left

6-keto-prostaglandin F1a and thromboxane B2 were determined in order to obtain more information about the prostacyclin synthesis and thromboxane A2 release in 3- to 18-year-old healthy children and in offspring of parents who have had an acute myocardial infarction before the age of 45. The authors demonstrated a reduction of plasma prostacyclin synthesis in children with a positive family history of premature coronary arterial disease. Thromboxane levels in the affected adolescent boys were significantly lower compared with the controls. The ratio of thromboxane:prostacyclin in endangered children did not show a significant difference from that of healthy controls. These data indicate that prostaglandins are a definitive marker for identifying cardiovascular risk children. It must be supposed that in adolescence, only in boys, with a positive family history of premature coronary arterial disease, a compensatory mechanism exists to protect them from developing an imbalance in the regulation of prostaglandins.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Biomarkers; Child; Child, Preschool; Epoprostenol; Female; Humans; Male; Myocardial Infarction; Risk Factors; Thromboxane B2

The effects of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) on infarct size, myeloperoxidase (MPO) activity and plasma prostanoid levels were studied using coronary artery occlusion (1 h)-reperfusion (3 h) model in rabbits, comparing with acetylsalicylic acid (ASA). Myocardial infarct size, MPO activity in the infarcted region and plasma glutamate oxalo-acetate transaminase, lactate dehydrogenase and creatine kinase were significantly suppressed by treatment with KC-764 (2 mg/kg i.v.), but not by ASA (10 mg/kg i.v.). KC-764 completely depressed the increase in plasma TXB2 level during occlusion-reperfusion with a little influence on plasma 6-keto-PGF1 alpha. Thus, the ratio of 6-keto-PGF1 alpha to TXB2 levels was increased by KC-764. On the other hand, ASA treatment depressed both plasma TXB2 and 6-keto-PGF1 alpha levels to the same extent. The in vitro study with guinea-pig neutrophils showed that KC-764 reduced the chemotaxis induced by formyl-methionyl-leucyl- phenylalanine at 3 x 10(7)-3 x 10(-6) mol/l, while ASA did not influence the neutrophil chemotaxis. These results suggest that KC-764 may salvage the damaged ischemic myocardium by the selective inhibition of TXA2 synthesis and the suppression of leukocyte migration.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspartate Aminotransferases; Aspirin; Bridged Bicyclo Compounds; Chemotaxis, Leukocyte; Creatine Kinase; Guinea Pigs; L-Lactate Dehydrogenase; Male; Myocardial Infarction; Myocardial Reperfusion Injury; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nicotinic Acids; Platelet Aggregation Inhibitors; Rabbits; Thromboxane B2

Prostacyclin (PGI2) improves regional contractility of postischemically dysfunctional ("stunned") myocardium. We determined whether defibrotide, a fraction of mammalian DNA known to stimulate endogenous formation of PGI2, also improves contractile recovery of stunned myocardium. Anesthetized, open-chest minipigs were subjected to coronary occlusion of 5 min (left anterior descending branch, LAD) followed by 120 min of reperfusion. The animals were treated with defibrotide (32 mg x kg-1 x h-1, intravenously, i.v.) or vehicle throughout the experimental period. Defibrotide improved regional contractility in the ischemic reperfused area from 30 (vehicle) to 78% of the preischemic control without altering the contractility of nonischemic myocardium. Transcardiac PGI2 formation, determined from the difference between coronary venous and arterial plasma concentrations, was elevated from 437 (preischemic control) to 869 pmol x l-1 in defibrotide-treated animals, but was unchanged in the vehicle-treated and a sham-operated group. Thromboxane A2 (TXA2) release was not modified. Defibrotide reduced ischemia-induced formation of platelet aggregates but did not affect the activity of polymorphonuclear neutrophil granulocytes. The data demonstrate an improvement of contractile recovery from stunning by defibrotide that may be related to an inhibition of ischemia-induced platelet activation and (or) membrane protection owing to enhanced transcardiac formation of PGI2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Coronary Vessels; Epoprostenol; Female; Fibrinolytic Agents; Heart; Hemodynamics; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion; Neutrophils; Platelet Count; Polydeoxyribonucleotides; Stimulation, Chemical; Swine; Swine, Miniature; Thromboxane B2; Time Factors

The effects of sophoridine on acute myocardial infarction induced by ligation of left anterior descending coronary artery in 16 anesthetized and open-chest dogs were studied. Treatment with sophoridine 20 mg.kg-1 iv reduced the size of myocardial infarct 6 h after ligation and lowered the elevated plasma levels of lactic acid and pyruvic acid 15, 30 and 60 min after ligation. Sophoridine also lowered the activity of serum CPK 60 and 120 min after ligation and reduced TXB2 and increased 6-keto-PGF1 alpha, hence the metabolites of PGI2/TXA2 ratio after ligation was increased. Electron microscopy showed that sophoridine protected mitochondria of ischemic cells. These results indicated that sophoridine showed protective effects on acute myocardial infarction. The beneficial effect on PGI2/TXA2 and mitochondria seems to contribute its protective action.

Topics: 6-Ketoprostaglandin F1 alpha; Alkaloids; Animals; Creatine Kinase; Dogs; Female; Lactates; Lactic Acid; Male; Matrines; Myocardial Infarction; Myocardium; Pyruvates; Pyruvic Acid; Quinolizines; Thromboxane B2

Captopril is an angiotensin-converting enzyme inhibitor that has been reported to be effective in salvaging post-ischemic reperfused myocardium by its ability to function as a free radical-scavenging agent. A study was performed in the isolated porcine-heart model evaluating the influence of pretreatment with captopril on salvage of myocardium after an induced myocardial infarction. Measurement was carried out of regional and global myocardial function, myocardial high-energy phosphate levels, creatine kinase release, malonaldehyde formation, and 6-keto-prostaglandin F1 alpha generation. In an in vitro preparation, the influence of captopril for scavenging various free radicals was evaluated. A dose-response curve was carried out using this free radical-generating system and differing levels of captopril. Results of the study demonstrate that pretreatment with captopril at a 45-mumol/L level reduced reperfusion injury in the pig heart model. This was manifested by improved cardiac performance, a reduction in creatine kinase release, and reduced malonaldehyde generation. In vitro evaluation of captopril and its free radical-scavenging ability indicated that it is a weak scavenger of superoxide anions (O2-) but behaves as a potent scavenger of hydroxyl radicals (-OH) as well as hypohalite radicals (OCl-). Based on the influence of captopril in reducing lipid peroxidation (decreased malonaldehyde formation) and its documented ability to scavenge -OH as well as OCl-, it is suggested that myocardial preservation in a postinfarction model is due primarily to its free radical-scavenging activity, primarily of the potent free radicals -OH and OCl-.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Triphosphate; Animals; Captopril; Coronary Circulation; Creatine Kinase; Female; Free Radical Scavengers; Lipid Peroxidation; Male; Myocardial Contraction; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Oxygen Consumption; Swine

In 16 dogs the endothelium of the left anterior descending coronary artery was injured mechanically. Then a copper wire was inserted into the lumen as a choke of flow and the vessel was slightly compressed from outside by a constrictor. Eight dogs had been treated beforehand with a preparation of flavone extracted from the root of the Chinese medicinal herb Andrographis paniculata (TFAP). In the control group, saline solution was given, the epicardially recorded ST segment started to elevate within 15 minutes, the platelet aggregation rate and the plasma levels of TXB2 increased rapidly, whereas the level of 6-k-PGF1 alpha remained stable. Platelet cGMP rose continuously; however, platelet cAMP rose only at 60 minutes. Histological findings confirmed the occurrence of arterial thrombus and myocardial necrosis. Contrariwise, in the pretreated group there was no elevation of the ST segment, plasma 6-k-PGF1 alpha and platelet cAMP were increased, the production of TXB2 and aggregation of platelets were inhibited, and no thrombus or myocardial infarction was induced. All data suggest that TFAP might promote the synthesis of PGI2, inhibit the production of TXA2, stimulate the synthesis of cAMP in platelets, impede aggregation of platelets, and thereby prevent the formation of thrombi as well as the development of myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Drugs, Chinese Herbal; Fibrinolytic Agents; Myocardial Infarction; Platelet Aggregation; Platelet Aggregation Inhibitors; Thromboxane B2

Twenty-five patients with myocardial infarction were monitored in the acute phase and during follow-up with regard to the in vivo production of prostacyclin (PGI2) and thromboxane (TxA2), by measurement of their major urinary metabolites, 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TxB2, respectively. In 22 of these patients PGI2 and TxA2 production were also assessed before, during and after an exercise test performed 6 weeks after discharge. In approximately 24% of patients the in vivo production of prostacyclin did not increase during the acute phase of the infarction process. This inability was usually associated with a decrease in the release of heart muscle enzymes, and was mostly frequently observed in women. During the exercise tolerance test, none of the patients showed any increase in prostacyclin production, in contrast to healthy volunteers, in whom a significant increase was seen. There were no differences between patients with and without an increase in prostacyclin production during the acute phase. At the follow-up 2 years after the myocardial infarction, eight cardiac events had occurred, all of which were noted among patients who exhibited an expected increase in prostacyclin production in association with the infarction. This would seem reasonable, since most of the patients in this group had larger primary infarctions.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Creatine Kinase; Epoprostenol; Exercise Test; Female; Follow-Up Studies; Humans; Isoenzymes; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Thromboxane A2; Thromboxane B2

The levels of thromboxane B2, prostaglandin 6-keto F1 alpha (PG F1 alpha), thrombocytic factor IV (TF IV), and beta-thromboglobulin (beta-TG) were measured in 66 patients with postinfarction cardiosclerosis concurrent with acute recurrent myocardial infarction or unstable angina pectoris. There was a substantial increase in thromboxane B2 activity and a less significant elevation of PG F1 alpha, as well as a rise of TF IV and beta-TG. Circulatory insufficiency, cardiac aneurysm, intracardiac thrombi were accompanied by much more severe abnormalities in the above-mentioned parameters.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood Coagulation; Coronary Thrombosis; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Platelet Factor 4; Recurrence; Thromboxane B2

To investigate the prostaglandin I2 (PGI2) half-life regulated by high density lipoprotein (HDL) in patients with coronary artery disease (CAD), we determined the stability of PGI2 and serum apolipoprotein A-I (Apo A-I) and apolipoprotein A-II (Apo A-II) levels in four age-matched groups of patients: controls (n = 17), angina pectoris (n = 18), unstable angina pectoris (n = 17), myocardial infarction (n = 19) (acute phase, 3.6 +/- 1.7 hours from onset; subacute phase, 75 +/- 15 hours from onset in the same patients). Serum PGI2 half-life and total serum Apo A-I levels were lower in the CAD group than in the control group. PGI2 was least stable in patients with unstable angina and the acute phase of myocardial infarction. In these patients, the molar ratio of Apo A-I to Apo A-II and HDL-associated Apo A-I levels were decreased, and free Apo A-I levels were increased. After in vitro incubation of HDL with increasing amounts of Apo A-II, Apo A-I in HDL was displaced by Apo A-II, with the parallel decrease in stability of PGI2. Free Apo A-I cannot stabilize PGI2. HDL-associated Apo A-I, whose amount is affected by Apo A-II, stabilized PGI2 and correlated well with stability of PGI2 in patients with CAD and control patients. Decreased PGI2 half-life may play an important role in the pathogenesis of atherosclerosis and thrombus formation in the coronary arteries, especially thrombus formation during an acute coronary event.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris; Angina, Unstable; Apolipoprotein A-I; Apolipoproteins A; Cholesterol, HDL; Epoprostenol; Half-Life; Humans; Lipoproteins, HDL; Middle Aged; Myocardial Infarction; Platelet Aggregation

Topics: 6-Ketoprostaglandin F1 alpha; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane B2

Essential fatty acid (EFA) deficiency, induced by elimination of the dietary (n-6) fatty acids, has been shown to limit inflammatory cell influx and consequent enhanced eicosanoid production in experimental glomerulonephritis and hydronephrosis. To determine whether EFA-deficiency exerts anti-inflammatory effects following left ventricular myocardial infarction (LVMI), male weanling rabbits were fed EFA-deficient diet for 3 months prior to 60 minutes of distal left circumflex coronary artery occlusion followed by reperfusion. One and 4 days later, corresponding to infiltration of cardiac tissue with polymorphonuclear (PMN) and mononuclear leukocytes respectively, infarcted hearts were buffer perfused and stimulated to produce eicosanoids with f-met-leu-phe or bradykinin. One day following LVMI, the hearts of EFA-deficient rabbits demonstrated a marked suppression of PMN infiltration and eicosanoid production relative to controls. Four days following myocardial infarction, no differences were observed in mononuclear cell invasion, collagen deposition, or eicosanoid production between EFA-deficient and normal hearts. Our data show that EFA-deficiency inhibits PMN influx and consequent enhanced eicosanoid production without affecting the later appearance of mononuclear cells, collagen deposition, or eicosanoid production. Recent studies have shown that suppression of PMN invasion limits the extent of tissue damage following LVMI. Selective inhibition of PMN infiltration is possible and may be useful in the management of acute myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Acute-Phase Reaction; Animals; Cell Migration Inhibition; Collagen; Dinoprostone; Fatty Acids, Essential; Inflammation; Leukotriene B4; Male; Myocardial Infarction; Myocardium; Neutrophils; Rabbits; Thromboxane B2

Twenty-eight subjects, 16 with old myocardial infarction (OMI) and a control group of 12, received ticlopidine 250 mg/day for 4 weeks. All subjects underwent the standard Bruce protocol exercise test before and after therapy. Blood was collected from a peripheral vein to study platelet function at pre-exercise (rest), peak exercise (end point), and 6 min post-exercise (recovery). Platelet count, platelet aggregatory response, plasma thromboxane B2 (TXB2), and 6-keto-PGF 1 alpha were measured by Coulter counter, aggregometry, and radioimmunoassay, respectively. The platelet count, aggregatory response (induced by ADP, adrenalin, and collagen) and the plasma concentration of TXB2 and 6-keto-PGF 1 alpha were not significantly affected by exercise in the OMI and control groups. Overall, there were no significant changes in exercise duration, heart rate, and blood pressure in both groups before or after ticlopidine treatment, with some minor exceptions. There were no significant changes in the peripheral blood profiles, the bleeding and coagulation times, the blood chemistry data, and the platelet counts between the groups before or after treatment. There was a significant decrease in collagen- and ADP-induced platelet aggregation in both groups after ticlopidine therapy. Prior to treatment, a higher plasma TXB2 concentration was noted in the OMI group during and after exercise; the difference was no longer statistically significant after ticlopidine therapy when both groups were compared. There was a significant reduction in the TXB2 levels in the OMI group after ticlopidine treatment despite exercise. Before therapy, plasma 6-keto-PGF 1 alpha was significantly elevated in the OMI group before or after exercise but was not statistically significant after ticlopidine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Blood Platelets; Female; Humans; Male; Middle Aged; Myocardial Infarction; Physical Exertion; Thromboxane B2; Ticlopidine

The changes of platelet functions including platelet membrane microviscosity (PMMV), plasma 5-HT, plasma TXB2 and 6-K-PGF1a were studied in 30 cases of AMI and 13 cases of unstable angina (UA), 20 normal subjects as control. After onset of AMI, PMMV, plasma 5-HT, 6-k-PGF1a all increased quickly, especially on the 1st day (P less than 0.001-0.01). During 3 weeks observation, only 6-K-PGF1a decreased to the normal level on 14th day. There were no obvious decrease of plasma TXB2, 5-HT and PMMV. It showed that in acute phase of AMI without intervention of any antiplatelet drugs the platelets were activated continuously. Plasma 5-HT was the most sensitive predictor for the severity of AMI as observed by the comparison between the cases with complications and serum peak CK greater than 1000 U/L, and those without complications and peak CK less than 1000 U/L (P less than 0.001-0.05). The great change of PMMV was a bad prognosis. In patients with UA, during acute myocardial ischemia, the platelets were also activated significantly, but the extent was not as high as that in AMI.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Blood Platelets; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Function Tests; Serotonin; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane B2

It has been suggested that coronary ischemia increases extravascular lung water. To determine whether pulmonary microvascular permeability is increased by coronary ischemia, we measured pulmonary hemodynamics, lung lymph flow (QL), and lymph-to-plasma protein concentration ratio (L/P) in 12 sheep with chronic lung lymph fistulas. Studies were done in 3 groups: in group 1 (n = 7) a marginal branch of the left circumflex artery (Lcx) was occluded, in group 2 (n = 5) left atrial pressure (Pla) was mechanically raised by 10 mmHg, and in group 3 (n = 5) Lcx was occluded and Pla was raised by 10 mmHg. In group 1, coronary occlusion increased QL (4.6 +/- 0.4 to 8.3 +/- 2.6 ml/h) without changes in L/P. In group 2, elevated Pla increased QL (5.1 +/- 1.2 to 10.1 +/- 3.0 ml/h) with decreases in L/P (0.71 +/- 0.02 to 0.61 +/- 0.02). In group 3, coronary occlusion with elevated Pla caused a further increase in QL (5.0 +/- 1.5 to 16.9 +/- 4.6 ml/h) without significant decreases in L/P (0.71 +/- 0.01 to 0.65 +/- 0.06). Lung lymph concentrations of 6-keto-prostaglandin F1 alpha (a degradation product of prostacyclin) increased transiently after coronary occlusion. These results indicate that coronary occlusion can increase transcapillary protein transport in lungs of conscious sheep and simultaneously increase prostacyclin production in the lung.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Capillary Permeability; Coronary Disease; Extracellular Space; Hemodynamics; Leukocyte Count; Lung; Lymph; Myocardial Infarction; Oxygen; Platelet Count; Sheep; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Female; Male; Myocardial Infarction; Platelet Aggregation; Propranolol; Pyrimidines; Rabbits; Thromboxane B2; Trapidil

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Blood Platelets; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation; Thromboxane B2; Thromboxanes; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Myocardial Infarction; Thromboxanes

The endogenous arachidonic acid metabolism was investigated ex vivo, in separated serum from clotted whole blood, soon after the onset of acute myocardial infarction (3.3 +/- 0.7 hr). A group of eight consecutive male patients was selected, since no evidence was obtained of any associated disease known to increase platelet activity or any recent exposure to cyclo-oxygenase inhibitors. This group of patients compared to an age and sex matched control group showed a large decrease in the platelet cyclo-oxygenase end-products in whole blood: thromboxane B2 (TXB2), 12-hydroxy-5-cis, 8-cis, 10-trans-heptadecatrienoic acid (HHT) and 6-keto-PGF1 alpha (p less than .01). In addition, platelet lipoxygenase produced an increased amount of 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid (12-HPETE) as measured by its reduced metabolite 12-HETE (p less than .05). Furthermore, the TXB2 plasma concentration was significantly elevated in patients (p less than .01), confirming the enhanced platelet reactivity during the early stages of acute myocardial infarction. These results point out that a decreased level of cyclo-oxygenase end-products and an increased level of lipoxygenase end-product in serum is consistent with a previous in vivo cyclo-oxygenase hyperactivity.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Fatty Acids, Unsaturated; Humans; Hydroxyeicosatetraenoic Acids; Lipoxygenase; Male; Middle Aged; Myocardial Infarction; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Thromboxane B2

There is increasing evidence that platelets play an important role in the pathogenesis of acute ischemic heart disease. Therefore, an understanding of factors which impact on platelet performance is important. The present study was undertaken 1. to characterize during evolving myocardial infarction (MI) platelet activity in the peripheral circulation and across the ischemic/infarcting myocardial compartment, the locus of presumed platelet hyperactivity, and 2. to evaluate the effects of prostacyclin (PGI2), a most potent antiplatelet agent and vasodilator. A total of 59 patients with evolving MI were studied. 22 patients were instrumented with arterial and coronary sinus catheters and received intravenous infusion of PGI2, 13 +/- 4.5 ng/kg/min (mean +/- SD), for 90 minutes. In 15 of these patients, who had an anterior MI, transcardiac platelet function and response to PGI2 were studied. The results are as follows: Plasma levels of beta-thromboglobulin (beta-TG) and of thromboxane B2 (TxB2), in vivo measures of platelet activity, are elevated three and ten fold. 6-keto-prostaglandin F1 alpha, the stable end product of PGI2, is less than 10 pg/ml, reflecting a leftward shift of the TxB2/PGI2 ratio. Platelets, circulating during evolving MI ("ischemic platelets") are hyperaggregable in response to adenosine diphosphate and relatively resistent to PGI2, both in vivo and in vitro. Concentrations of platelet cyclic adenosine monophosphate and the cAMP response to PGI2 are diminished. The platelet hyper-reactivity is most intense early during infarct evolution and decreases with time. Transcardiac measurements indicate that thromboxane is produced across the ischemic/infarcting compartment in ten of 15 patients with anterior MI. The antiplatelet effect of PGI2 is greatly diminished. In summary, the data define an abnormal pattern of platelet behavior during evolving MI characterized by a pro-aggregatory environment, heightened platelet re-activity, both in the peripheral and coronary circulation, and relative resistance to PGI2. The clinical consequence of the data are that the infarct patient in the acute phase may benefit from platelet function suppression and requires significantly greater doses of prostacyclin than normal subjects. The data also suggest future directions for therapeutic manipulation of platelet hyper-reactivity in the setting of acute myocardial ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; beta-Thromboglobulin; Blood Platelets; Epinephrine; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Norepinephrine; Platelet Aggregation; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Blood Vessel Prosthesis; Epoprostenol; Gas Chromatography-Mass Spectrometry; Humans; Myocardial Infarction; Thromboxane A2; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatine Kinase; Dogs; Female; Ginsenosides; Male; Myocardial Infarction; Perfusion; Saponins; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Electrocardiography; Female; Lactates; Male; Myocardial Infarction; Rabbits; Thromboxane B2

The in vivo production of prostacyclin and thromboxane was monitored by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in ten patients with acute myocardial infarction, five on standard treatment and five receiving prostacyclin infusion. During acute myocardial infarction excretion of 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, measured by a gas chromatography-mass spectrometry method with deuterated internal standards, was significantly increased. This indicates that thromboxane and prostacyclin synthesis are increased during the development of acute myocardial infarction. The excretion data for 2,3-dinor-thromboxane B2 showed that after administration of aspirin there was less pronounced and more variable inhibition than expected. Prostacyclin infusion did not markedly affect the excretion of the thromboxane metabolite.

Topics: 6-Ketoprostaglandin F1 alpha; Epoprostenol; Humans; Infusions, Parenteral; Myocardial Infarction; Thromboxane B2; Thromboxanes

Pathological and clinical studies have suggested that platelets have a role in the pathogenesis of unstable angina and myocardial infarction. However, the relation of platelet activation to episodic ischemia in patients with unstable angina is unknown. We assessed the biosynthesis of thromboxane and prostacyclin as indexes of platelet activation in patients with stable and unstable coronary disease by physicochemical analysis of metabolites in plasma and urine. Prostacyclin biosynthesis was markedly elevated in patients with acute myocardial infarction and correlated with plasma creatine kinase (r = 0.795; P less than 0.001). The largest rise in thromboxane synthesis was observed in patients with unstable angina, in whom 84 percent of the episodes of chest pain were associated with phasic increases in the excretion of thromboxane and prostacyclin metabolites. However, 50 percent of such increases were not associated with chest pain, possibly reflecting silent myocardial ischemia. These data indicate that platelet activation occurs during spontaneous ischemia in patients with unstable angina. The increment in prostacyclin biosynthesis during such episodes may be a compensatory response of vascular endothelium that limits the degree or effects of platelet activation. If so, biochemically selective inhibition of the synthesis or action of thromboxane A2 would be desirable in the treatment of unstable angina. In contrast, thromboxane inhibitors or antagonists would not be expected to be effective in patients with chronic stable angina, in whom there was no increase in the formation of thromboxane A2.

Topics: 6-Ketoprostaglandin F1 alpha; Angina Pectoris; Angina, Unstable; Blood Platelets; Epoprostenol; Humans; Myocardial Infarction; Thromboxane A2; Thromboxane B2

An experimental model of acute myocardial infarction is presented. Intracoronary thrombus was precipitated by a mock ruptured atheromatous plaque, which is a cholesterol-collagen mixture, protruding into the stenosed left anterior descending coronary artery. Twenty-five dogs, divided into two groups, were studied: a control group of 15 dogs and a treated group of 10 dogs. Intracoronary thrombus was precipitated by the mock atheromatous plaque in 13 of 15 control animals. Myocardial infarction was induced in 10 and sudden death in two. Coronary blood flow decreased gradually or cyclically to end in myocardial infarction. The model was utilized to investigate the effects of a thromboxane synthetase inhibitor, OKY-046, on 10 additional animals. OKY-046 could significantly decrease the incidence of occlusive thrombus formation and myocardial infarction when administered intravenously during coronary blood flow reduction (3 of 10 in the treated group vs 12 of 15 in the control group, p less than 0.02). Thromboxane B2 was significantly elevated in the coronary venous blood during reduction of the coronary blood flow, while thromboxane B2 was reduced and 6-ketoprostaglandin F1 alpha increased during OKY-046 administration. The reduction in thromboxane A2 production associated with increased prostacyclin appeared to be the major mechanism of the interruption of the thrombus formation by OKY-046.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Thrombosis; Dogs; Epoprostenol; Female; Male; Methacrylates; Myocardial Infarction; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effects of lipoxygenase enzyme inhibitor nafazatrom on infarct size, haemodynamics, and prostanoid release was studied in a canine occlusion-reperfusion model of ischaemic myocardial injury. Treatment was with 10 mg/kg nafazatrom i.d., starting before coronary occlusion, 2 h and 6 h thereafter, and was repeated in 6 h intervals. The left anterior descending (LAD) coronary artery was occluded for 6 h and reperfused for 42 h. Infarct size and anatomic area dependent on the occluded LAD were determined post mortem by the tetrazolium staining technique. Nafazatrom significantly reduced the extent of irreversible myocardial ischaemic damage whether it was expressed as g/100 g left ventricle (24 +/- 4 vs. 46 +/- 6 in controls; p less than 0.01; mean +/- SEM) or as percentage of LAD risk region for infarcting (38 +/- 8 vs. 65 +/- 7% in controls; p less than 0.05). Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure and dP/dtmax decreased while filling pressure, heart rate, and the S-T segments of the ECG increased. The incidence of ventricular fibrillation was 8% during drug treatment and coronary ligature vs. 25% in controls (n.s.). During reperfusion, nafazatrom reduced the incidence of ventricular premature contractions and tachycardia. Ex vivo platelet aggregation in response to collagen was not inhibited by nafazatrom. Prostanoid release (thromboxane B2 and 6-keto-prostaglandin F1 alpha as breakdown products of thromboxane A2 and prostacyclin, respectively) remained unaltered in vehicle controls but nafazatrom treatment elevated prostacyclin release significantly at 4 and 5 h during LAD occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Electrocardiography; Female; Male; Myocardial Infarction; Perfusion; Platelet Aggregation; Pyrazoles; Pyrazolones; Thromboxane B2

In order to diagnose patients in thrombotic state, it is quite important to detect increased concentration of plasma thromboxane B2 (TXB2), a stable catabolite of TXA2. To determine plasma TXB2 levels with high sensitivity and selectivity, we employed gas chromatography-mass spectrometry (GC/MS). The trimethylsilyl (TMS) ether derivatives conventionally employed in GC/MS analysis of prostanoids are not suitable for quantitation of plasma prostanoids, because the mass spectra are deficient in ions with high intensity in the high mass range and TMS ether derivatives are sensitive to moisture. To solve these problems we employed tert-butyldimethylsilyl (t-BDMS) ether derivatives, based on the observation that t-BDMS ether derivatives afforded abundant ions at [M-57]+ and showed good hydrolytic stability. The reaction conditions of tert-butyldimethylsilylation were also examined to optimize the selected ion monitoring response. The t-BDMS ether derivatives of prostanoids were successfully analyzed with a short capillary column with a relatively large diameter, with maintaining good separation. In conjunction with the use of reversed-phase high performance liquid chromatography as purification procedure, a sensitive and reproducible stable isotope dilution assay of plasma TXB2 was developed. The values obtained by this method correlated well with those obtained by the radioimmunoassay we have developed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Coronary Vasospasm; Dinoprost; Dinoprostone; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Myocardial Infarction; Organosilicon Compounds; Prostaglandin D2; Prostaglandins D; Prostaglandins E; Prostaglandins F; Silicon; Thromboxane B2; Thromboxanes

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.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Disease; Adult; Aged; Arrhythmias, Cardiac; Epoprostenol; Female; Humans; Male; Middle Aged; Myocardial Infarction; Prostaglandins; Thromboxane A2; Thromboxane B2

To investigate the role of a factor in serum stimulating prostacyclin synthesis in acute myocardial infarction, we compared the activities of the factor among 7 patients with acute myocardial infarction (2.5 +/- 0.8 hrs and 80 +/- 17 hrs after the onset of symptoms), 12 patients with angina pectoris, and 7 normal subjects. In this study, we found that in patients with acute myocardial infarction, this activity is much lower immediately after infarction (2.5 +/- 0.8 hrs) than 80 +/- 17 hrs later, or in patients with stable angina pectoris, or in healthy volunteers. Since prostacyclin is antiaggregating and vasodilating, the deficiency in this ability during the very early phase of acute myocardial infarction may be related to the development of the thrombosis of acute myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Humans; Middle Aged; Myocardial Infarction; Rats; Rats, Inbred Strains; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Angina Pectoris; Epoprostenol; Humans; Middle Aged; Myocardial Infarction; Radioimmunoassay; Thromboxane A2; Thromboxane B2; Thromboxanes

Topics: 6-Ketoprostaglandin F1 alpha; Creatinine; Humans; Middle Aged; Myocardial Infarction; Time Factors

Topics: 6-Ketoprostaglandin F1 alpha; Humans; Kinetics; Myocardial Infarction

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Urea Nitrogen; Creatine Kinase; Isoproterenol; Male; Myocardial Infarction; Prostaglandins F; Rats; Sulfinpyrazone; Thromboxane B2