6-ketoprostaglandin-f1-alpha and Hypercholesterolemia

Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Abdominal; Aortic Diseases; Atherosclerosis; Cholesterol; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Induction; Epoprostenol; Hypercholesterolemia; Indomethacin; Male; Norepinephrine; Rabbits; Thiophenes; Vasoconstriction; Vasoconstrictor Agents

The efficacy of OPC-29030, a newly developed inhibitor of 12(S)-hydroxyeicosatetraenoic acid (12-HETE) production, was evaluated on intimal hyperplasia of experimental autologous vein grafts in a distal poor-runoff model and a hyperlipidemic model in rabbits. First, rabbits were divided into two groups, the distal poor-runoff group (PR group) and the hyperlipidemic group (HL group). After 4 weeks preparing the PR model and the HL model, the femoral vein was implanted into the ipsilateral femoral artery. Then they were subdivided into two groups, depending on the diet provided; diet group with 0.1% OPC-29030 (OPC-29030 group) and normal diet group (control group). At 4 weeks, the grafts were harvested, and intimal hyperplasia of the graft was measured with an ocular cytometer. Intimal cell proliferation was determined by bromodeoxyuridine (BrdU) incorporation at 2 weeks after surgery. In addition, the effect of OPC-29030 on the proliferation or migration of rat aortic smooth muscle cells in culture was investigated. In the in vivo study in the PR group, the intimal hyperplasia and the plasma 12-HETE levels in the OPC-29030 group were significantly inhibited, compared with those of the control group. However, in the HL group, the intimal hyperplasia in both the OPC-29030 and control groups showed a remarkable degree of intimal hyperplasia. There was no significant difference between those two groups. Furthermore, there was no significant difference in the plasma 12-HETE levels in the HL group irrespective of the presence of OPC-29030. The BrdU labeling index at 2 weeks after grafting was significantly lower in the OPC-29030 group compared with that in the control group in the PR group. In the in vitro study, OPC-29030 did not inhibit smooth muscle cell proliferation; however, OPC-29030 inhibited the migration. These results demonstrate the efficacy of OPC-29030 in reducing the degree of intimal hyperplasia under PR conditions, but not under hyperlipidemic conditions. The mechanism of reducing the intimal hyperplasia may be that OPC-29030 inhibited 12-HETE production, which did not inhibit proliferation while inhibiting migration of the smooth muscle cell. These results suggested the possible involvement of 12-HETE with the intimal hyperplasia under PR conditions.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Cholesterol; Femoral Vein; Graft Survival; Hypercholesterolemia; Hyperplasia; Imidazoles; Male; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Quinolones; Rabbits; Rats; Sulfur Compounds; Thromboxane B2; Tunica Intima

The aim of the present work was to assess if the cardioprotective drug defibrotide could counteract the hypercholesterolemia noxious effects on cardiovascular function. Aortas and hearts from normal- or cholesterol-fed rabbits, treated or not with chronic oral defibrotide (100 mg/kg/day) for 45 days, were used in in vitro tests throughout the experiment. Hypercholesterolemia worsened: aorta stickiness toward polymorphonuclear leukocytes, aorta relaxation to acetylcholine, heart left ventricular end-diastolic pressure and coronary perfusion pressure, heart left ventricular diastolic pressure, acetylcholine and endothelin-1 activity on coronary perfusion pressure, and heart generation of 6-Keto-prostaglandin F1alpha. Oral defibrotide counteracted and/or obliterated the above hypercholesterolemia noxious effects. Particularly, oral defibrotide counteracted the parameters associated with early endothelial cell disfunction: that is, increased adherence of leukocytes to endothelium and endothelial vasorelaxation induced by acetylcholine, which acts through the release of endothelium-derived relaxing factor. These activities of defibrotide are probably exerted through the increased generation of prostacyclin. The fact that acetylcholine induced vasorelaxation is partially protected by oral defibrotide points to a partial rescue of endothelial ability to generate endothelium-derived relaxing factor, as acethylcoline acts through the release of endothelium-derived relaxing factor, by defibrotide itself. Defibrotide's endothelial protection could, in turn, explains why defibrotide protected cardiovascular function. This is not surprising as, in a few cases, endothelial dysfunction, observed in hypercholesterolemia, was found to be prevented or reversed, pharmacologically, by PN-2001-10, a calcium channel blocker, dipyridamole, and lovastatin.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Aorta; Blood Pressure; Cholesterol, Dietary; Fibrinolytic Agents; Heart; Hypercholesterolemia; Myocardium; Polydeoxyribonucleotides; Rabbits; Vasoconstriction; Ventricular Function, Left

The effects of vitamin E supplementation in a dose of 450 mg/1000 g chow on the myointimal proliferation of the abdominal aorta after balloon injury were studied in 4 groups of rabbits (24 each). The animals were fed regular diet, regular diet plus vitamin E, 1% cholesterol-enriched diet, and 1% cholesterol-enriched diet plus vitamin E. Each animal underwent a balloon injury of the abdominal aorta and left common iliac artery after 2 weeks of feeding. The animals remained on their respective diets thereafter. In 8 balloon-injured and 8 sham-operated animals of each group, the abdominal aortas were harvested 3 days after the procedure for the analysis of prostacyclin and thromboxane A2 synthesis, thiobarbituric acid reactive substances (TBARS) levels, enzyme activities of glutathione reductase (GR) and glutathione peroxidase (GP) as well as reduced (GSH) and oxidized (GSSG) glutathione levels, 3H-thymidine uptake, cholesterol as well as vitamin E contents. In the other 8 balloon-injured rabbits of each group, the tissue was harvested 3 weeks later for the morphometric study. In dependent of high cholesterol feeding, the vitamin E-treated rabbits had lower aortic production of thromboxane B2, higher 6-keto-PGF1 alpha and higher 6-keto-PGF1 alpha/thromboxane B2 ratios in both procedures. The aortic TBARS levels of the rabbits treated high cholesterol alone were significantly higher than the other three groups in both procedures. Balloon injury had a trend to increase TBARS levels and had significantly higher 3H-thymidine uptake (each p < 0.001) than sham operation in each group. Vitamin E supplement to high cholesterol diet or regular chow reduced aortic TBARS levels (p < 0.005 and 0.01, respectively) and 3H-thymidine uptake (p < 0.05 and 0.01, respectively), as well as attenuated myointimal proliferation of the abdominal aorta and left common iliac artery after balloon injury; but only supplement to high cholesterol diet reached statistical significances (both p < 0.05 compared to rabbits fed high cholesterol alone). These results suggest that vitamin E supplement changes prostanoid metabolism to a favorable pattern and reduces lipid peroxidation of the abdominal aortic wall, thus attenuates myointimal proliferation after balloon injury; these presentations are particularly obvious in diet-induced hypercholesterolemic rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Angioplasty, Balloon; Animals; Antioxidants; Aorta, Abdominal; Cell Division; Cholesterol, Dietary; Diet; Hypercholesterolemia; Lipid Metabolism; Lipid Peroxidation; Lipids; Male; Rabbits; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Thymidine; Tunica Intima; Vitamin E

The effects of supplementing with fish oil on the myointimal proliferation of the abdominal aorta after balloon injury were studied in control and in rabbits fed a 1% cholesterol-enriched diet, with and without 10% fish oil supplementation. Twenty-one animals in each group underwent a balloon injury of the abdominal aorta and left common iliac artery after 2 weeks of feeding. The animals remained on their respective diets thereafter. In 7 balloon-injured and 7 sham-operated animals of each group, the abdominal aorta was harvested 3 days later for the analysis of prostanoids, malondialdehyde, superoxide dismutase activity, [3H]thymidine uptake, and cholesterol levels. In the other 7 balloon-injured rabbits of each group, the tissue was harvested 3 weeks later for morphometric study. The fish oil-treated rabbits had the lowest aortic production of thromboxane B2 levels and the highest 6-keto-PGF1 alpha/thromboxane B2 ratios among the three groups after balloon injury. The aortic malondialdehyde levels of the cholesterol-fed rabbits were significantly higher than the other two groups (each P < 0.001) independent of balloon injury. The myointimal proliferation of the abdominal aorta and left common iliac artery in the fish oil-treated rabbits was less severe than in the cholesterol-fed animals (both P < 0.001) and was comparable with the controls. These results suggest that a fish oil supplement changes prostanoid metabolism to a favorable pattern and reduces lipid peroxidation on the abdominal aortic wall, thus attenuating myointimal proliferation after balloon injury in diet-induced hypercholesterolemic rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Aorta, Abdominal; Catheterization; Cell Division; Cholesterol, Dietary; Dietary Fats, Unsaturated; DNA; Fish Oils; Hypercholesterolemia; Iliac Artery; Lipid Peroxidation; Lipids; Male; 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

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

The plasma cholesterol, plasma malonaldehyde (MDA), platelet thromboxane A2 (TXA2) and vascular prostacyclin (PGI2) were measured in male Sprague-Dawley rats fed diets supplemented with cholesterol (1%) and cholic acid (0.5%). For comparisons, measurements were made in rats fed normal diets. The concentration of cholesterol in the plasma of rats had reached a maximum in 1 week of feeding experimental diets. TXA2 production from collagen and thrombin stimulated platelets was significantly decreased in animals fed experimental diets for 1 week. The production of MDA in the plasma of animals fed experimental diets for 8 weeks was significantly lower compared to the animals fed normal diets. There was a small but significant reduction in the formation of PGI2 in rats fed experimental diets for 8 weeks. These data suggest that feeding cholesterol rich diets to rats alters the platelet membrane properties differently from human and rabbit. Furthermore, cholesterol feeding to rats had some damaging effect on the arterial PGI2 synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Collagen; Epoprostenol; Hypercholesterolemia; Lipid Peroxidation; Male; Platelet Activation; Rats; Rats, Inbred Strains; Thrombin; Thromboxane A2; Thromboxane B2

Isolated Langendorff-hearts prepared from cholesterol fed rabbits (1% cholesterol for 3 months) showed a significant impairment in endothelium-dependent relaxation after short-term infusion of bradykinin (0.05 mumol/l) and carbamoylcholine (0.1 mumol/l). Generation of the endothelial mediators nitric oxide and prostacyclin by bradykinin was enhanced in hypercholesterolemia. Cicaprost treatment (5 micrograms/kg x d) largely prevented the hypercholesterolemia-related impairment of coronary vasodilation and nitric oxide release. It is concluded that (i) impairment of endothelium-dependent relaxation in the coronary microcirculation of hypercholesterolemic rabbits is not due to diminished endothelium-dependent mediator release but rather to accelerated inactivation or reduced activity of the released mediators and that (ii) oral cicaprost beneficially influence these alterations.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Epoprostenol; Hypercholesterolemia; In Vitro Techniques; Nitric Oxide; Rabbits; Vasodilation

The effect of purified eicosapentanoic acid on intimal fibrous hyperplasia in expanded polytetrafluoroethylene grafts was examined in 18 rabbits undergoing infrarenal aorta reconstruction. Six rabbits received commercial rabbit chow (control group), six a regular diet supplemented with 1% cholesterol (cholesterol group), and six the cholesterol diet with 91.1% pure eicosapentanoic acid 500 mg/day (eicosapentanoic acid group). Grafts were harvested 3 months after surgery for histologic examination. The platelet count and serum beta-thromboglobulin and platelet factor 4 concentrations were not significantly different between groups. Serum arachidonic acid level in the cholesterol group was significantly higher than in the control group, and serum eicosapentanoic acid levels in the eicosapentanoic acid group were significantly higher than in the remaining two groups. Intergroup differences in serum 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations were not significant. Intimal thickness at midgraft was 5.2 +/- 6.2 microns in the control group, 67.6 +/- 46.9 microns in the cholesterol group, and 19.2 +/- 18.4 microns in the eicosapntanoic acid group. intimal thickness in the cholesterol group was greater than in either the control or licosapentanoic acid group (p less than 0.01 and p less than 0.05, respectively). These data suggest that eicosapentanoic acid reduces intimal fibrous proliferation in expanded polytetrafluoroethylene grafting as a result of hypercholesterolemia and that this effect is independent of the platelet count, activated platelet factors, and the prostacyclin/thromboxane A2 ratio.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Abdominal; Arachidonic Acid; Arachidonic Acids; beta-Thromboglobulin; Blood Vessel Prosthesis; Cholesterol, Dietary; Eicosapentaenoic Acid; Elastic Tissue; Endothelium, Vascular; Hypercholesterolemia; Hyperplasia; Male; Platelet Count; Platelet Factor 4; Polytetrafluoroethylene; Rabbits; Radiography; Thromboxane B2; Wound Healing

The production of thromboxane A2 (TXA2) and prostacyclin (PGI2) is altered in hypercholesterolaemia. The purpose of this study was to investigate the effect of an acute rise in arterial pressure produced by pressor agents on the release of TXA2 and PGI2 in hypercholesterolaemic rabbits. Hypercholesterolaemia was induced in rabbits by feeding pellet food containing 1% cholesterol for 3 months. Administration of pressor agents (ergonovine 0.5-2.0 mg.kg-1, noradrenaline 5.0-20.0 micrograms.kg-1 and angiotensin-II 0.5-2.0 micrograms.kg-1) increased arterial pressure dose dependently, accompanied by a pressure dependent increase in the plasma concentrations of both TXB2 and 6-keto-PGF1 alpha (stable metabolites of TXA2 and PGI2) in control rabbits, but only of TXB2 in hypercholesterolaemic rabbits. In control rabbits the maximum increase in TXB2 was 51% with ergonovine, 73% with noradrenaline, and 51% with angiotensin-II; and the maximum increase in 6-keto-PGF1 alpha was 48% with ergonovine, 76% with noradrenaline, and 198% with angiotensin-II. In hypercholesterolaemic rabbits the maximum increase in TXB2 was 130% with ergonovine, 144% with noradrenaline, and 128% with angiotensin-II. The pressor induced increase in TXB2 was suppressed when the increase in arterial pressure was counteracted by the concomitant administration of vasodilators (glyceryl trinitrate 40 micrograms.kg-1.min-1 and verapamil 20 micrograms.kg-1.min-1) in both control and hypercholesterolaemic rabbits. Neither TXB2 biosynthesis nor phospholipase A2 activity in platelets was affected by ergonovine, noradrenaline or angiotensin-II in vitro. These results suggested that the acute rise in arterial pressure caused by these pressor agents increased TXA2 release in vivo and that the increase was greater in hypercholesterolaemic than in control rabbits.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin II; Animals; Blood Pressure; Dose-Response Relationship, Drug; Epoprostenol; Ergonovine; Hypercholesterolemia; Nitroglycerin; Norepinephrine; Rabbits; Thromboxane A2; Thromboxane B2; Verapamil

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Angina Pectoris; Animals; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Pre-Eclampsia; Pregnancy; Rabbits; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane B2

The influences of experimental hypercholesterolemia in the rabbit on platelet-vessel wall interactions have been studied by evaluating the aggregatory response of platelet rich plasma (PRP) to arachidonic acid (AA) stimulation and levels of 6-keto-PGF1 alpha in PRP from normal (N) and hypercholesterolemic (HC) animals prior and after perfusion through the corresponding aortas. In addition, the responses of N PRP to aggregation after perfusion through HC aortas and those of HC PRP perfused through N aortas, and the platelet response to the inhibitory effect of exogenous prostacyclin have been evaluated. The data indicate that in HC rabbits, on one side platelets are hyperreactive to AA and less sensitive to the inhibitory activity of prostacyclin and, on the other, the antiaggregatory activity and prostacyclin production of vessel walls is higher, suggesting compensatory mechanisms in the haemostatic balance.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Arachidonic Acid; Arachidonic Acids; Cholesterol; Epoprostenol; Hypercholesterolemia; Male; Platelet Aggregation; Prostaglandins; Rabbits

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Aorta, Thoracic; Blood Platelets; Blood Vessels; Cholesterol; Chromonar; Coumarins; Epoprostenol; Hypercholesterolemia; In Vitro Techniques; Male; Platelet Aggregation; Rabbits; Thromboxane B2