iloprost and Arteriosclerosis

Topics: Angiography; Arterial Occlusive Diseases; Arteriosclerosis; Cilostazol; Clinical Trials as Topic; Clopidogrel; Endothelial Growth Factors; Genetic Therapy; Humans; Iloprost; Leg; Lymphokines; Multicenter Studies as Topic; Phosphodiesterase Inhibitors; Platelet Aggregation Inhibitors; Prognosis; Prospective Studies; Protein Isoforms; Randomized Controlled Trials as Topic; Tetrazoles; Ticlopidine; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vasodilator Agents

Thromboangiitis obliterans (Buerger's disease) is an inflammatory obliterative, nonatherosclerotic, vascular disease that affects the small- and medium-sized arteries, veins, and nerves. It is causally related to tobacco use, although the exact mechanism is unknown. Its clinical presentation is manifested by distal arterial ischemia and superficial thrombophlebitis. Thromboangiitis obliterans usually becomes quiescent if the patient is able to stop smoking cigarettes. However, if smoking continues, amputation commonly results.

Topics: Amputation, Surgical; Arteriosclerosis; Diagnosis, Differential; Embolism; Female; Humans; Iloprost; Male; Smoking; Thromboangiitis Obliterans

Topics: Animals; Arteriosclerosis; Cell Division; Chronic Disease; Disease Models, Animal; Estradiol; Graft Rejection; Heart Transplantation; Iloprost; Male; Muscle, Smooth; Oligopeptides; Peptides, Cyclic; Rabbits; Somatostatin; Transplantation, Homologous

Platelet function and levels of vascular adhesion molecule-1 (VCAM-1) were investigated in 24 patients with peripheral arterial disease at Fontaine stage II undergoing a 2 weeks treatment with iloprost (0.5-2 ng/kg/h i.v. infused, 6 h/day) or a 2 weeks supervised physical training, randomly assigned. Patients were studied before (T0) and after (T14) treatments and 10 days later (T24). The adhesion of washed platelets to fibrinogen coated microwells was reduced after treatment both with iloprost (1.9+/-0.4 vs 6.8+/-0.7%; T24 vs T0; M+/-SEM; p<0.05) and physical exercise (3.0+/-1.0 vs 6.7+/-0.7; p<0.05) while adhesion to human plasma coated microwells was reduced only after treatment with iloprost (1.9+/-0.8 vs 5.8+/-0.9; p<0.05). The expression of fibrinogen receptor (glycoprotein IIb/IIIa) on platelets, measured by flow-cytometry was also reduced after iloprost treatment (17.1+/-1.5 vs 31.8+/-4.8 AU; p<0.05) and physical exercise (14.6+/-1.5 vs 34.0+/-3.3; p<0.05). Theurinaryexcretion of platelet thromboxane A2 metabolite 2,3-dinor-thromboxane B2 decreased only in patients treated with iloprost (154.7+/-97.9 vs 256.2+/-106.4 pg mg creatinine(-1); p<0.05). Similarly plasma VCAM-1 was lower in patients who were treated with iloprost (827.7+/-77.4 vs 999.0+/-83.8 ng ml(-1); p<0.05). In conclusion, both iloprost and physical exercise seem to act on reversible phenomena such as the expression of adhesion molecules or ex vivo adhesion, whereas only iloprost reduces thromboxane A2 biosynthesis in vivo. This anti-platelet activity seems to be extended in time and to be associated with an improvement in vascular function.

Topics: Aged; Arteriosclerosis; Blood Glucose; Blood Pressure; Cholesterol; Endothelium, Vascular; Exercise; Fibrinogen; Humans; Iloprost; Male; Middle Aged; Peripheral Vascular Diseases; Platelet Activation; Platelet Function Tests; Treatment Outcome; Triglycerides; Vascular Cell Adhesion Molecule-1

The influence of intravenous infusions of various prostaglandins on in vivo platelet function was studied after labelling of autologous platelets with 100 mu ci 111 indium-oxinesulfate in patients with peripheral vascular disease stage II according to FONTAINE. PGI2 (5 ng/kg/min) provoked a significant decrease of platelet deposition and a prolongation in platelet half-life time (74 +/- 6 vs 68 +/- 5 hours). PGE1 (25 ng/kg/min) failed to influence platelet deposition, but prolonged significantly platelet half-life time (82 +/- 6 vs 76 +/- 8 hours). CG 4203 (25 ng/kg/min) decreased significantly platelet deposition and prolonged significantly platelet half-life time (73 +/- 10 vs 67 +/- 11 hours). Iloprost (1 and 2 ng/kg/min) reduced significantly platelet deposition without dose relation. Half-life time was increased significantly after therapy compared to placebo (1 ng: 76 +/- 7 vs 69 +/- 7; 2 ng: 73 +/- 9 vs 67 +/- 9 hours).

Topics: Aged; Alprostadil; Arteriosclerosis; Cardiovascular Agents; Epoprostenol; Humans; Iloprost; Male; Middle Aged; Platelet Aggregation Inhibitors

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

Migration and proliferation of medial smooth muscle cells (SMC) in the arterial intima contributes to the development of atherosclerotic plaques and restenotic processes after coronary angioplasty. Prostacyclin (PGI2)-mediated stimulation of cyclic adenosine 3'5'-monophosphate (cAMP) signaling is believed to be important for maintaining SMC in a quiescent state. In order to identify new cellular targets of PGI2/cAMP action, we have used microarray screening to examine changes in the transcriptional profile in human vascular SMC in response to exposure to the stable PGI2 mimetic iloprost. We have identified 83 genes with significantly altered expression after iloprost (100 nM) exposure for 6 hr. Fifty-one genes were upregulated, among them stanniocalcin precursor (18.8+/-2.7), zinc finger transcription factor (7.8+/-2.0), hyaluronan synthase 2 (6.8+/-1.8), cyclooxygenase 2 (4.7+/-0.8), dual specific phosphatase (3.9+/-0.5) and vascular endothelial growth factor (2.3+/-0.4). Thirty-two genes were reduced, among them cystein-rich angiogenic protein (-14.9+/-1.3), monocyte chemotactic protein 1 (-7.4+/-1.1) and plasminogen activator inhibitor PAI-1 (-4.5+/-0.5). By means of semi-quantitative RT-PCR, time-courses of gene expression were established. The present study identified genes not hitherto recognized to be targets of PGI2 action, providing further insight into its cAMP-mediated effects on SMC growth, migration and matrix secretion.

Topics: Arteriosclerosis; Cells, Cultured; Cyclic AMP; Epoprostenol; Gene Expression; Gene Expression Profiling; GTP-Binding Protein alpha Subunits, Gs; Humans; Iloprost; Muscle, Smooth, Vascular; Oligonucleotide Array Sequence Analysis; Receptors, Epoprostenol; Time Factors

Currently available drug therapies for patients suffering severe ischaemia with rest pain and trophic lesions of the limbs remain unsatisfactory. Also vascular reopening procedures are suitable in only about half of the patients. In atherosclerotic disease when the vascular endothelium is damaged prostacyclin synthesis is decreased and thromboxane A2 production increases. Prompted by this knowledge of the importance of prostacyclin in pathogenesis of atherosclerotic disease an attempt was made to employ PGI2 clinically--for treatment of advanced forms of peripheral arterial atherosclerotic disease. Favourable effects of the stable analogue of prostacyclin (Iloprost), were reported in various studies, which included patients with peripheral atherosclerotic arterial disease, thromboangiitis obliterans and Raynaud's phenomenon. The use of Iloprost resulted in a significantly superior response than other drugs and placebo in terms of alleviation of rest pain, ulcer healing and decrease of amputation rate of ischaemic limbs. Therefore prostacyclin provides a therapeutic option in patients with advanced forms of arterial disease--including critical ischaemia.

Topics: Arteriosclerosis; Epoprostenol; Extremities; Humans; Iloprost; Ischemia; Raynaud Disease; Thromboangiitis Obliterans

The physiological basis of postischemic hyperemia is not yet fully understood. The present study investigated the effects of pharmacologic manipulation of the prostaglandin system on local hemodynamics. Strain-gauge plethysmography was used to study 8 normal subjects and 9 patients with obliterating arterial disease of the lower limbs. Hemodynamic evaluations were performed before treatment, after seven days of low-dose acetylsalicylic acid (100 mg/day) to inhibit platelet thromboxane synthesis, and after acute infusion of 1 g of acetylsalicylic acid to inhibit endothelial prostacyclin synthesis. In patients with arterial disease, the hemodynamic study was also carried out after infusion of iloprost, a synthetic prostacyclin analogue. Acute infusion of acetylsalicylic acid significantly reduced basal blood flow in normal subjects, but not in patients with arterial disease. In the latter group, iloprost affected neither basal nor maximal postischemic flow. The study also evaluated the role of endothelin in musculocutaneous hemodynamic regulation, both in physiological conditions and in atherosclerosis. This part of the study addressed the possibility that the hemodynamic effects of vasodilator prostanoids like prostacyclin might affect endothelin release in vivo. During reactive hyperemia, plasma endothelin was reduced in normal subjects (-1.02 pg/mL, 95% CI: -2.23, 0.08), but not in patients with atherosclerosis (-0.35 pg/mL, 95% CI: -1.45, 0.75). In both groups, plasma endothelin was not affected by aspirin. These findings confirm the role of prostacyclin in local hemodynamic regulation. In the normal subject, musculocutaneous blood flow seems to depend at least in part on the action of vasodilator prostanoids and endothelin. This is not the case in patients with arterial disease, in whom plasma endothelin does not seem to be affected by postischemic changes in blood flow. A possible explanation for this difference could be alteration of the endothelial function in patients with arterial disease, related to the functional and structural characteristics of the artery wall in atherosclerosis.

Topics: Aged; Arteriosclerosis; Aspirin; Endothelins; Epoprostenol; Hemodynamics; Humans; Hyperemia; Iloprost; Ischemia; Leg; Middle Aged; Platelet Aggregation Inhibitors; Plethysmography; Regional Blood Flow; Vasodilator Agents

This study determines the antiplatelet effects of oral ticlopidine (100 mg/kg x day) in experimental hypercholesterolemia. Rabbits were fed either a standard diet or a cholesterol-enriched diet (0.5% for 3 months, 1% for 1 month). In normocholesterolemic controls ADP-, but not collagen-induced platelet aggregation was inhibited by ticlopidine treatment. This was accompanied by a significantly enhanced inhibition of ADP-induced platelet aggregation and stimulation of cyclic AMP accumulation by iloprost. Hypercholesterolemia considerably attenuated the inhibition of ADP-induced aggregation by ticlopidine but did not change its effect on the iloprost-induced inhibition of platelet function and cyclic AMP formation. ADP-induced platelet-derived thromboxane formation was considerably greater in hypercholesterolemic rabbits and not reduced by ticlopidine. Ticlopidine did also not significantly influence the extent and severity of atherosclerotic plaque formation although a tendency for improvement was observed in a subgroup of animals. The data suggest that hypercholesterolemia attenuates the inhibitory effect of ticlopidine on ADP-induced platelet aggregation. This might be related to the stimulation of thromboxane formation by ADP in hypercholesterolemia. The maintained protection from ADP-induced inhibition of cAMP accumulation suggests a minor role of this mechanism in the progression of hypercholesterolemia-induced vessel disease in this model.

Topics: Adenosine Diphosphate; Animals; Aortic Diseases; Arteriosclerosis; Biotransformation; Cholesterol, Dietary; Collagen; Cyclic AMP; Hypercholesterolemia; Iloprost; Indomethacin; Liver; Male; Platelet Aggregation; Rabbits; Signal Transduction; Thromboxane B2; Ticlopidine

Thirty-four patients with ischaemic rest pain in 42 limbs and ankle pressure equal to or less than 50 mmHg have been treated with intravenous infusion of synthetic prostacyclin (iloprost) for eight days. Leg blood flow was measured with air plethysmography before treatment, on day 4 and day 8 of treatment. Total relief of pain for at least 6 weeks occurred in 91% of patients with leg blood flow > or = 40 ml/min, in 18% with leg flow 30-39 ml/min and in 11% with leg flow < 30 ml/min. Complete relief of pain for at least 6 weeks occurred in 92% of patients in whose limbs the blood flow on day 8 was greater than 50 ml/min but only in 6% with blood flow less than 50 ml/min. These results indicate that iloprost increases leg blood flow and that patients likely to respond can be identified from the baseline air plethysmographic measurement of leg blood flow.

Topics: Arteriosclerosis; Humans; Iloprost; Infusions, Intravenous; Ischemia; Leg; Plethysmography; Regional Blood Flow; Time Factors

Topics: Animals; Arteriosclerosis; Coronary Vessels; Cyclosporins; Graft Rejection; Heart Transplantation; Iloprost; Oligopeptides; Peptides, Cyclic; Rats; Rats, Inbred Strains; Somatostatin

This study examined the effects of laser-generated tissue debris from thrombus, atheroma, and normal aorta on platelet aggregation. Debris supernatant and suspension from lased thrombus induced dose-related aggregation, maximal at 48 +/- 12% and 65 +/- 2%, respectively. Debris suspension from normal aorta induced maximal aggregation of 35 +/- 12%, but the debris from atheromatous aorta surprisingly had no effect on platelet aggregation. The debris particle count was in the range of 10(10) to 10(12) per liter. Aspirin, 0.2 and 2.0 mmol/L, only weakly inhibited the debris-induced aggregation, and heparin up to 10 U/ml was ineffective. However, iloprost reduced aggregation to 40 +/- 11% of control at 0.3 ng/ml, and totally abolished it at 3 ng/ml. Soluble and particulate laser-generated debris from vascular tissue and thrombus may cause platelet aggregation in vitro. This may have implications for laser coronary angioplasty.

Topics: Aged; Angioplasty, Laser; Animals; Aorta; Aortic Diseases; Arteriosclerosis; Aspirin; Blood Coagulation; Heparin; Humans; Iloprost; In Vitro Techniques; Middle Aged; Platelet Aggregation; Swine; Thrombosis

Plasma fibrinolytic activity and tissue-type plasminogen activator (t-PA) were defective in response to venous stasis in five out of ten patients with peripheral occlusive artery disease. Discontinuous infusions of iloprost, a stable synthetic analogue of prostacyclin, restored a normal fibrinolytic response in all five patients but did not induce a parallel increase of plasma t-PA. These findings suggest that in addition to the possible benefits due to its vasodilatory and antiplatelet activity, iloprost may improve the fibrinolytic activity in patients with atherosclerotic disease, providing them with further antithrombotic protection. The profibrinolytic effect of iloprost seems not to depend on its ability to induce vascular t-PA release. Rather, it might be related to its inhibitory effect on PAI release from platelets, endothelial cells and/or hepatocytes. Venous occlusion test represents an easy diagnostic approach to fibrinolytic defects, even if related to arterial disease, and may help select patients who need therapeutic intervention.

Topics: Adult; Aged; Arteriosclerosis; Cardiovascular Agents; Epoprostenol; Fibrinolysis; Humans; Iloprost; Male; Middle Aged; Tissue Plasminogen Activator

The effect of drugs on eicosanoid production and on the development of atherogenic index was investigated in canine myocardial ischemia. Iloprost, verapamil, the trapidil derivative AR 12463 or 0.9% NaCl solution were administered 60 min after coronary artery ligation in anaesthetized dogs. Both iloprost and AR 12463 reduced the thromboxane A2/prostacyclin (TXA2/PGI2) ratio in coronary sinus plasma in comparison to controls. The atherogenic index was significantly decreased in the iloprost as well as in the AR 12463-treated group in comparison to the control group. Verapamil had no influence on the investigated parameters.

Topics: Animals; Antihypertensive Agents; Arteriosclerosis; Biomarkers; Coronary Disease; Dogs; Epoprostenol; Female; Iloprost; Male; Pyrimidines; Reference Values; Thromboxane A2; Trapidil

Iloprost is a chemically stable derivative of carbaprostacyclin. We studied its hemodynamic effects in 10 patients in an intensive care unit. Iloprost was infused intravenously for 3 days for the treatment of advanced obliterative arterial disease of the lower extremities. Clinically significant hemodynamic responses were obtained with an infusion rate of 0.5 ng/kg/min. All subjects tolerated the dose of 4 ng/kg/min, which increased heart rate an average of 11% and cardiac index an average of 26%. This infusion rate decreased mean arterial pressure by 15%, total peripheral resistance by 31%, and pulmonary vascular resistance by 34%. Mean pulmonary arterial pressure, pulmonary capillary wedge pressure, left and right ventricular stroke work indices, and rate pressure product did not change. At higher doses of up to 8 ng/kg/min, responses were augmented only slightly, but side effects such as headache, nausea, and abdominal colics became more prominent. The data show iloprost to be a potent vasodilator that reduces both pre- and afterload and presumably induces a compensatory increase in cardiac output and heart rate, but does not increase the work load or oxygen demand of the heart.

Topics: Adult; Aged; Arteriosclerosis; Blood Pressure; Cardiac Output; Drug Evaluation; Epoprostenol; Female; Heart Rate; Hemodynamics; Humans; Iloprost; Infusions, Parenteral; Male; Middle Aged; Platelet Aggregation; Stroke Volume; Vascular Resistance; Vasodilator Agents