6-ketoprostaglandin-f1-alpha and Arteriosclerosis

Topics: 6-Ketoprostaglandin F1 alpha; Arteriosclerosis; Bartter Syndrome; Biomarkers; Humans; Hypertension, Pulmonary; Immunoenzyme Techniques; Ischemia; Prostaglandins I; Radioimmunoassay; Reference Values; Specimen Handling

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Blood Platelets; Blood Vessels; Diet, Atherogenic; Epoprostenol; Hemodynamics; Humans; Lipid Peroxides; Lipoproteins, LDL; Lipoproteins, VLDL; Muscle, Smooth, Vascular; Platelet Aggregation; Rabbits; Risk; Stress, Physiological; Thrombosis; Thromboxane A2; Time Factors

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

Prostacyclin emanating from the uterus is proposed as a major contributor to the reduced risk of coronary disease among women. The hypothesis is supported by (1) epidemiologic evidence that the risk of myocardial infarction increases markedly following hysterectomy whether or not the ovaries are removed, (2) evidence that premenopausal women may have higher circulating levels of prostacyclin than men of comparable ages, (3) production of prostacyclin by uterine tissue homogenates, (4) preliminary data showing high levels of prostacyclin's stable end-product metabolite in the venous drainage of the uterus, and (5) plausible mechanisms through which prostacyclin could produce a salutary effect on coronary disease. If an appreciable portion of woman's coronary advantage over man relates to differences in uterine production and circulating levels of this natural hormone or similar hormones such as 6-keto-PGE1, then the implications for therapy, prevention, and understanding of the underlying disease processes are considerable. In any case, physicians in practice should recognize the potential of the uterus as a systemically active organ whose removal significantly increases subsequent risk of myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aging; Arteriosclerosis; Blood Coagulation; Blood Viscosity; Coronary Disease; Epoprostenol; Female; Humans; Hysterectomy; Iron; Menopause; Menstruation; Middle Aged; Platelet Aggregation; Prostaglandins; Risk; Sex Factors; Uterus

This trial evaluated the effect of antioxidant supplementation on the urinary excretion of 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio, a marker of the pathogenesis of thrombosis and arteriosclerosis.. This study was a randomised, double-blind, placebo-controlled trial involving 186 presumably healthy volunteers. One hundred received a multi-antioxidant supplementation and 86 a placebo for two years. Blood zinc, selenium, beta-carotene, vitamin C and E and urinary excretion of 11-dehydro TXB(2) and 2,3 dinor 6 keto PGF(1alpha) were measured.. Baseline subject characteristics did not differ between the two groups. Blood zinc, selenium, and beta-carotene concentrations significantly increased between baseline and two years in the multi-antioxidant supplementation group supporting subject compliance (p < 0.05). At two years, the median urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio was significantly lower in the multi-antioxidant supplementation group (3.4 versus 2.78, p = 0.015). Serum selenium concentration was the only antioxidant studied that was significantly related to the urinary 11-dehydro TXB(2)/2,3 dinor 6 keto PGF(1alpha) ratio.. These results support the hypothesis that a low-dose multi-antioxidant supplementation may contributes to a reduction in platelet activation which is beneficial for cardiovascular function.

Topics: 6-Ketoprostaglandin F1 alpha; Antioxidants; Arteriosclerosis; beta Carotene; Biomarkers; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Compliance; Platelet Activation; Prostaglandins I; Selenium; Thrombosis; Thromboxane B2; Thromboxanes; Trace Elements; Vitamins; Zinc

To investigate the effect of dietary saturated fat (SFA) from animal sources on the urine excretion 11-dehydro thromboxane B2 (TXB2) and 6-keto prostaglandin F 1alpha (PGF 1alpha) in 27 healthy free-living male subjects aged 30 to 55 years.. It was a randomized crossover design. Each volunteer was randomly assigned to one of the two diets (high fat and low fat) for a period of 4 weeks, after which each subject resumed his usual diet for 2 weeks as a 'wash-out period', before being assigned to the other diet for an additional 4 weeks.. Serum proportion of 20:4n-6 was 5% lower in the high fat (6.2% of total fatty acid) than in the low fat diet (6.5% of total fatty acid), which was associated with a significantly decreased ratio of the urinary excretion 11-dehydro TXB2 to 6-keto PGF 1alpha (P < 0.05). However, there was no significant fall in the absolute urinary excretion of 11-dehydro TXB2.. Diet rich in SFA from animal sources may influence TXA2 formation via effect on tissue proportion of 20:4n-6.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Cross-Over Studies; Dietary Fats; Fatty Acids; Humans; Male; Middle Aged; Thrombosis; Thromboxane B2

The formation of prostacyclin (PGI(2)), thromboxane (TX) A(2), and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis.. The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB(2) and 2,3-dinor-6-keto-PGF(1alpha), metabolites of TXA(2) and PGI(2), respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211+/-533 versus 679+/-63 pg/mg creatinine, P<0.001; 594+/-156 versus 130+/-22 pg/mg creatinine, P<0.05, respectively), as was the level of the isoprostane 8-iso-PGF(2alpha). Nimesulide reduced 2, 3-dinor-6-keto-PGF(1alpha) excretion by 46+/-5% (378.3+/-103 to 167+/-37 pg/mg creatinine, P<0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB(2) before (2678+/-694 to 2110+/-282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF(2alpha) excretion.. Both COX-1 and -2 are expressed and contribute to the increase in PGI(2) in patients with atherosclerosis, whereas TXA(2) is generated by COX-1.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Isoenzymes; Macrophages; Male; Membrane Proteins; Microscopy, Fluorescence; Muscle, Smooth, Vascular; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane A2; Thromboxane B2

Effects of a dietary intake of the polyunsaturated omega-6 essential fatty acids (EFAs) linoleic and gamma-linolenic acids (GLA) on blood lipids, platelet function, and vascular prostacyclin production were studied 12 hyperlipidemic patients (doses of 3 g/day) and 12 male Wistar rats (doses of 3 mg/kg/day) for 4 months. In humans, GLA supplementation decreased plasma triglyceride (TG) levels by 48% (p < 0.001) and increased HDL-cholesterol concentration by 22% (p < 0.01). Total cholesterol and LDL-cholesterol levels were significantly decreased by omega-6 EFAs. Platelet aggregation induced by low concentrations of adenosine diphosphate (ADP) and epinephrine, and serum thromboxane B2 decreased by 45% both in humans and animals after GLA supplementation. Bleeding time increased 40% (p , 0.01). In rats, vascular prostacyclin production measured by radioimmunoassay of 6-keto-PGF1 alpha was enhanced by GLA intake. These effects of omega-6 EFAs may contribute to cardiovascular protection and prevention of the atherosclerotic disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Arteriosclerosis; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats, Unsaturated; Epinephrine; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; gamma-Linolenic Acid; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thromboxane B2; Triglycerides

Although thromboxane A2 is a potent platelet agonist and vasoconstrictor in vitro, our knowledge of its pathophysiologic importance in human disease is limited. To facilitate the elucidation of its role in vivo, we sought to define a human syndrome in which pharmacologic interventions designed to inhibit the biosynthesis or biologic actions of thromboxane A2 might be appropriately assessed. Patients with severe peripheral vascular disease were selected on the basis of elevated plasma beta-thromboglobulin and circulating platelet aggregates and compared with healthy, age-matched control subjects. In addition to the platelet indexes, their bleeding time was shorter and excretion of 2,3-dinor-thromboxane B2, a noninvasive index of thromboxane formation in vivo, and 2,3-dinor-6-keto-prostaglandin F 1 alpha, the major urinary metabolite of prostacyclin, was markedly increased. A selective inhibitor of thromboxane synthase, imidazo (1,5-2) pyridine-5-hexanoic acid, was administered to these patients under randomized, double-blind, controlled conditions. Platelet aggregation ex vivo, the circulating platelet aggregate ratio, and the bleeding time were all unaltered, despite almost maximal inhibition of platelet thromboxane formation 1 hr after dosing. By contrast, pronounced inhibition of aggregation was observed when platelet cyclooxygenase was inhibited by aspirin. During long-term dosing with the synthetic inhibitor, inhibition of thromboxane biosynthesis was incomplete, which would permit continued thromboxane-dependent platelet aggregation to occur. However, the failure of enzyme blockade to influence platelet function at the time of maximal drug action, despite efficient inhibition of serum thromboxane B2, suggests that accumulation of proaggregatory endoperoxides is also likely to have contributed to the persistence of platelet activation. We have characterized a human preparation in which platelet activation coexists with increased thromboxane biosynthesis. In this setting, platelet activation persists despite long-term administration of a thromboxane synthase inhibitor in a dosing regimen representative of that employed in clinical trials. Prolongation of drug action and combination with antagonists of the shared endoperoxide/thromboxane A2 receptor may be necessary to assess the potential of selective inhibition of thromboxane synthase as a therapeutic strategy in man.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arteriosclerosis; beta-Thromboglobulin; Epoprostenol; Female; Humans; Imidazoles; Male; Middle Aged; Platelet Aggregation; Platelet Factor 4; Pyridines; Thromboxane B2; Thromboxane-A Synthase

Hyaluronic acid (HA) is a prominent constituent of the extracellular matrix of atherosclerotic vascular lesions in humans known to modulate vascular smooth muscle phenotype. The regulation of HA synthesis by vasodilatory prostaglandins was analyzed in human arterial smooth muscle cells (SMCs). The prostacyclin analogue, iloprost (100 nmol/L), markedly increased pericellular formation of HA coats and HA secretion into the cell culture medium in human arterial SMCs (8.7+/-1.6-fold). Expression of HA synthase 2 (HAS2) was determined by semiquantitative RT-PCR and found to be strongly upregulated at concentrations of iloprost between 1 and 100 nmol/L after 3 hours. Furthermore, endogenous cyclooxygenase-2 (COX2) activity was required for basal expression of HAS2 mRNA in SMCs in vitro. Total HA secretion in response to iloprost was markedly decreased by RNA interference (RNAi), specific for HAS2. In addition, siRNA targeting HAS2 strongly increased the spreading of human SMCs compared with mock-transfected cells. HAS2 mRNA levels were also stimulated by a selective prostacyclin receptor (IP) agonist, cicaprost (10 nmol/L), prostaglandin E(2) (10 nmol/L), and the EP(2) receptor agonist, butaprost (1 micromol/L). Induction of HAS2 mRNA and HA synthesis by prostaglandins was mimicked by stable cAMP analogues and forskolin. In human atherectomy specimens from the internal carotid artery, HA deposits and COX2 expression colocalized frequently. In addition, strong EP(2) receptor expression was detected in SMCs in HA-rich areas. Therefore, upregulation of HAS2 expression via EP(2) and IP receptors might contribute to the accumulation of HA during human atherosclerosis, thereby mediating proatherosclerotic functions of COX2.

Topics: 6-Ketoprostaglandin F1 alpha; Acetophenones; Alprostadil; Arteriosclerosis; Becaplermin; Benzopyrans; Bucladesine; Carotid Artery Diseases; Carotid Artery, Internal; Cells, Cultured; Colforsin; Cyclic AMP; Cyclooxygenase 2; Enzyme Induction; Epoprostenol; Extracellular Matrix; Glucuronosyltransferase; Humans; Hyaluronan Synthases; Hyaluronic Acid; Iloprost; Indoles; Isoenzymes; Isoquinolines; Macrophages; Maleimides; Membrane Proteins; Muscle Cells; Muscle, Smooth, Vascular; Pertussis Toxin; Platelet-Derived Growth Factor; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-sis; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; RNA, Messenger; RNA, Small Interfering; Sulfonamides; Vasodilator Agents

31 cases of atherosclerosis (AS) were treated with Jiang Zhi Tong Mai Fang ([symbol: see text], formula of JZTMF), and its effect was compared with 30 cases treated with lovastatin in the control group. Clinically, the JZTMF formula showed an effect of regulating blood lipids, and therefore it was antiatherosclerotic. The mechanism is, probably, restoration of the function of endothelial cells (EC) by increasing the synthesis of 6-keto-PGF1 alpha and decreasing the release of endothelin (ET) as evidenced in the experimental study.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Cholesterol, LDL; Drug Combinations; Drugs, Chinese Herbal; Endothelins; Endothelium, Vascular; Female; Humans; Lovastatin; Male; Middle Aged; Phytotherapy; Rabbits

Atherosclerosis is the main lesion in allografts undergoing chronic rejection. We investigated the effect of OP-2507 (prostaglandin I2 analogue) and OKY-046 (thromboxane A2 synthetase inhibitor) on graft atherosclerosis morphologically and the production of eicosanoids in grafts in a rat aortic allograft model.. Abdominal aortic allografts of Lewis (RT-1(l)) rats were transplanted orthotopically into fully major histocompatibility complex mismatched Wistar King A/Qdj (RT-1(u)) rats that were subcutaneously administered OP-2507 (0.1 mg/kg/d) or OKY-046 (125 mg/kg/d), or both, with an osmotic pump. Four, 8, or 12 weeks later, the grafts were harvested and examined histologically, and the concentration of eicosanoids in the grafts were analyzed.. Lewis aortic allografts in Wistar King A recipients with no treatment displayed atherosclerosis, which involved gradual intimal thickening and medial thinning with continuous inflammation in adventitia. Neither OP-2507 nor OKY-046 treatment affected the intensity of adventitial inflammation. Although inhibition of medial thinning or a decrease in medial nuclear density was not observed, OKY-046 administration alone significantly inhibited an increase in intimal thickness. OP-2507 administration alone significantly inhibited a decrease in medial nuclear density and intimal thickening. Combined treatment with OP-2507 and OKY-046 further decreased the alteration of media and intima. The ratio of thromboxane B2 and 6-keto-prostaglandin F(1alpha) in the grafts was significantly reduced by OKY-046 but not by OP-2507 alone.. We have demonstrated that atherosclerosis in aortic allografts is inhibited by the continuous administration of either OP-2507 or OKY-046, and a combination of both agents strongly increases this inhibitory effect. Amelioration of balance in eicosanoid production in the grafts by the use of thromboxane A2 synthetase inhibitor and the simultaneous usage of stable prostaglandin I2 analogue may be a strategy for preventing atherosclerosis that results from chronic rejection.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cell Nucleus; Drug Therapy, Combination; Enzyme Inhibitors; Epoprostenol; Kinetics; Male; Methacrylates; Rats; Rats, Inbred Lew; Rats, Wistar; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Homologous

PGI(2)and 8-epi-prostaglandin(PG)F(2 alpha)are antagonizing compounds. For both a key role in vascular pathology has been hypothesized. The isoprostane 8-epi-PGF(2 alpha)and the stable derivative of PGI(2), 6-oxo-PGF(1 alpha)were determined immunologically in the arterial wall of various species including humans. Human arterial tissue contained the highest amounts of 8-epi-PGF(2 alpha)and synthesized the lowest PGI(2). A significant negative correlation between 8-epi-PGF(2 alpha)and 6-oxo-PGF(1 alpha)was observed. Atherosclerotic segments showed significantly higher 8-epi-PGF(2 alpha)and lower 6-oxo-PGF(1 alpha). 8-epi-PGF(2 alpha)in the intima was higher than in the media, the highest amounts being found in foam-cell rich areas. Synthetic (activated) smooth muscle cells were associated with an enhanced 8-epi-PGF(2 alpha)as well as 6-oxo-PGF(1 alpha). Tissue samples derived from smokers contained more 8-epi-PGF(2 alpha)and produced less PGI(2). The by far highest 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio was found in foam cell rich areas. Similar findings were obtained in rabbit and in minipig arteries. The total 8-epi-PGF(2 alpha)/6-oxo-PGF(1 alpha)ratio is low in normal tissue, increases significantly in an active atherosclerotic process and seems to be even further increased in an inactive atherosclerotic process. These findings are providing an information on the extent of oxidation injury at various sites of different types of atherosclerotic process.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Aged, 80 and over; Animals; Arteries; Arteriosclerosis; Dinoprost; F2-Isoprostanes; Female; Foam Cells; Humans; Male; Middle Aged; Oxygen; Phenotype; Rabbits; Radioimmunoassay; Smoking

In a previous paper we gave evidence that chronic oral defibrotide antagonizes the noxious effect of developing atherosclerosis in the cardiovascular system. In the present paper we give evidence that defibrotide is still capable of exerting beneficial effects on cardiovascular function once atherosclerosis is established. In fact, there was statistically significant amelioration by defibrotide infusion in the following, all of which were hampered by established atherosclerosis: in rabbit aorta relaxation to acetylcholine, prostaglandin E2, and 6-keto-prostaglandin F1alpha generation from rabbit aortas, rabbit heart left ventricular end-diastolic pressure, coronary perfusion pressure, and left ventricular developed pressure, vasopressor activity of acetylcholine and endothelin-1 on coronary perfusion pressure, and 6-keto-prostaglandin F1alpha generation from the rabbit heart. Since prostacyclin takes part in NO generation, is cellular protective, and inhibits 5-lipoxygenase product synthesis, its increase, caused by defibrotide, could explain defibrotide cardioprotective activity. Prostacyclin activity could be backed by prostaglandin E2, another cardioprotective prostaglandin.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Animals; Aorta; Arteriosclerosis; Blood Pressure; Body Weight; Cardiovascular Physiological Phenomena; Cholesterol, Dietary; Dinoprostone; Endothelin-1; Fibrinolytic Agents; Heart; In Vitro Techniques; Lipids; Male; Muscle Contraction; Muscle, Smooth, Vascular; Organ Size; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Rabbits; Reperfusion; 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

Olive oil is the main source of dietary fatty acids in the Mediterranean region. The objective of this study was to evaluate the effect of dietary supplementation with virgin olive oil in an experimental model with rabbits fed an atherogenic diet (saturated fat 48% of total fat). Four different groups of 10 animals each were studied: (1) normolipemic diet (NLD), (2) atherogenic diet or saturated fatty acid-enriched diet (SFAED), (3) NLD with 15% olive oil (NLD+OLIV), and (4) SFAED with 15% virgin olive oil (SFAED+OLIV). The animals were fed the experimental diets for 6 weeks, after which we determined serum lipid profile (total cholesterol, HDL-cholesterol, and triglycerides), platelet aggregation, platelet thromboxane B(2), aortic prostacyclin, and platelet and vascular lipid peroxidation. Scanning electron microscopic images of the vascular endothelium were studied, as were morphometric parameters in the arterial wall and thrombogenicity of the subendothelium (annular perfusion chamber). Animals fed the SFAED showed platelet hyperactivity and increased subendothelial thrombogenicity. Animals fed the SFAED+OLIV showed, compared with the SFAED group, an improved lipid profile with decreased platelet hyperactivity and subendothelial thrombogenicity and less severe morphological lesions of the endothelium and vascular wall. We conclude that supplementation of the SFAED with 15% olive oil reduced vascular thrombogenicity and platelet activation in rabbits. Although the percentage of olive oil in the diet was higher than the amount in the human diet, these results may be helpful in determining the effect of olive oil in the human thrombogenic system.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Fatty Acids; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hyperlipidemias; Lipids; Male; Malondialdehyde; Microscopy, Electron, Scanning; Olive Oil; Plant Oils; Platelet Aggregation; Rabbits; Stress, Mechanical; Thrombosis; Thromboxane B2

Isoprostanes are a new family of compounds generated by the free radical catalyzed action on arachidonic acid. Formed during oxidation they have been claimed to be a reliable indicator of in vivo oxidation injury. We assessed the amount of 8-epi-PGF2alpha in human surgical specimens as compared to PGI2 (via its stable metabolite 6-oxo-PGF1alpha), the major compound generated by vascular tissue. 8-epi-PGF2alpha is low in normal vascular tissue as is the 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio. The vessels of smokers in general exhibited an increased 8-epi-PGF2alpha (r=0.82) and a decreased 6-oxo-PGF1alpha (r=0.71). The 8-epi-PGF2alpha/6-oxo-PGF1alpha ratio is, not significantly, increased in vessels derived from hyperlipidemics and hypertensives. These findings indicate that lipid peroxidation occurs within the human arterial wall as evidenced by 8-epi-PGF2alpha, probably further decreasing the synthesis of PGI2 and promoting atherogenic mechanisms.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Aged; Arteriosclerosis; Blood Vessels; Dinoprost; Epoprostenol; F2-Isoprostanes; Female; Humans; Immunoassay; In Vitro Techniques; Male; Middle Aged

Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung.. Controlled experiment using isolated organs.. Experimental laboratory.. Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis).. Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg.. Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups.. We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Aspartic Acid Endopeptidases; Atrasentan; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Myocardial Contraction; Oligopeptides; Peptides, Cyclic; Protein Precursors; Pulmonary Embolism; Pyrrolidines; Rabbits; Thromboxane B2; Vasoconstriction

The early atherosclerotic lesion is characterized by the migration of inflammatory cells, including monocytes, which may serve as a source of cytokines such as monocyte chemoattractant protein 1 (MCP-1), a homologue of mouse JE. We investigated the effect of MCP-1 on the growth of vascular smooth muscle cells (VSMC) isolated from rat aortae. In Northern blot analysis, MCP-1/JE transcripts were not observed in unstimulated VSMC, but its expression was clearly observed by exposure to lipopolysaccharide (1 micrograms/ml) for 6 h. Human recombinant MCP-1 inhibited the uptake of [3H]thymidine by VSMC cultured in 0.5% fetal bovine serum (FBS) containing Dulbecco's modified Eagle's medium (DMEM) in a dose-dependent manner. The inhibitory effect of MCP-1 on the growth of VSMC was also confirmed by a change in cell counts. The antiproliferative effect of MCP-1 was significantly blocked in the presence of an anti-MCP-1 antibody. MCP-1-induced inhibition of [3H]thymidine uptake was not affected in the presence of indomethacin (1 micrograms/ml) or NG-monomethyl-L-arginine (0.1 mM), and MCP-1 showed no effect on 6-ketoprostaglandin F1 alpha, guanosine 3',5'-cyclic monophosphate, and adenosine 3',5'-cyclic monophosphate syntheses in VSMC. These results indicate that MCP-1 inhibits the proliferation of VSMC in vitro and that its effect is independent of prostaglandin or nitric oxide generation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arginine; Arteriosclerosis; Cell Division; Cells, Cultured; Chemokine CCL2; Chemotactic Factors; Cyclic AMP; Cyclic GMP; DNA; Gene Expression; Humans; Indomethacin; Lipopolysaccharides; Muscle, Smooth, Vascular; omega-N-Methylarginine; Rats; Recombinant Proteins; Thymidine

27 Japanese white male rabbits were divided into 3 groups for evaluation of Tongmai Jiangzhi Oral Liquor (TMJZ) in reducing the serum cholesterol, the level of plasma lipid peroxidation (LPO), the plasma TXB2 and suppressing of atherosclerotic plaque formation in atherogenesis. The results indicated that TMJZ not only decreased significantly the levels of serum cholesterol, triglyceride, LPO and TXB2, but also increased markedly blood glutathion peroxidase (GSH-Px) activity and regulated the balance of TXB2/6-keto-PGF1 alpha. The area of atherosclerotic plaque coverage in aorta and the thickness of plaque after oral TMJZ were much smaller than those of high cholesterol-fed rabbits. It is suggested that the effect of TMJZ on above-mentioned indexes might be important mechanism of its anti-atherosclerotic effect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Cholesterol; Drugs, Chinese Herbal; Glutathione Peroxidase; Hypolipidemic Agents; Male; Malondialdehyde; Rabbits; Thromboxane B2

The objectives of this study were to determine if, and at what dose, aspirin could attenuate atherosclerosis in hypercholesterolemic Yucatan miniature swine, and to determine the influence of aspirin on aortic wall prostacyclin production and platelet aggregation. 30 Yucatan miniature swine (age 3 months) were fed either regular diet (RD), atherogenic diet (AD), or AD plus one of four aspirin dosages (2,4,8, or 16 mg/kg/d) for 6 months. The extent of atherosclerotic lesions in the abdominal aorta and coronary arteries was evaluated by sudanophilic staining and histological grading using Stary's classification, respectively. Aortic wall production of prostacyclin (PGI2) and platelet aggregation were assessed. Lesions were similar among the AD groups (45.3 +/- 4.3%) and significantly higher than RD (1.4 +/- 0.4%). PGI2 production was significantly lower (p < 0.05) in all aspirin-treated groups. Platelet aggregation was not affected by treatment. It is concluded that the range of aspirin dosages (2-16 mg/kg/d) does not attenuate the development of atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Aspirin; Azo Compounds; Coloring Agents; Coronary Vessels; Epoprostenol; Female; Hypercholesterolemia; Male; Platelet Aggregation; Swine; Swine, Miniature

Angioplasty of stenotic iliac artery was performed in 23 Japanese white rabbits. Angiography and histopathology examinations were performed one day (6 rabbits), 3 days (5 rabbits), one week (5 rabbits) and one month (7 rabbits) after dilation. TXB/PGF in blood was analyzed with radio-immunologic method. TXB/6-K-PGF increased at 1st day, began to reduce at 3rd day, became almost normal after one week and returned to normal level week after one month. Restenosis occurred in all animals. Platelet aggregation and mural thrombi were observed at 1st and 3rd day. New endothelial cells covered the surface of denuded endothelium at 3rd day. At 7th day, repairing of endothelium was completed and proliferation of smooth muscle cells were prominent in new intimia. Stenosis of lumen occurred again after 1 month. The results suggested that intimia injury during the procedure initiates the process of restenosis and aggregation of platelets, imbalance of between TXA and PGI is and proliferation of smooth muscle cells play important roles in the formation of restenosis.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon, Coronary; Animals; Arteriosclerosis; Endothelium, Vascular; Iliac Artery; Platelet Aggregation; Rabbits; Recurrence; Thromboxane B2

Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Body Weight; Diet, Atherogenic; Disease Models, Animal; Epoprostenol; Female; Hematocrit; Hypercholesterolemia; Lipids; Male; Random Allocation; Risk Factors; Swine; Thromboxane A2; Thromboxane B2

To evaluate the effect of angioplasty on the production of prostanoids in atherosclerotic vessels in rabbits.. Open study.. 38 Rabbits.. Rabbits in group A (n = 12) were given a cholesterol rich diet (2%) for 10 weeks, and then treated with angioplasty. Rabbits in group B (n = 11) were given a cholesterol rich diet for 10 weeks, and then returned to a normal diet until the serum cholesterol concentration returned to the reference range (a further 12 weeks). Rabbits in group C (n = 15) were anaesthetised, and a 3 mm balloon was introduced into the right femoral artery, fed 20 cm proximally, inflated, and pulled twice along the aorta; the animals were then given a cholesterol rich diet (2%) for eight weeks, and treated with angioplasty.. Serum cholesterol concentrations were measured once a week. Prostacyclin and thromboxane were measured as 6-keto prostaglandin F1 alpha and thromboxane B2 in both treated and control segments of aorta.. 15 Rabbits died while atherosclerosis was being induced, leaving 23 for analysis. Angioplasty reduced the amounts of prostanoids released in animals in which the atherosclerosis had been induced by diet alone. When endothelial injury and diet were used together, there was no difference between the treated and control segments in the amounts of prostanoids released.. These findings could be of use in the comparison of methods used to induce atherosclerosis, and in the study of the mechanisms of thrombosis after transluminal angioplasty.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon; Animals; Aorta; Arachidonic Acids; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Epoprostenol; Rabbits; Thromboxane B2; Thromboxanes

This paper reports the treatment with Yiqi Huoxue and Shugan Liqi agents in atherosclerosis of rabbit. The results suggested: 1. Both decoctions could reduce the cholesterol of hypercholesterolemia and improve the atherosclerosis, but the former was better than the latter. 2. Both decoctions could alter the components of bile lipids, but on the contrary, the latter was better than the former in reducing the formation of gallstones. 3. Both decoctions could decrease the plasma concentration of LPO and ratio of TXB2/6-K-PGF1 alpha, while increase the ratio of cAMP/cGMP in plasma. So, the different prescriptions of TCM affecting the same link of pathogenesis might play the role of "Different Treatments in Same Disease".

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Cholelithiasis; Drugs, Chinese Herbal; Lipid Peroxides; Rabbits; Thromboxane B2

We have studied the relationship between levels of lipids and prostacyclin in 3- to 14-year-old children with a family history of ischaemic heart disease. The total levels of cholesterol in the serum of these children increased, while levels of the HDL-fraction and prostacyclin (measured as 6-keto-prostaglandin F1a) decreased significantly. Levels of thromboxane B2 in the plasma were unchanged. It is suggested that, in childhood, abnormalities of lipid metabolism co-exist with decreased levels of prostacyclin. The latter may be a new important indicator of early atherosclerotic disease.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Arteriosclerosis; Child; Child, Preschool; Cholesterol; Cholesterol, HDL; Coronary Disease; Female; Humans; Male; Risk Factors; Thromboxane B2

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arteriosclerosis; Aspirin; Bleeding Time; Blood Platelets; Drug Administration Schedule; Endothelium, Vascular; Epoprostenol; Female; Humans; Male; Microcirculation; Middle Aged; Thromboxane A2; Thromboxane B2

In young patients with borderline arterial hypertension and, to a greater extent, with Stage 1 hypertensive disease (HD), changes were found in the proatherogenic plasma lipid and apoprotein composition, which were manifested as higher levels of total cholesterol, triglycerides, low and very low density lipoprotein cholesterols along with increased apolipoprotein B and apolipoprotein B:apolipoprotein AI ratio. The prostacyclin-thromboxane system in borderline arterial hypertension was in an activated state by retaining the physiological ratio of its components. The patients with Stage I HD exhibited a considerable increase in thromboxane activity, which determined the system's imbalance towards its predominance. In Stage I HD, the thrombocytic link of hemostasis was characterized by enhanced platelet aggregability mediated by the imbalance of the prostacyclin-thromboxane system in the direction of thromboxane.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Epoprostenol; Female; Humans; Hyperlipidemias; Hypertension; Lipids; Male; Platelet Aggregation; Thromboxane A2; Thromboxane B2; Time Factors

The influence of dipyridamole and lysine acetylsalicylate on the incidence of atherosclerotic lesions and on arterial prostacyclin formation was studied in rabbits. Male New Zealand rabbits received i.m. for 16 months dipyridamole (12.5 mg/kg/day) and lysine acetylsalicylate (0.5 mg/kg/day). The incidence of spontaneous atherosclerotic lesions in the aorta was reduced by 16.4% with respect to untreated animals. Administration of the drugs significantly increased prostacyclin formation with respect to the untreated rabbits both in animals developing (1124 +/- 197 pg/mg/3 min vs 316 +/- 49 pg/mg/3 min) or not developing lesions (499 +/- 40 pg/mg/3 min vs 246 +/- 19 pg/mg/3 min). The observed increase in prostacyclin formation could account for the lowered incidence of atherosclerotic lesions in rabbits receiving the combination of dipyridamole and lysine acetylsalicylate.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteries; Arteriosclerosis; Aspirin; Dipyridamole; Drug Therapy, Combination; Epoprostenol; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Rabbits

Topics: 6-Ketoprostaglandin F1 alpha; Angiography; Arteriosclerosis; Cyclic AMP; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Physical Exertion; Polydeoxyribonucleotides; Thromboangiitis Obliterans; Thromboxane B2

The mechanism by which atherosclerotic disease is induced by cigarette smoking has not yet been identified unequivocally. Chronic cigarette smoking and the generation of vasoactive prostanoids and the size of carotid atherosclerotic plaques were studied in nine pairs of identical male twins discordant for smoking for over 20 years. The urinary excretion of 2,3-dinor-thromboxane B2 (thromboxane B2 metabolite) of the smoking twin was significantly higher (on average 1.8 times higher) in every pair and that of 2,3-dinor-6-keto-prostaglandin F1 alpha (prostacyclin metabolite) was significantly higher (on average 1.3 times higher) in eight of the nine pairs. The ratio of excretion of these metabolites was significantly higher, being 4.0 (95% confidence interval 2.7 to 5.4) among the smokers compared with 2.9 (2.1 to 3.8) among the non-smokers, thus favouring a mechanism of vasoconstriction. Excretion of the thromboxane B2 metabolite was related to the urinary concentrations of nicotine metabolites. Atherosclerotic plaques detected by ultrasonography in the carotid arteries were significantly larger among smokers but did not correlate with the urinary excretion of prostacyclin and thromboxane B2 metabolites or intensity of smoking. Smoking was concluded to induce activation of platelets by an effect mediated by nicotine. The increased prostacyclin production, on the other hand, suggested a compensatory mechanism for the general vasoconstrictive properties of cigarette smoking.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Carotid Artery Diseases; Cotinine; Diseases in Twins; Humans; Male; Middle Aged; Smoking; Thromboxane B2; Twins; Twins, Monozygotic; Ultrasonography

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; Cardiopulmonary Bypass; Complement Activation; Complement C3; Complement C4; Complement C5; Complement Pathway, Alternative; Female; Humans; Leukocyte Count; Leukocytosis; Lung; Male; Middle Aged; Neutrophils; Platelet Count; Time Factors

A simple method to measure the biological effect of ASA based on the determination of the desaggregation rate (DR) of platelet aggregation induced by ADP is described. DR correlates with the inhibition of the production of malondialdehyde (MDA) by platelets (r = 0.66, P less than 0.001). Therefore, the DR was used for laboratory monitoring of the ASA effect. Here we report on a study including 41 patients with peripheral arterial disease and/or coronary heart disease before treatment and after receiving ASA in an individually controlled dosage regimen. Before treatment we found an increased level of MDA, 150-200% compared with healthy volunteers (n = 16). Extremely different doses of ASA were required to normalize initially elevated MDA-levels in patients. This normalization of MDA was found to correspond to a DR of at least 50% (in comparison to 0-13% without treatment). When judging the ASA-dose individually from the 50%-DR we demonstrated that there were no differences of the levels of cyclooxygenase- and lipoxygenase-derived eicosanoids between healthy volunteers (n = 16) and arteriosclerotic patients receiving 100-250 mg ASA/d (n = 18), 500 mg ASA/d (n = 17), or 750-1500 mg ASA/d (n = 6).

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Arteriosclerosis; Aspirin; Biomarkers; Humans; Hydroxyeicosatetraenoic Acids; Malondialdehyde; Platelet Aggregation; Reference Values

Topics: 6-Ketoprostaglandin F1 alpha; Arteriosclerosis; Blood Platelets; Epoprostenol; Humans; Leg; Physical Exertion; Thromboxane B2

Thromboxane and prostacyclin metabolite determinations (radioimmunoassay) were performed in obliterative atherosclerosis and in diabetes mellitus with microangiopathy. The shift of these metabolites to the thromboxane side could have been documented in both diseases. This phenomenon calls attention to an increased platelet activation and endothelial cell damage. In a third group patients received aspirin (500 mg on alternative days) which caused a marked inhibition of both thromboxane and prostacyclin production, measured this way. The possible role of altered balance of these two prostanoids in atherogenesis and diabetic angiopathy is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arteriosclerosis; Aspirin; Diabetes Mellitus; Epoprostenol; Female; Humans; Male; Middle Aged; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Thromboxane B2

Coronary arteries and aortic rings were isolated from rabbits fed either a control diet or a high cholesterol (1 to 2%) diet for 8 to 11 weeks and studied for their vasoactive properties to a variety of vasoconstrictor and vasodilator agents. Perfused coronary arteries without intact endothelium constrict markedly to a thromboxane A2 agonist (i.e., carbocyclic thromboxane A2, CTA2) and dilate markedly to iloprost, a prostacyclin analog. No differences occurred between the coronary arteries isolated from control or atherosclerotic rabbits. Additional studies were conducted on rabbit aortic vascular smooth muscle rings containing functionally intact endothelium and in rings denuded of their endothelium. Acetylcholine (20 to 2000 ng/ml) neither constricted nor dilated control aortic rings without endothelium, and markedly dilated aortic rings with intact endothelium in a concentration dependent manner. In atherosclerotic aortic rings, acetylcholine constricted preparations without endothelium, and dilated rings with endothelium to a much lesser extent than that observed in control rings. Similar reductions in responsiveness occurred with adenosine diphosphate (ADP), another endothelium-dependent vasodilator, but not with iloprost, a nonendothelium-dependent dilator. No differences were observed in constrictor responses to norepinephrine. Aortae from atherosclerotic rabbits produced less prostacyclin in response to arachidonic acid than control aortae. These data point to an important role of the endothelium in modulating the vascular response to vasodilators in atherosclerotic rabbit arterial vessels.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Adenosine Diphosphate; Animals; Aorta, Thoracic; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Coronary Vessels; Endothelium, Vascular; Epoprostenol; Male; Muscle, Smooth, Vascular; Nitroglycerin; Norepinephrine; Perfusion; Rabbits; Vasoconstrictor Agents; Vasodilator Agents

It is of great importance to clarify the role of thromboxane and prostacyclin in the process of atherosclerosis. In order to study this we induced atherosclerosis in rabbits through cholesterol feeding (1% w/w) for three to 12 weeks. After sacrifice the aorta was quickly removed and incubated. The in vitro thromboxane production measured as immunoreactive thromboxane B2 increased by 86 per cent in atherosclerotic vessels compared to control vessels (p less than 0.0005). The in vitro production of prostacyclin measured as immunoreactive 6-keto-prostaglandin F1 alpha showed a tendency to higher values in the atherosclerotic vessels compared to the control vessels (31%, p less than 0.025). This suggests that an increased thromboxane production rather than a decreased prostacyclin production might be important for the progression of atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cholesterol, Dietary; Male; Rabbits; Thromboxane B2

Molecular markers of hemostatic activation provide a reliable measure of the endogenous pathophysiologic state in atherosclerosis. Measurement of these markers before and after exercise provides a diagnostic probe for cellular-vascular interactions in patients with atherosclerosis. Molecular markers may possibly identify very early stages of atherosclerosis due to their inherent sensitivity. A high-risk cardiovascular population can be easily recognized by profiling molecular markers of hemostatic activation. Newly developed immunoassays can be used to quantitate these markers in routine laboratories. Additional clinical studies are needed to establish the diagnostic role of these molecular markers in patients with atherosclerosis and related disorders.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; beta-Thromboglobulin; Exercise Test; Fibrinopeptide A; Hemostasis; Humans; Middle Aged; Platelet Aggregation; Platelet Factor 4; Thromboxane B2; Tissue Plasminogen Activator

Populations that consume a diet rich in marine lipids may have a lower risk of atherosclerotic disease. Fish oil contains the N-3 polyunsaturated fatty acid eicosapentaenoate, and the biosynthesis of thromboxanes and prostacyclins from eicosapentaenoate (thromboxane A3 and prostaglandin I3), rather than from the usual precursor arachidonate (thromboxane A2 and prostaglandin I2), may help to reduce the risk. To examine this hypothesis, we studied the effect of eicosapentaenoate supplementation (10 g per day) for one month on the synthesis of thromboxanes and prostacyclins, as assessed by urinary metabolite excretion, in six patients with peripheral vascular disease and seven normal controls. Supplementation markedly increased the eicosapentaenoate content of phospholipids from red cells and platelets. Synthesis of the platelet agonist thromboxane A2, which was elevated in the patients at base line, declined by 58 percent during supplementation but did not reach normal values. The decline in thromboxane A2, which is synthesized from arachidonate, coincided with the formation of the inactive thromboxane A3, which is synthesized from eicosapentaenoate. A lower dose of eicosapentaenoate (1 g per day) was not sufficient to maintain the changes in thromboxane A2 synthesis. Platelet function was only moderately inhibited during eicosapentaenoate supplementation, consistent with incomplete suppression of thromboxane A2 synthesis. These studies show that a high dose of eicosapentaenoate alters the pattern of synthesis of thromboxanes and prostacyclins. However, effects comparable to those of aspirin require long-term administration in high doses. Whether other properties of fish oil might render it a more attractive antithrombotic therapy remains to be determined.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; beta-Thromboglobulin; Bleeding Time; Blood Platelets; Dietary Fats; Eicosapentaenoic Acid; Epoprostenol; Erythrocytes; Fatty Acids; Fish Oils; Humans; Male; Middle Aged; Phospholipids; Platelet Count; Platelet Factor 4; Thromboxane A2; Thromboxane B2; Thromboxanes

Patients were treated with defibrotide (3 X 200 mg/day) for 7 days. Plasma PGI2 and TXB2 levels were measured by RIA using EDTA-aspisol as anticoagulant and cyclooxygenase inhibitor. Isolated platelet c-AMP levels were also determined by RIA, using EDTA-dipyridamole as anticoagulant and phosphodiesterase inhibitor. Blood PGI2 levels were found to increase significantly upon treatment while the increase in TXB2 levels was not significant. Blood PGI2/TXB2 ratio increased 51%, 30 min after intravenous injection and it remained 28% higher during therapy than the predrug blood level. Significantly higher platelet c-AMP levels were also obtained after the injection of drug (0.02 less than p less than 0.05).

Topics: 6-Ketoprostaglandin F1 alpha; Arteriosclerosis; Blood Platelets; Cyclic AMP; Fibrinolytic Agents; Humans; Malondialdehyde; Platelet Aggregation; Polydeoxyribonucleotides; Prostaglandins; Thromboxane B2; Time Factors

This study demonstrates the presence of PGI2 in blood and its influence on platelet retention tests, possibly by the intermediate of a releasing system in the columns, which is followed by a proximate recuperation on the erythrocyte sites after the passage. The presence of prostacyclin on the erythrocyte sites seems to depend upon the red cell deformability in relation to the good condition of their erythrocyte ATP reserve. The load of the erythrocyte sites increases with the daily dose of dipyridamole. The maximum load of the sites appears to be reached with a daily dose of dipyridamole 450 mg. Approximately 10% of the atherosclerosis patients who have been treated by dipyridamole keep their platelet hyperaggregability and their abnormally lowered prostacyclin level.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arteriosclerosis; Binding Sites; Dipyridamole; Drug Administration Schedule; Epoprostenol; Erythrocytes; Female; Humans; Male; Middle Aged; Platelet Aggregation

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Arteries; Arteriosclerosis; Biological Transport; Cholesterol; Cholesterol Esters; Cyclic AMP; Dinoprostone; Epoprostenol; Humans; In Vitro Techniques; Lipoproteins, LDL; Muscle, Smooth, Vascular; Nucleotides, Cyclic; Prostaglandins; Prostaglandins E; Sterol Esterase; Sterol O-Acyltransferase; Vasodilator Agents

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol 1, PAF (10(-9) or 10(-8) mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42.1% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the alpha 2-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B2 and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB2 levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial coronary arterial TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Adrenergic alpha-Antagonists; Animals; Arteriosclerosis; Coronary Circulation; Coronary Disease; Dogs; Hemodynamics; Imidazoles; Male; Platelet Activating Factor; Platelet Aggregation; Serotonin Antagonists; Thromboxane B2

Plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha in the blood samples taken at the coronary sinus and ascending aorta from twenty-one Japanese patients with variant angina and twenty with effort angina were measured by radioimmunoassay, the objective being to search for the contribution of prostanoids in coronary spasm. The data were compared with data on thirteen subjects free from coronary artery diseases. In coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. These with variant angina also had high levels, albeit without a statistically significant difference. Eight patients with variant angina and for whom the coronary angiogram showed more than 50% of narrowing had statistically significant high levels of TXB2, and the other thirteen with variant angina and normal coronaries or less than 50% of narrowing had the same plasma levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in both coronary sinus and aortic blood of patients with variant angina were very low, as compared with normal controls. Statistically significant low levels of 6-keto PGF1 alpha were noted in the coronary sinus blood of patients with variant angina with normal coronaries and in the aortic blood of those with variant angina, as compared with data on the normal controls. Neither ergonovine test nor spontaneous attacks in patients with variant angina revealed characteristic changes in levels of TXB2 and 6-keto PGF1 alpha in the coronary sinus. These data suggest that high levels of TXB2 in patients with atherosclerotic coronaries may be one factor leading to spasm, while low levels of PGI2 may be a contributing factor.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Angina Pectoris, Variant; Arteriosclerosis; Coronary Vessels; Ergonovine; Exercise Test; Female; Humans; Male; Middle Aged; Thromboxane B2

Effect of dexamethasone administration on aortic morphology, cholesterol content and synthesis of prostaglandins from (14C)-arachidonic acid in aorta of spontaneously atherosclerosis susceptible pigeons was examined. Dexamethasone markedly inhibited the synthesis of prostaglandin E2 and stimulated the synthesis of prostaglandin I2 in aorta. In aorta of glucocortocoid treated animals, endothelial abnormalities noted in control birds were decreased and numerous surface protrusions or 'microvilli' were noted. The possibility that glucocorticoid induced inhibition of PGE2 synthesis in pigeon aorta may contribute to improved aortic morphology is discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Cholesterol; Columbidae; Dexamethasone; Dinoprost; Dinoprostone; Endothelium; Epoprostenol; Male; Microscopy, Electron, Scanning; Microvilli; Prostaglandins; Prostaglandins E; Prostaglandins F

We have briefly summarized only the data obtained in our own laboratory without including an extensive literature review. We have evaluated the changes in platelet membrane phospholipids and prostanoid formation in platelets. In atherosclerosis platelets show an activated prostanoid formation, whereas the plasma PGI2 levels are decreased.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Blood Platelets; Coronary Disease; Dinoprost; Humans; Middle Aged; Prostaglandins; Prostaglandins E; Prostaglandins F; Reference Values; Serum Albumin, Bovine

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Aspirin; Diet, Atherogenic; Epoprostenol; Lysine; Male; Platelet Aggregation; Rabbits; Thiophenes; Ticlopidine

Cholesterol and cholesteryl esters (CE) are the two major classes of lipids which accumulate in arteries during human arteriosclerosis. Mechanisms responsible for this arterial lipid accretion remain to be fully elucidated. In recent years, we have suggested that prostaglandins may have an important role in the modulation of intracellular arterial CE metabolism through their interaction with cyclic nucleotides. This hypothesis was based on observations that arteriosclerotic arteries produce less prostaglandins, particularly prostacyclin, and have altered CE synthetic and hydrolytic activities as compared to uninvolved arteries. This review is a summary of our present knowledge concerning the role of eicosanoids and cyclic nucleotides in the modulation of enzyme activities responsible for arterial CE synthesis and hydrolysis.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Arachidonic Acid; Arachidonic Acids; Arteriosclerosis; Cholesterol; Cholesterol Esters; Cyclic AMP; Dinoprostone; Epoprostenol; Humans; Hydrolysis; Muscle, Smooth, Vascular; Prostaglandins; Prostaglandins E

Prostacyclin is a potent vasodilator and platelet inhibitor produced by vascular endothelium. Endogenous production of prostacyclin under physiologic conditions is extremely low, far below the capacity of vascular tissue to generate this substance in response to stimulation in vitro. This may reflect a low frequency or intensity of stimulation of prostacyclin production. We postulated that if prostacyclin does act as an endogenous platelet-inhibitory agent, it should be produced in greater amounts in a clinical setting in which platelet-vascular interactions are likely to be increased. To test this hypothesis, we examined prostacyclin biosynthesis in patients with severe atherosclerosis and evidence of platelet activation in vivo. Excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha, a major urinary prostacyclin metabolite, was significantly higher in 9 patients with severe atherosclerosis and evidence of platelet activation (251 to 1859 pg per milligram of creatinine) than in 54 healthy volunteers (45 to 219 pg per milligram of creatinine; P less than 0.001). This difference represented an alteration in biosynthesis rather than in metabolism, since the fractional conversion of infused prostacyclin to the dinor metabolite was identical in both groups. Prostacyclin production may be low in healthy persons because there is almost no stimulus for its production but enhanced in patients with severe atherosclerosis as a consequence of platelet interactions with endothelium or other vascular insults. These observations are compatible with a role for prostacyclin as a local regulator of platelet-vascular interactions.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Arteriosclerosis; beta-Thromboglobulin; Blood Platelets; Epoprostenol; Humans; Male; Middle Aged; Platelet Aggregation

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Arterial Occlusive Diseases; Arteriosclerosis; Endothelium; Epoprostenol; Femoral Artery; Fibromuscular Dysplasia; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Rabbits

Human aortic samples were taken from uninvolved areas, fatty streaks and atherosclerotic plaques within 3 hrs after sudden death. Prostacyclin formed after 3-min incubation was estimated by ADP-induced platelet aggregation inhibitory method and by radioimmunoassay as 6-keto prostaglandin FI alpha. Atherosclerotic plaques exhibited a strong decrease in their capacity to synthesize prostacyclin. In comparison with normal there was not significant difference in the prostacyclin releasing value from the fatty streaks while individual samples had considerable variety.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aorta; Arteriosclerosis; Epoprostenol; Humans; Male; Middle Aged

Plasma levels of thromboxane B2, and 6-Keto-PGF1 alpha, stable metabolites of thromboxane and of prostacyclin were determined by radioimmunoassay in 17 patients with arterial disease and 10 control subjects. The production of prostacyclin from incubates of aortic microsomal fractions of patients was also studied. There was a significant elevation of thromboxane B2 in the peripheral venous blood of patients with arterial lesions (142 +/- 152 pg/ml vs 22 +/- 2 pg/ml, p less than 0.005); levels of 6-KetoPGF1 alpha were equally low in controls and patients. Rate of production of prostacyclin, which was 450 +/- 24 pmol/50 mg of proteins in 10 minutes in controls, was reduced to 97 +/- 86 pmol/50 mg prot. 10 min (p less than 0.01) in patients. Co-existence of raised plasma thromboxane levels and a reduced capacity for prostacyclin synthesis in the same patients is supportive evidence of the thrombogenic theory of arterial disease.

Topics: 6-Ketoprostaglandin F1 alpha; Aorta; Arteriosclerosis; Epoprostenol; Humans; Leg; Male; Middle Aged; Thromboxane B2; Thromboxanes

The effect of an atherogenic diet on the endothelium of the central artery of the rabbit ear was studied by scanning and transmission electron microscopy. Examination of the inner surface of the artery after only 5 weeks on the diet revealed morphological changes including irregularly shaped cells, breaks at intercellular junctions, swelling of the membrane over the central part of the cells, and occasional holes in the cells. By 9 weeks more severe damage was seen including lifting off of cells and some holes. In addition, arrays of dark spots were seen by scanning electron microscopy in some cells in arteries of rabbits fed the diet for 5 to 9 weeks. The dark spots may correspond to abnormally large vacuoles seen inside endothelial cells by transmission electron microscopy. The central ear artery and aorta of some rabbits were tested for their ability to convert arachidonic acid into prostacyclin and thromboxane A2 by radioimmunoassay of the stable metabolites 6-keto-prostaglandin F1 alpha and thromboxane B2. The vessels from rabbits fed the atherogenic diet did not differ from vessels of rabbits on the control diet in their production of either metabolite.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Arteries; Arteriosclerosis; Cell Membrane; Diet, Atherogenic; Ear; Endothelium; Male; Microscopy, Electron; Rabbits; Thromboxane B2; Vacuoles