iloprost and Disease-Models--Animal

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

Prostacyclin inhalation is increasingly used to treat acute pulmonary hypertension and right ventricular failure, although its pharmacodynamic properties remain controversial. Prostacyclins not only affect vasomotor tone but may also have cAMP-mediated positive inotropic effects and modulate autonomic nervous system tone. We studied the role of these different mechanisms in the overall haemodynamic effects produced by iloprost inhalation in an experimental model of acute pulmonary hypertension.. In this prospective, randomized, placebo-controlled animal study, twenty-six pigs (mean weight 35 +/- 2 kg) were instrumented with biventricular conductance catheters, a pulmonary artery flow probe and a high-fidelity pulmonary artery pressure catheter. The effects of inhaled iloprost (50 microg) were studied in the following groups: animals with acute hypoxia-induced pulmonary hypertension, and healthy animals with and without blockade of the autonomic nervous system.. During pulmonary hypertension, inhalation of iloprost resulted in a 51% increase in cardiac output compared with placebo (5.6 +/- 0.7 versus 3.7 +/- 0.8 l/minute; P = 0.0013), a selective reduction in right ventricular afterload (effective pulmonary arterial elastance: 0.6 +/- 0.3 versus 1.2 +/- 0.5 mmHg/ml; P = 0.0005) and a significant increase in left ventricular end-diastolic volume (91 +/- 12 versus 70 +/- 20 ml; P = 0.006). Interestingly, right ventricular contractility was reduced after iloprost-treatment (slope of preload recruitable stroke work: 2.2 +/- 0.5 versus 3.4 +/- 0.8 mWatt.s/ml; P = 0.0002), whereas ventriculo-vascular coupling remained essentially preserved (ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance: 0.97 +/- 0.33 versus 1.03 +/- 0.15). In healthy animals, inhaled iloprost had only minimal haemodynamic effects and produced no direct effects on myocardial contractility, even after pharmacological blockade of the autonomic nervous system.. In animals with acute pulmonary hypertension, inhaled iloprost improved global haemodynamics primarily via selective pulmonary vasodilatation and restoration of left ventricular preload. The reduction in right ventricular afterload is associated with a paradoxical decrease in right ventricular contractility. Our data suggest that this reflects an indirect mechanism by which ventriculo-vascular coupling is maintained at the lowest possible energetic cost. We found no evidence for a direct negative inotropic effect of iloprost.

Topics: Acute Disease; Administration, Inhalation; Animals; Cardiac Output; Disease Models, Animal; Hypertension, Pulmonary; Iloprost; Prospective Studies; Sus scrofa; Ventricular Function, Left; Ventricular Function, Right

In 2 randomized, double-blind studies, 109 diabetic patients with trophic lesions and 101 non-diabetics suffering from peripheral vascular disease (PVD) stage IV (Fontaine) received daily 6-hour i.v. infusions of iloprost (less than or equal to 2ng/kg/min) or of placebo over 28 days. Iloprost treatment was superior to placebo, showing ulcer healing in more than 60% of patients compared to less than 25% in the control group. The beneficial effects were sustained during a 1 year follow-up period. Platelet activation, adhesion, aggregation and release reaction on atherosclerotic lesions, impaired microvascular perfusion, loss of microvascular barrier function, increased white blood cell - vessel wall interaction and hemorheological disturbances are all believed to play a role in PVD. Stable PGI2-mimetics inhibit platelet activation by all endogenous mediators as well as platelet release of mitogenic factors (PDGF).

Topics: Animals; Blood Platelets; Cardiovascular Agents; Clinical Trials as Topic; Diabetic Angiopathies; Disease Models, Animal; Double-Blind Method; Epoprostenol; Humans; Iloprost; Infusions, Intravenous; Microcirculation; Random Allocation; Rats; Thrombosis; Ulcer; Vascular Diseases

Surgical delay is a well-described technique to improve survival of random and pedicled cutaneous flaps. The aim of this study was to test the topical agents minoxidil and iloprost as agents of pharmacologic delay to induce vascular remodeling and decrease overall flap necrosis as an alternative to surgical delay.. Seven groups were studied (n = 8 in each group), including the following: vehicle, iloprost, or minoxidil before treatment only; vehicle, iloprost, or minoxidil before and after treatment; and a standard surgical delay group as a positive control. Surgical flaps (caudally based modified McFarlane myocutaneous skin flaps) were elevated after 14 days of pretreatment, reinset isotopically, and observed at various time points until postoperative day 7. Gross viability, histology, Doppler blood flow, perfusion imaging, tissue oxygenation measurement, and vascular casting were performed for analysis.. Pharmacologic delay with preoperative application of topical minoxidil or iloprost was found to have comparable flap viability when compared to surgical delay. Significantly increased viability in all treatment groups was observed when compared with vehicle. Continued postoperative treatment with topical agents had no effect on flap viability. The mechanism of improved flap viability was inducible increases in flap blood volume and perfusion rather than the acute vasodilatory effects of the topical agents or decreased flap hypoxia.. Preoperative topical application of the vasodilators minoxidil or iloprost improved flap viability comparably to surgical delay. Noninvasive pharmacologic delay may reduce postoperative complications without the need for an additional operation.. Preoperative use of topical vasodilators may lead to improved flap viability without the need for a surgical delay procedure. This study may inform future clinical trials examining utility of preoperative topical vasodilators in flap surgery.

Topics: Administration, Cutaneous; Animals; Disease Models, Animal; Graft Survival; Iloprost; Male; Minoxidil; Surgical Flaps; Vascular Remodeling; Vasodilator Agents

Mouse iloprost lung cancer chemoprevention studies typically use oral delivery. Here, we present a protocol for intranasal iloprost delivery within a urethane lung adenocarcinoma mouse model. We detail steps for intraperitoneal urethane injection in mice, followed by nine-week monitoring, intranasal iloprost treatment, and lungs harvesting for analysis. This iloprost delivery approach parallels an ongoing phase II clinical trial of inhaled iloprost for lung cancer chemoprevention. This protocol diversifies options for chemoprevention studies and offers a relevant and translatable model. For complete details on the use and execution of this protocol, please refer to Sompel et al. (2022).

Topics: Animals; Carcinogens; Chemoprevention; Disease Models, Animal; Enzyme Inhibitors; Iloprost; Lung Neoplasms; Mice; Urethane

Iloprost, a stable prostaglandin I

Topics: Animals; Cell Differentiation; Cells, Cultured; Cytokines; Dendritic Cells; Disease Models, Animal; Epoprostenol; Female; Forkhead Transcription Factors; Humans; Hypersensitivity; Iloprost; Immune Tolerance; Lymphocyte Activation; Mice; Mice, Inbred BALB C; T-Cell Antigen Receptor Specificity; T-Lymphocytes, Regulatory

Acute allergic nasal inflammation is very common in the clinical allergic diseases, Prostaglandin I2 (PGI2) has been found to effective in combating inflammation. Iloprost, as an analog of PGI2, whose role and mechanisms in the acute allergic nasal inflammation remains unclear. It's necessary to elucidate the efficacy and potential mechanism of Iloprost in acute allergic nasal inflammation.. 36 female mice were randomly divided into DMSO group, IL 33 group, Iloprost group and IL 33+Iloprost intervention group. Mice were stimulated with IL 33 to construct an acute allergic nasal inflammation model. Hematoxylin and eosin (HE) and periodic acid Schiff reagent (PAS) staining, flow cytometry, Real time PCR and Enzyme linked immunosorbent assay (ELISA) was used to identify the role of Iloprost in acute allergic nasal inflammation. The comparison between multiplied groups was analyzed by ANOVA, and the Bonferroni method was used for further comparison of two groups.. Compared with IL 33 group, the inflammatory cell infiltration around the trachea and blood vessels of the lung tissue in the IL 33+ Iloprost group were reduced; goblet cell hyperplasia was observed in airway mucosa of IL 33 group, and the mucus secretion increased; the percentage of EOS and ILC2s in the BALF and lung single cell suspensions in IL 33+ Iloprost group were statistically lower than that of IL 33 group (p < 0.05); The mRNA expression levels of IL 5, IL 13, ST2 and GATA3 in the lung tissue of IL 33 group were higher than those in DMSO group (p < 0.05). After intervention with Iloprost, the mRNA expression levels of IL 5, IL 13, GATA3 and ST2 were lower than those in IL 33 group (p < 0.05) CONCLUSION: Iloprost may potentially inhibit the proliferation and activation of innate lymphoid cells 2 in mice with acute allergic inflammation, which maybe an effective option for the treatment of acute allergic inflammation related diseases.

Topics: Animals; Disease Models, Animal; Female; GATA3 Transcription Factor; Goblet Cells; Hyperplasia; Iloprost; Interleukin-1 Receptor-Like 1 Protein; Interleukin-13; Interleukin-33; Interleukin-5; Lung; Lymphocytes; Mice; Mucus; Nasal Mucosa; Random Allocation; Respiratory Mucosa; Rhinitis, Allergic; RNA, Messenger; Trachea

Myocardial ischemia-reperfusion injury continues to be observed during open heart surgery. Various experimental models have been developed to overcome this injury and to increase postoperative prognosis. \ This study was conducted to assess the effect that iloprost, a prostacyclin analogue, can have on myocardial ischemia-reperfusion injury. We evaluated tissue damage by measuring the levels of malonyldialdehyde (MDA), glutathione, and nitric oxide (NO) in tissue and perfusates.\ In this study, 20 guinea pig hearts were prepared by using the modified Langendorff perfusion apparatus to form control (n = 10) and experimental study groups (n = 10). Following a preischemic period of perfusion and an ischemic period of 20 minutes, control hearts were perfused with Krebs–Henseleit solution. In the experimental group, iloprost \ (0.45 μg/kg per hour) was included in the perfusates for the last 10 minutes of the preischemic phase. Following cardiac stabilization, heart rate (pulse/min), contractility (mm), and aortic pressure (mmHg) values were recorded at the end of preischemia, postischemia, and reperfusion. Perfusate and tissue analyses for glutathione, MDA, and NO levels were made in each group at the end of experiments. \ Iloprost was found to have protective effects against myocardial ischemia by means of increased myocardial contractility, decreased tissue/perfusate glutathione levels and inhibited rise of tissue/perfusate MDA observed in the iloprost-treated experimental group. Future investigations on myocardial ischemia-reperfusion injury must evaluate iloprost-related mechanisms.

Topics: Animals; Arterial Pressure; Disease Models, Animal; Epoprostenol; Female; Guinea Pigs; Heart Rate; Iloprost; Male; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Treatment Outcome; Vasodilator Agents

Topics: Animals; Disease Models, Animal; Iloprost; Ischemic Preconditioning; Reperfusion Injury; Surgical Flaps

Free jejunal flaps are among the most commonly used flaps for esophageal reconstruction. However, ischemia-reperfusion injury caused by warm ischemia seen during transfer limits their use. Iloprost, a prostacyclin analogue, has been shown to reduce ischemia-reperfusion injury in various organs. The authors investigated tissue damage in jejunal flaps with iloprost and ischemic preconditioning and compared the effectiveness of these two modalities.. Thirty-four Sprague-Dawley rats were randomized into five groups: sham, ischemia-reperfusion (control), ischemic preconditioning, iloprost, and ischemic preconditioning plus iloprost. All flaps, except those in the sham group, underwent ischemia for 60 minutes and reperfusion for 2 hours. Flap perfusion was assessed by laser Doppler perfusion monitoring. Histologic sections were scored using the Chiu scoring system. Superoxide dismutase and myeloperoxidase levels were measured spectrophotometrically.. Animals that were administered iloprost and/or underwent ischemic preconditioning had better postischemic recovery of mesenteric perfusion (ischemic preconditioning, 78 percent; iloprost, 83 percent; ischemic preconditioning plus iloprost, 90 percent; versus ischemia-reperfusion, 50 percent; p < 0.05). All intervention groups showed improved histology of jejunal flaps following ischemia-reperfusion injury (ischemic preconditioning, 3; iloprost, 2.3; ischemic preconditioning plus iloprost, 3.2; versus ischemia-reperfusion, 4.7; p < 0.01, p < 0.001, and p < 0.05, respectively). Superoxide dismutase levels were higher in ischemic preconditioning, iloprost plus ischemic preconditioning, and iloprost groups (ischemic preconditioning, 2.7 ± 0.2; ischemic preconditioning plus iloprost, 2.5 ± 0.3; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.01; iloprost, 2.4 ± 1.1; versus ischemia-reperfusion, 1.2 ± 0.1; p < 0.05). Myeloperoxidase, a marker for neutrophil infiltration, was lower in the iloprost group (iloprost, 222 ± 5; versus ischemia-reperfusion, 291 ± 25; p < 0.05).. This study showed that both iloprost and ischemic preconditioning reduced reperfusion injury in jejunal flaps. Based on histologic results, iloprost may be a novel treatment alternative to ischemic preconditioning.

Topics: Animals; Antioxidants; Biomarkers; Disease Models, Animal; Esophagus; Free Tissue Flaps; Iloprost; Ischemic Preconditioning; Jejunum; Laser-Doppler Flowmetry; Male; Neutrophil Infiltration; Peroxidase; Platelet Aggregation Inhibitors; Random Allocation; Rats, Sprague-Dawley; Reperfusion Injury; Superoxide Dismutase

Purpose Acute lower extremity ischemia is still a main cause of mortality and morbidity in orthopedic traumatology and reconstructive surgery. In acute lower extremity ischemia, the skeletal muscles are the tissues that are the most vulnerable to ischemia. The aim of this study was to evaluate the effects of iloprost (IL) therapy on skeletal muscle contractile impairment and mitochondrial degeneration in an acute lower extremity ischemia-reperfusion rat model. Main Methods Forty Wistar albino rats were randomly divided into a control group and four experimental groups. Experimental groups were either subjected to 2 h of lower extremity ischemia followed by a 4-h reperfusion period or to 4 h of ischemia followed by an 8-h reperfusion period. Except for the animals in the control group, all animals received IL (1 ng/kg/min) or saline (1 ml/kg) by intraperitoneal infusion for 10 min immediately before reperfusion. At the end of the recording of skeletal muscle electrical activity and contractility, all rats were sacrificed by decapitation and muscle samples of lower extremity were immediately harvested for histopathologic analyses. Results After ischemia-reperfusion, a breakdown in the force-frequency curves of extensor digitorum longus muscle was observed, showing the diminished muscle contractility. However, IL significantly improved muscle contractility following injury induced by 2 h of ischemia followed by a 4-h reperfusion period. In addition, IL partially ameliorated mitochondrial degeneration in the muscle cells of ischemia groups. Conclusion This study indicates that immediate IL therapy repairs muscle damage especially after 2 h of ischemia and 4 h of reperfusion and therefore that IL improves contractile function.

Topics: Action Potentials; Animals; Disease Models, Animal; Iloprost; Male; Mitochondria, Muscle; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Rats, Wistar; Recovery of Function; Reperfusion Injury; Time Factors

A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH

Topics: Amino Alcohols; Animals; Anticonvulsants; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Mice; Models, Molecular; Molecular Structure; Rats; Seizures; Structure-Activity Relationship

Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions.. In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro- and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood.. During hemorrhage, gastric mucosal oxygenation decreased from 77 ± 4 to 37 ± 7%. This effect was attenuated by nitroglycerin (78 ± 6 to 47 ± 13%) and iloprost (82 ± 4 to 54 ± 9%). Sucrose plasma levels increased during hemorrhage from 7 ± 4 to 55 ± 15 relative amounts. This was alleviated by nitroglycerin (5 ± 8 to 29 ± 38 relative amounts). These effects were independent of systemic hemodynamic variables.. During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function.

Topics: Administration, Topical; Animals; Disease Models, Animal; Dogs; Female; Gastric Absorption; Gastric Mucosa; Iloprost; Microcirculation; Nitroglycerin; Oxygen; Oxyhemoglobins; Permeability; Shock, Hemorrhagic; Sucrose; Time Factors; Vasodilator Agents

Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1β (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 μmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients.

Topics: Administration, Intranasal; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Iloprost; Lipopolysaccharides; Male; Mice, Inbred C57BL; Neutrophil Infiltration; Pulmonary Disease, Chronic Obstructive; Respiratory Hypersensitivity

Central retinal artery occlusion (CRAO) is one of the serious ophthalmological emergencies with poor visual prognosis. Iloprost is a stable prostacyclin analogue and has prominent anti-edema, anti-inflammatory, vasodilatory, and antiagregant effects. The main objective of this work was to investigate iloprost as an alternative agent versus hyperbaric oxygen (HBO) in the treatment of CRAO.. Twenty-eight healthy Wistar albino male rats were randomly assigned into control (n = 7, sham operation), HBO (n = 7), iloprost (n = 7), and sham groups (n = 7). CRAO model was created through optic nerve exploration and ligation. Full-thickness retina (FTR), outer nuclear layer (ONL), inner nuclear layer (INL) and ganglion cell layer (GCL) thickness were measured on Hematoxylin/Eosin (H&E) stained retinal sections and immunohistochemical analysis including terminal deoxynucleotidyl transferase-mediated biotindeoxyuridine triphosphate nick-end labeling (TUNEL) assay was performed to determine the apoptotic index (AI).. AI values of HBO (0.204 ± 0.067) and iloprost (0.197 ± 0.052) groups were significantly lower than sham (0.487 ± 0.046) group (p < 0.001). Any significant difference was found between the HBO and iloprost groups in terms of AI (p = 0.514). A statistically significant increase in thickness of FTR, ONL, INL and GCL was detected in HBO, iloprost and sham groups compared to the control group (p = 0.002). FTR, ONL, INL and GCL thickness were significantly thinner in HBO and iloprost groups than in the sham group (p = 0.002). A significant lesser increase was observed in all the retinal layers thickness in iloprost group versus HBO group (p = 0.002) except for INL (p = 0.665).. The study results demonstrated anti-edema, neuroprotective, and anti-apoptotic effects of iloprost quantitatively; thus, iloprost may be a beneficial alternative agent in the treatment of CRAO.

Topics: Animals; Apoptosis; Disease Models, Animal; Hyperbaric Oxygenation; Iloprost; In Situ Nick-End Labeling; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Retinal Artery Occlusion; Retinal Ganglion Cells; Treatment Outcome; Vasodilator Agents

To evaluate the effects of alprostadil (prostaglandin [PGE1] analog) and iloprost (prostacyclin [PGI2] analog) on renal, lung, and skeletal muscle tissues after ischemia reperfusion (I/R) injury in an experimental rat model.. Wistar albino rats underwent 2 hours of ischemia via infrarenal aorta clamping with subsequent 2 hours of reperfusion. Alprostadil and iloprost were given starting simultaneously with the reperfusion period. Effects of agents on renal, lung, and skeletal muscle (gastrocnemius) tissue specimens were examined.. Renal medullary congestion, cytoplasmic swelling, and mean tubular dilatation scores were significantly lower in the alprostadil-treated group than those found in the I/R-only group (P<0.0001, P=0.015, and P<0.01, respectively). Polymorphonuclear leukocyte infiltration, pulmonary partial destruction, consolidation, alveolar edema, and hemorrhage scores were significantly lower in alprostadil- and iloprost-treated groups (P=0.017 and P=0.001; P<0.01 and P<0.0001). Polymorphonuclear leukocyte infiltration scores in skeletal muscle tissue were significantly lower in the iloprost-treated group than the scores found in the nontreated I/R group (P<0.0001).. Alprostadil and iloprost significantly reduce lung tissue I/R injury. Alprostadil has more prominent protective effects against renal I/R injury, while iloprost is superior in terms of protecting the skeletal muscle tissue against I/R injury.

Topics: Alprostadil; Animals; Disease Models, Animal; Hindlimb; Iloprost; Kidney; Lung; Muscle, Skeletal; Rats; Rats, Wistar; Reperfusion Injury

Iloprost has the potential to protect the liver transplant graft before and during cold ischemia. We studied iloprost administration during organ procurement and reperfusion in an extracorporeal pig liver perfusion model.. German Landrace pigs (n = 7/group; 22-26 kg each) were used as donors. Preservation was performed by aortic perfusion with 2 L Bretschneiders' Histidine-Tryptophan-Ketoglutarate solution HTK and cold ischemia time (4°C) 20 hours followed by normothermic extracorporeal perfusion for 8 hours. Untreated controls (1) were compared to iloprost (2) donor bolus-treatment (1 μg/kg body weight), (3) addition of iloprost to Bretschneiders' Histidine-Tryptophan-Ketoglutarate solution HTK (0.0125 μg/mL), (4) continuous infusion during reperfusion (2 ng/kg/min), and (5) combined treatment (2) and (4).. Iloprost donor treatment led to significantly higher bile production. Addition of iloprost to the preservation solution significantly improved hepatic artery perfusion and was accompanied by improvements of microcirculation and bile production. Iloprost reperfusion treatment alone significantly improved bile production. Enzyme levels were positively affected by all treatment regimens. Combined use of iloprost before and after ischemia improved hepatic artery flow and microcirculation and showed significantly lower hypoxia staining versus controls.. Iloprost donor treatment and use of iloprost in the preservation solution significantly improved graft perfusion and function. The effects of graft treatment seemed greater before than after reperfusion. Combined treatment did not reveal a synergistic advantage.

Topics: Animals; Bile; Blood Flow Velocity; Cold Ischemia; Cytoprotection; Disease Models, Animal; Extracorporeal Membrane Oxygenation; Iloprost; Liver; Liver Circulation; Liver Transplantation; Microcirculation; Organ Preservation; Organ Preservation Solutions; Oxygen Consumption; Reperfusion Injury; Swine; Time Factors; Tissue and Organ Harvesting

The aim of this study was to investigate the effects of iloprost (IL) on ischemia-reperfusion injury in a rodent model.. Twenty-four Wistar Albino rats were randomized into four groups (n = 6). Laparotomy was performed in all groups under general anesthesia. Only laparotomy was applied in group S (Sham). Ischemia-reperfusion group (group I/R) underwent ischemia and reperfusion performed by clamping and declamping of the infrarenal abdominal aorta for 120 min. The iloprost group (group IL) received intravenous infusion of IL 0.5 ng/kg/min, without I/R. Group I/R + IL received intravenous infusion of IL 0.5 ng/kg/min immediately after 2 h period of ischemia. At the end of the reperfusion period, all rats were killed under anesthesia and skeletal muscle samples of lower extremity were harvested for biochemical and histopathologic analyses.. Tissue levels of endothelial nitric oxide were significantly higher in I/R groups than those in groups S and IL. The heat shock protein 60 levels were higher in group I/R than the other groups. But the heat shock protein 60 levels in group I/R + IL were found to be similar with the groups S and IL. Malondialdehyde levels were significantly higher in group I/R. On the other hand, in group I/R + IL, malondialdehyde levels were higher than those in groups S and IL but lower than those in group I/R. Superoxide dismutase (SOD) enzyme activities were found to be significantly lower in group I/R than the other groups. Also in group I/R/I, the SOD enzyme activities were higher than those in group I/R. But, in group I/R + IL, SOD levels were found to be higher than those in group I/R but lower than those in groups S and IL.. These results indicate that IL has protective effects on I/R injury in skeletal muscle in a rodent model.

Topics: Animals; Aorta, Abdominal; Chaperonin 60; Disease Models, Animal; Iloprost; Malondialdehyde; Muscle, Skeletal; Nitric Oxide; Nitric Oxide Synthase Type III; Random Allocation; Rats; Reperfusion Injury; Superoxide Dismutase; Vasodilator Agents

The aim of this study was to investigate the effects of iloprost, on colonic anastomotic healing in rats, under obstructive ileus conditions.. Eighty male Albino rats were randomized into four groups of 20 animals each. They underwent colonic resection followed by an inverted anastomosis. The rats of group 1 (control) and group 2 (ileus) received 3 mL of saline 0.9% intraperitoneally and those of group 3 (iloprost), and group 4 (ileus + iloprost) iloprost (2 μg/kg of body weight), immediately postoperatively and daily until the day of sacrifice. Each group was further divided into two equal subgroups, depending on the day of sacrifice. The animals of subgroup "a" were sacrificed on the fourth postoperative day, whereas those of "b" on the eighth day. Macroscopic and histologic assessment was performed, whereas anastomotic bursting pressures and the tissue concentrations in hydroxyproline and collagenase I were evaluated.. Means of bursting pressure, neoangiogenesis, fibroblast activity, and hydroxyproline concentration were significantly increased in group 4 compared with group 2. In addition, on the fourth postoperative day, the inflammatory cell infiltration and the collagenase I concentration were significantly decreased in group 4 compared with group 2. Moreover, on the eighth postoperative day, collagen deposition was significantly increased in group 4 compared with group 2.. Iloprost after intraperitoneal administration reverses the negative effect of obstructive ileus. It promotes not only the angiogenic activity but also collagen formation, resulting in increased bursting pressures on the fourth and eighth postoperative days.

Topics: Anastomosis, Surgical; Animals; Body Weight; Collagenases; Colon; Disease Models, Animal; Hydroxyproline; Ileus; Iloprost; Injections, Intraperitoneal; Male; Pressure; Random Allocation; Rats; Surgical Wound Dehiscence; Tissue Adhesions; Vasodilator Agents; Wound Healing

Prostacyclin (PGI2) is a biomolecule capable of enhancing angiogenesis and cellular proliferation.. We investigated the influence of a PGI2 analogue (iloprost) on dental pulp revascularization in vitro and in vivo by using human dental pulp cells (HDPCs) and a rat tooth injury model, respectively. Iloprost stimulated the human dental pulp cell mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and platelet-derived growth factor (PDGF) in a significant dose-dependent manner. This mRNA up-regulation was significantly inhibited by pretreatment with a PGI2 receptor antagonist and forskolin (a protein kinase A activator). In contrast, a protein kinase A inhibitor significantly enhanced the iloprost-induced mRNA expression of VEGF, FGF-2, and PDGF. Pretreatment with a fibroblast growth factor receptor inhibitor attenuated the VEGF, FGF-2, and PDGF mRNA expression, indicating opposing regulatory mechanisms.. The effect of iloprost on the dental pulp was investigated in vivo by using a rat molar pulp injury model. The iloprost-treated group exhibited a significant increase in pulpal blood flow at 72 hours compared with control.. The present study indicates that iloprost may be a candidate agent to promote neovascularization in dental pulp tissue, suggesting the potential clinical use of iloprost in vital pulp therapy.

Topics: Adolescent; Adult; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Animals; Cells, Cultured; Colforsin; Cyclic AMP-Dependent Protein Kinases; Dental Pulp; Dental Pulp Exposure; Disease Models, Animal; Dose-Response Relationship, Drug; Fibroblast Growth Factor 2; Humans; Iloprost; Molar; Neovascularization, Physiologic; Platelet-Derived Growth Factor; Rats; Receptors, Fibroblast Growth Factor; Regional Blood Flow; Vascular Endothelial Growth Factor A; Young Adult

Prostacyclin (PGI2), a member of the prostaglandin family, can promote angiogenesis and cell proliferation.. In this study, the effect of the application of a PGI2 analog (iloprost) on dentin repair was examined in vitro and in vivo.. Iloprost significantly stimulated the expression of vascular endothelial growth factor and osteo-/odontogenic marker messenger RNA in human dental pulp cells (HDPCs) under osteoinductive conditions in vitro. In addition, iloprost enhanced HDPC alkaline phosphatase enzymatic activity and mineral deposition. An in vivo study was performed using a rat molar mechanical pulp exposure model. After 30 days, histologic analysis revealed that there was a dramatic tertiary dentin formation in the iloprost-treated group compared with the calcium hydroxide and the untreated control groups. Furthermore, vascular endothelial growth factor protein expression in dental pulp tissue was increased in the iloprost-treated group as determined by immunohistochemical staining.. Taken together, the present study, for the first time, shows that iloprost induces the expression of osteo-/odontogenic markers in vitro and promotes angiogenic factor expression and enhances tertiary dentin formation in vivo. This implies the potential clinical usefulness of iloprost in vital pulp therapy.

Topics: Adult; Alkaline Phosphatase; Angiogenic Proteins; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Protein 4; Calcification, Physiologic; Calcium Hydroxide; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Dental Pulp; Dental Pulp Exposure; Dentin, Secondary; Disease Models, Animal; Humans; Iloprost; Male; Odontogenesis; Osteogenesis; Rats; Rats, Wistar; Transcription Factors; Vascular Endothelial Growth Factor A

Pulmonary hypertension (PH) is a life-threatening disease that causes endothelial dysfunction in the pulmonary vascular bed. Systemic endothelial dysfunction has also been reported in PH. This study compared the systemic and pulmonary vascular responses and some blood biomarkers of endothelial function in monocrotaline (MCT)-induced PH of rats. It also investigated the effect of sildenafil and iloprost treatment. MCT application induced elevation in the right ventricular pressures of the rat heart that had been reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated pulmonary artery were decreased in the PH group and this failure was reversed by sildenafil and iloprost treatment. Acetylcholine-induced endothelium-dependent relaxations of the isolated thoracic aorta were similar in all groups. Serotonin-induced contractions of the pulmonary artery were augmented by PH. In the isolated aorta, serotonin-stimulated contraction was not different in the control and MCT groups, but sildenafil and iloprost treatment decreased serotonin responses. The nitric oxide (NO) level in systemic circulation was not significantly changed by PH. However, sildenafil and iloprost treatments caused a decrease in the plasma level of NO. Asymmetric dimethylarginine levels in plasma were significantly decreased after MCT application and were not recovered by sildenafil and iloprost treatment. Total antioxidant capacity and H2S level of plasma were similar in all groups. Results of this study showed that MCT-induced PH caused specific toxic effects on pulmonary vasculature without any functional effects on the aorta. In addition, it was also demonstrated that sildenafil and iloprost treatments were effective in the MCT-induced PH.

Topics: Animals; Aorta, Thoracic; Arginine; Disease Models, Animal; Endothelium, Vascular; Hydrogen Sulfide; Hypertension, Pulmonary; Iloprost; Male; Monocrotaline; Nitric Oxide; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilation; Vasodilator Agents

Ischemia/reperfusion (I/R) damage of the lung is a frequently encountered complication following aortic surgery. The aim of the present study is to investigate the histopathological effects of Iloprost on pulmonary damage developed after I/R.. Twenty-four Sprague-Dawley rats were randomly divided into 3 groups. In the control group, aortas were not clamped. In the I/R group, aortas were occluded, and after 1 h of ischemia, clamps were removed. After 2 h of reperfusion period, lungs of the rats were extracted. In the I/R + Iloprost group after 1 h of ischemia, Iloprost infusion was initiated, and maintained for the duration of 2 h reperfusion period. For histopathological scoring, density of polymorphonuclear leucocytes, congestion, interstitial edema, and bleeding were semiquantitatively evaluated, and histopathological changes were scored.. In the I/R group, multifocal-marked histopathological changes in 5 (62.5%), and multifocal-moderate histopathological changes in 3 (37.5%) rats were detected. In the I/R + Iloprost group, multifocal-moderate histopathological changes in 4 (50%), and multifocal-mild changes in 4 (50%) rats were detected.. In the experimental rat model, administration of Iloprost has been shown to have preventive effects for pulmonary damage occurring after I/R generated by infrarenal aortic occlusion.

Topics: Animals; Aorta; Cardiovascular Agents; Cytoprotection; Disease Models, Animal; Drug Administration Schedule; Female; Iloprost; Infusions, Intravenous; Lung Injury; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors

The aim of our study was (1) the pharmacological characterization of EP(3) receptors in human pulmonary arteries and (2) the examination of the potential involvement of these receptors in the regulation of neurogenic tachycardia in pithed rats. L-826266 served as the EP(3) receptor antagonist.. Experiments were performed on isolated human pulmonary arteries and pithed rats.. The prostanoid EP(1)/EP(3) receptor agonist sulprostone (1 nM - 100 μM) concentration-dependently contracted isolated human pulmonary arteries (pEC50, 6.88 ± 0.10). The EP(1) receptor antagonist SC 19920 (100 μM) did not affect the vasoconstriction induced by sulprostone, the TP receptor antagonist sulotroban (10 μM) only slightly attenuated the effects elicited by sulprostone >>3 μM, whereas L-826266 (10 μM) shifted its concentration-response curve to the right (apparent pA(2) value 6.18; incubation time 0.5 h). In rings exposed to L-826266 (0.1, 1 or 10 μM) for 3 h, a concentration-dependent inhibitory effect against the sulprostone-induced vasoconstriction was obtained, yielding a Schild plot-based pA(2) value of 7.39. In pithed rats, sulprostone (10 - 1,000 nmol/kg), but not the IP/EP(1) receptor agonist iloprost (1-100 nmol/kg), inhibited the electrically evoked increase in heart rate (HR) dose-dependently, maximally by at least 80%. L-826266 (3 μmol/kg) did not affect basal HR and diastolic blood pressure, but reduced the inhibitory effect of sulprostone 1,000 nmol/kg by about 20%.. EP(3) receptors (1) located postsynaptically strongly contract human pulmonary arteries and (2) located presynaptically on sympathetic nerve fibers supplying the heart of pithed rats strongly inhibit the neurogenic tachycardia.

Topics: Acrylamides; Aged; Animals; Decerebrate State; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Heart Rate; Humans; Iloprost; Male; Middle Aged; Naphthalenes; Pulmonary Artery; Rats; Rats, Wistar; Receptors, Prostaglandin E, EP3 Subtype; Signal Transduction; Sulfonamides; Sympathetic Nervous System; Tachycardia; Vasoconstriction

Polymorphoneutrophils (PMNs) are activated by inflammatory mediators following splanchnic ischemia/reperfusion (I/R), potentially injuring organs such as the lung. As a result, some patients develop respiratory failure following abdominal aortic aneurysm repair. Pulmonary cyclooxygenase (COX)-2 protects against acid aspiration and bacterial instillation via lipoxins, a family of potent anti-inflammatory lipid mediators. We explored the role of COX-2 and lipoxin A(4) in experimental I/R-mediated lung injury.. Sprague-Dawley rats were assigned to one of the following five groups: (1) controls; (2) aortic cross-clamping for 45 min and reperfusion for 4 h (I/R group); (3) I/R and SC236, a selective COX-2 inhibitor; (4) I/R and aspirin; and (5) I/R and iloprost, a prostacyclin (PGI(2)) analogue. Lung injury was assessed by wet/dry ratio, myeloperoxidase (MPO) activity, and bronchoalveolar lavage (BAL) neutrophil counts. BAL levels of thromboxane, PGE(2), 6-keto-PGF(1)α (a hydrolysis product of prostacyclin), lipoxin A(4), and 15-epi-lipoxin A(4) were analyzed by enzyme immunoassay (EIA). Immunostaining for COX-2 was performed.. I/R significantly increased tissue MPO, the wet/dry lung ratio, and neutrophil counts. These measures were significantly further aggravated by SC236 and improved by iloprost. I/R increased COX-2 immunostaining and both PGE(2) and 6-keto-PGF(1α) levels in BAL. SC236 markedly reduced these prostanoids and lipoxin A(4) compared with I/R alone. Iloprost markedly increased lipoxin A(4) levels. The deleterious effect of SC236 and the beneficial effect of iloprost was associated with a reduction and an increase, respectively, in lipoxin A(4) levels.. Lipoxin A(4) warrants further evaluation as a mediator of COX-2 regulated lung protection.

Topics: Animals; Aspirin; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Iloprost; Lipoxins; Lung; Lung Injury; Male; Protective Agents; Pyrazoles; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sulfonamides

Prostanoid-modulatory approaches in heart failure patients have displayed effects which may seem to be mutually incompatible. Both treatment with prostanoids and inhibition of prostanoid synthesis have resulted in increased mortality in heart failure patients. Currently, it is unknown if prostanoids mediate contractile effects in failing human heart and if this can explain some of the clinical effects seen after prostanoid modulatory treatments. Therefore, the objectives of this study were to determine if prostanoids could elicit direct inotropic responses in human ventricle, and if so to determine if they are modified in failing ventricle. Contractile force was measured in left ventricular strips from non-failing or failing human and rat hearts. The ratio of phosphorylated to non-phosphorylated myosin light chain 2 (MLC-2) was measured by Western blotting in myocardial strips, and the levels of prostanoid FP receptor mRNA and protein were measured in rat by real-time RT-PCR and receptor binding assays. In non-failing human hearts, prostanoids evoked a positive inotropic effect and an increase of MLC-2 phosphorylation which was absent in failing human hearts. In failing rat heart, the prostanoid FP receptor-mediated inotropic response and prostanoid FP receptor-density was reduced by ~40-50% compared to non-failing rat heart. Prostanoids mediate a sustained positive inotropic response in non-failing heart, which appears to be down regulated in failing heart. The pathophysiological significance of changes in prostanoid-mediated inotropic support in the failing heart remains to be determined.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alprostadil; Animals; Cardiac Myosins; Child; Disease Models, Animal; Female; Heart Failure; Heart Ventricles; Humans; Iloprost; Male; Middle Aged; Myocardial Contraction; Myosin Light Chains; Prostaglandins F, Synthetic; Rats; Receptors, Prostaglandin; Ventricular Function

Experimental Study.. The aim of this study was to investigate the neuroprotective effects of iloprost and piracetam on spinal cord ischemia/reperfusion (I/R) injury in the rabbit.. The Experimental Research Center of Selcuk University, Konya, Turkey.. A total of 24 rabbits were divided into four groups of six rabbits each, as follows: group 1 (n = 6) sham, laparotomy only; group 2 (n = 6) I/R; group 3 (n = 6) I/R+iloprost; and group 4 (n = 6) I/R+piracetam. I/R was established in groups 2, 3 and 4. Subsequently, they were followed up neurologically for 24 h until the rabbits were killed; biochemical and histopathological examinations of samples from the spinal cord were carried out.. Neurological examination results were significantly better in the iloprost and piracetam groups compared with the I/R group (P < 0.05). Neuroprotection was achieved with iloprost and piracetam by suppressing malondialdehyde (P < 0.05), increasing glutathione peroxidase activity (P < 0.05) and decreasing the xanthine oxidase level. In histopathological assessment, iloprost and piracetam groups were statistically different from the I/R group in terms of the number of apoptotic neurons in gray matter and white matter, as well as in terms of degenerated neurons and glial cells (P < 0.05). No statistical difference was determined between the four groups in the number of degenerated glial cells (P > 0.05).. This study has shown that iloprost and piracetam have neuroprotective effects in I/R injury both neurologically and histopathologically because of inhibition of lipid peroxidation.

Topics: Animals; Antioxidants; Disease Models, Animal; Iloprost; Male; Piracetam; Rabbits; Reperfusion Injury; Spinal Cord Ischemia; Vasodilator Agents

The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.. Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).. BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.. The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Topics: Administration, Oral; Airway Resistance; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hypertension, Pulmonary; Iloprost; Infusion Pumps, Implantable; Infusions, Parenteral; Lung; Lung Volume Measurements; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins I; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Signal Transduction; Sildenafil Citrate; Sulfones; Tetrazoles; Time Factors; Vasoactive Intestinal Peptide; Vasodilator Agents

Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge.

Topics: Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Collagen; Cytokines; Dinoprostone; Disease Models, Animal; Drug Administration Schedule; Histocytochemistry; Humans; Iloprost; Infusion Pumps, Implantable; Leukocyte Count; Lung; Male; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Pulmonary Fibrosis; Real-Time Polymerase Chain Reaction; Severity of Illness Index

Mechanical ventilation at high tidal volume (HTV) may cause pulmonary capillary leakage and acute lung inflammation culminating in ventilator-induced lung injury. Iloprost is a stable, synthetic analog of prostaglandin I(2) used to treat pulmonary hypertension, which also showed endothelium-dependent antiedemagenic effects in the models of lung injury. To test the hypothesis that iloprost may attenuate lung inflammation and lung endothelial barrier disruption caused by pathologic lung distension and coagulation system component thrombin, we used cell and animal 2-hit models of ventilator-induced lung injury. Mice received a triple injection of iloprost (2 microg/kg, intravenous instillation) at 0, 40, and 80 min after the onset of HTV mechanical ventilation (30 mL/kg, 4h), combined with the administration of a thrombin receptor-activating peptide 6 (TRAP6, 3 x 10(-7)mol/mouse, intratracheal instillation). After 4h of ventilation, bronchoalveolar lavage (BAL), histologic analysis, and measurements of Evans blue accumulation in the lung tissue were performed. The effects of iloprost on endothelial barrier dysfunction were subsequently assessed in pulmonary endothelial cells (ECs) exposed to thrombin and pathologic (18%) cyclic stretch. The combination of HTV and TRAP6 enhanced the accumulation of neutrophils in BAL fluid and lung parenchyma, as well as increased the BAL protein content and endothelial permeability judged by Evans blue extravasation in the lung tissue. These effects were markedly attenuated by iloprost. The application of 18% cyclic stretch to pulmonary ECs enhanced the thrombin-induced EC paracellular gap formation and Rho-GTPase-mediated phosphorylation of regulatory myosin light chains and myosin phosphatase. Iloprost markedly inhibited the Rho-kinase-mediated site-specific phosphorylation of myosin phosphatase, and it prevented cyclic stretch- and thrombin-induced endothelial monolayer disruption. This study characterizes for the first time the protective effects of iloprost in the in vitro and in vivo 2-hit models of VILI and supports consideration of iloprost as a new therapeutic treatment of VILI.

Topics: Animals; Capillary Permeability; Cells, Cultured; Disease Models, Animal; Endothelial Cells; Humans; Iloprost; Lung; Male; Mice; Mice, Inbred C57BL; Oligopeptides; rho GTP-Binding Proteins; rho-Associated Kinases; Signal Transduction; Thrombin; Ventilator-Induced Lung Injury

Metabolites of arachidonic acid such as prostacyclin (PGI2) have been shown to participate in the pathogenesis of pulmonary fibrosis by inhibiting the expression of pro-inflammatory and pro-fibrotic mediators. In this investigation, we examined whether iloprost, a stable PGI2 analogue, could prevent bleomycin-induced pulmonary inflammation and fibrosis in a mouse model.. Mice received a single intratracheal injection of bleomycin with or without intraperitoneal iloprost. Pulmonary inflammation and fibrosis were analysed by histological evaluation, cellular composition of bronchoalveolar lavage (BAL) fluid, and hydroxyproline content. Lung mechanics were measured. We also analysed the expression of inflammatory mediators in BAL fluid and lung tissue.. Administration of iloprost significantly improved survival rate and reduced weight loss in the mice induced by bleomycin. The severe inflammatory response and fibrotic changes were significantly attenuated in the mice treated with iloprost as shown by reduction in infiltration of inflammatory cells into the airways and pulmonary parenchyma, diminution in interstitial collagen deposition, and lung hydroxyproline content. Iloprost significantly improved lung static compliance and tissue elastance. It increased the expression of IFNgamma and CXCL10 in lung tissue measured by RT-PCR and their levels in BAL fluid as measured by ELISA. Levels of TNFalpha, IL-6 and TGFbeta1 were lowered by iloprost.. Iloprost prevents bleomycin-induced pulmonary fibrosis, possibly by upregulating antifibrotic mediators (IFNgamma and CXCL10) and downregulating pro-inflammatory and pro-fibrotic cytokines (TNFalpha, IL-6, and TGFbeta1). Prostacyclin may represent a novel pharmacological agent for treating pulmonary fibrotic diseases.

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Bleomycin; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hydroxyproline; Iloprost; Inflammation Mediators; Injections, Intraperitoneal; Lung; Lung Compliance; Male; Mice; Mice, Inbred C57BL; Pneumonia; Pulmonary Fibrosis; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Weight Loss

There are several animal models for studying human pulmonary hypertension (PH). An increased flow model in pigs was developed at the University Hospital in Heidelberg in order to simulate congenital heart disease. The high pulmonary blood flow is achieved by installation of a Blalock-Taussig anastomosis. In order to further improve this model by adding a pressure component, the left pulmonary artery is ligated. An acute model, which is used at the Innsbruck Medical University, addresses another disease entity. Human meconium is placed deeply into the trachea of the pigs in order to induce an acute respiratory distress syndrome-like response in the lungs. Animals were randomly assigned to four treatment groups. Inhaled iloprost, due to its pulmonary and intrapulmonary selectivity, was the only substance that significantly reduced intrapulmonary shunt volumes. In humans, PH encompasses multiple disease subtypes. Pulmonary arterial hypertension (PAH) accounts for only 6% of PH cases, however, all existing treatments are indicated only for PAH. This means that for 94% of patients with PH, no specific medication is available. Therefore, huge efforts have been made to better understand the pathophysiology of PH and to detect new signalling pathways that may allow new compounds to be developed that will ultimately improve the prognosis of PAH and non-PAH PH patients. Promising new substances include riociguat, a stimulator of the soluble guanylate cyclase (sGC), as well as cinaciguat, a sGC activator, and an elastase inhibitor. Riociguat (BAY 63-2521) is an oral agent that targets the intact/native form of sGC. It enhances the sensitivity of sGC to low levels of bioavailable nitric oxide (NO) and is also capable of stimulating native sGC independently of NO. Thus, unlike phosphodiesterase-5 inhibitors, the effect of riociguat is not limited by low NO levels. In a multicentre open-label phase II study, riociguat exerted strong and significant effects on pulmonary haemodynamics and exercise capacity in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is currently being evaluated in phase III clinical trials both in PAH and in CTEPH patients. Clinical studies with riociguat in earlier development stages have addressed PH in lung diseases and systolic left ventricular failure. An elastase inhibitor is currently being investigated in phase I clinical trials in patients with PH owing to chronic obstructive pulmona

Topics: Animals; Disease Models, Animal; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Pyrazoles; Pyrimidines; Vasodilator Agents

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) are responsible for the majority of cases of heritable pulmonary arterial hypertension (PAH). Mutations lead to reduced Smad1/5-driven expression of inhibitor of DNA binding protein 1 (Id1) and loss of the growth suppressive effects of BMPs. The impact of existing PAH therapies on BMP signaling is lacking.. Because prostacyclin analogues are effective treatments for clinical PAH, we hypothesized that these agents enhance Smad1/Id1 signaling.. Iloprost alone induced Id1 expression in human pulmonary artery smooth muscle cells (PASMCs), an effect that was independent of Smad1/5 activation but dependent on a cAMP-responsive element in the Id1 promoter. In addition, iloprost and treprostinil enhanced BMP-induced phosphorylation of Smad1/5 and Id1 expression in a cAMP-dependent manner. The mechanism involved suppression of inhibitory Smad, Smad6. Furthermore, iloprost rescued the deficit in Smad1/5 phosphorylation and Id gene expression in PASMCs harboring mutations in BMPR-II and restored growth suppression to BMP4 in mutant PASMCs. We confirmed a critical role for Id1 in PASMC proliferation. Reduced expression of Id1 was observed in concentric intimal lesions of heritable PAH cases. In the monocrotaline rat model of PAH, associated with reduced BMPR-II expression, we confirmed that treprostinil inhibited smooth muscle cell proliferation and prevented progression of PAH while enhancing Smad1/5 phosphorylation and Id1 gene expression.. Prostacyclin analogues enhance Id1 expression in vitro and in vivo and restore deficient BMP signaling in BMPR-II mutant PASMCs.

Topics: Animals; Antihypertensive Agents; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II; Cell Proliferation; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Epoprostenol; Humans; Hypertension, Pulmonary; Iloprost; Inhibitor of Differentiation Protein 1; Male; Monocrotaline; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Phosphorylation; Promoter Regions, Genetic; Pulmonary Artery; Rats; Rats, Sprague-Dawley; RNA Interference; Smad Proteins; Smad1 Protein; Smad5 Protein; Smad6 Protein; Transfection; Up-Regulation

The aim of this study was to examine the effect of iloprost in renal injury induced by abdominal aortic ischemia-reperfusion (IR) and how it can modulate the expression of adhesion molecules during this effect. Twenty-four Wistar-Albino rats were randomized into three groups (n=8) as follows: control (sham laparotomy), aortic IR (120 min ischemia and 120 min reperfusion), and aortic IR + iloprost (0.45 microg/kg/hr intravenous infusion during 120 min reperfusion). Blood and renal tissue samples were obtained for biochemical analysis. A histological evaluation with both hematoxylin-eosin staining and immunostaining was also done. Biochemical analyses showed that aortic IR significantly increased (p<0.05 vs. control) whereas iloprost significantly decreased (p<0.05 vs. aortic IR) plasma levels of malondialdehyde, P-selectin, intercellular adhesion molecule-1 (ICAM-I), and tissue levels of malondialdehyde and catalase. Histological evaluation with immunostaining showed that aortic IR significantly increased (p<0.05 vs. control) whereas iloprost significantly decreased (p<0.05 vs. aortic IR) the immunoreactivity of P-selectin, tumor necrosis factor-alpha, CD11b, CD18, and ICAM-1. Hematoxylin-eosin staining showed that iloprost also attenuated the morphological changes associated with aortic IR. The results of this study show that iloprost reduces renal injury induced by aortic IR in rats and downregulates expression of adhesion molecules at both the local and systemic levels after aortic IR during this protective effect.

Topics: Animals; Aorta, Abdominal; Catalase; CD11b Antigen; CD18 Antigens; Cell Adhesion Molecules; Constriction; Disease Models, Animal; Down-Regulation; Female; Iloprost; Infusions, Intravenous; Intercellular Adhesion Molecule-1; Kidney; Kidney Diseases; Male; Malondialdehyde; P-Selectin; Rats; Rats, Wistar; Reperfusion Injury; Tumor Necrosis Factor-alpha; Vascular Surgical Procedures

Prostacyclin is a pulmonary vasodilator and is produced by prostacyclin synthase and stimulates adenylate cyclase (AC) via the prostacyclin receptor (IP) to produce cAMP. Forskolin is a direct stimulant of AC. Phosphodiesterase 3 hydrolyzes cAMP and is inhibited by milrinone.. To characterize the prostacyclin-AC-cAMP pathway in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN).. University-based laboratory animal facility.. Lambs delivered to time-dated pregnant ewes.. Fifth generation pulmonary arteries (PA) and lung parenchyma were isolated from control fetal lambs (n = 8) and fetal lambs with PPHN induced by antenatal ductal ligation (n = 9). We studied relaxation responses to various agonists (milrinone, forskolin, prostacyclin, and iloprost, a prostacyclin analog) that increase cAMP in PA after half-maximal constriction with norepinephrine and pretreatment with propranolol +/- indomethacin. Lung protein levels of prostacyclin synthase, IP, AC2, and phosphodiesterase 3A were analyzed by Western blot and cAMP by enzyme-linked immunoassay.. Milrinone relaxed control and PPHN PA and pretreatment with indomethacin significantly impaired this response. Relaxation to milrinone, prostacyclin, and iloprost were significantly impaired in PA from PPHN lambs. Pretreatment with milrinone markedly enhanced relaxation to prostacyclin and iloprost in PPHN PA, similar to relaxation in control PA. Relaxation to forskolin was similar in control and PPHN PAs indicating normal AC activity. Protein levels of prostacyclin synthase and IP were decreased in PPHN lungs compared with control, but AC2, cAMP, and phosphodiesterase 3A remained unchanged.. Prostacyclin and iloprost are dilators of PAs from PPHN lambs and their effect is enhanced by milrinone. This combination therapy may be an effective strategy in the management of patients with PPHN.

Topics: Animals; Animals, Newborn; Blotting, Western; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Hypertension, Pulmonary; Iloprost; Male; Milrinone; Pregnancy; Pregnancy, Animal; Probability; Pulmonary Artery; Random Allocation; Reference Values; Sensitivity and Specificity; Sheep, Domestic; Vasodilation

Pulmonary arterial hypertension (PAH) is a significant disease process characterized by elevated pulmonary vascular resistance leading to increased right ventricular afterload and ultimately progressing to right ventricular dysfunction and often death. Irreversible remodeling of the pulmonary vasculature is the hallmark of pulmonary hypertension and frequently leads to progressive functional decline in patients with PAH despite treatment with currently available therapies. Metabolites of the arachidonic acid cascade play an important homeostatic role in the pulmonary vasculature, and dysregulation of pathways downstream of arachidonic acid plays a central role in the pathobiology of PAH. Cyclooxygenase-2 (COX-2) is up-regulated in pulmonary artery smooth muscle cells (PASMC) and inflammatory cells during hypoxia and plays a protective role in the lung's response to hypoxia. We recently demonstrated that absence of COX-2 was detrimental in a mouse model of hypoxia-induced pulmonary hypertension. Exposure of COX-2 null mice to hypoxia resulted in severe pulmonary hypertension characterized by enhanced pulmonary vascular remodeling and significant up-regulation of the endothelin-1 receptor ET(A)R in the lung after hypoxia. Absence of COX-2 in vitro led to enhanced contractility of PASMC after exposure to hypoxia, which could be attenuated by iloprost, a prostaglandin I(2) analog. These findings suggest that selective inhibition of COX-2 may have detrimental pulmonary vascular consequences in patients with preexisting pulmonary hypertension or underlying hypoxemic lung diseases. Here, we discuss our recent data demonstrating the adverse consequences of COX-2 inhibition on pulmonary vascular remodeling and PASMC contractility.

Topics: Animals; Arachidonic Acid; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Humans; Hypertension, Pulmonary; Hypoxia; Iloprost; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Pulmonary Artery; Signal Transduction; Vasoconstriction; Vasodilator Agents

Inhaled NO (iNO) has an established role in the treatment of pulmonary hypertension (PH) in the newborn. However, costs and potential toxicity associated with iNO have generated interest in alternative inhaled selective pulmonary vasodilators such as iloprost. In a preterm lamb model of respiratory distress syndrome, we studied effects of increasing doses of iloprost followed by iNO on right ventricular pressure (RVP) and circulation including cerebral oxygenation. Fetal sheep were randomized to three doses (0.2-4 mg/kg) of iloprost (n = 9) or saline (n = 10), administered as 15-min inhalations with 15-min intervals after a 60-min postnatal stabilization. No differences were found in RVP, arterial PO2, or cardiac index according to treatment. The cerebral oxygenation, measured with near-infrared spectroscopy, deteriorated in control lambs, but not in iloprost lambs. Iloprost treatment followed by iNO resulted in a larger decrease (p = 0.007) in RVP than saline treatment followed by iNO. In conclusion, iloprost stabilized cerebral oxygenation and when followed by iNO had a larger effect on RVP than iNO alone. Although species differences may be relevant, these results suggest that iloprost should be studied in newborn infants for the treatment of PH.

Topics: Administration, Inhalation; Animals; Animals, Newborn; Disease Models, Animal; Female; Humans; Iloprost; Infant, Newborn; Infant, Premature; Nitric Oxide; Pregnancy; Random Allocation; Respiratory Distress Syndrome, Newborn; Sheep; Vasodilator Agents

Ovarian torsion is a surgical emergency affecting not only the ipsilateral ovary but also contralateral ovary. Although the conventional treatment is salpingo-oophorectomy, recent studies advocate detorsion. We hypothesized that iloprost, an analogue of prostacyclin with cytoprotective properties, may prevent the harmful effects of ischaemia-reperfusion injury in bilateral ovaries after unilateral ovarian torsion-detorsion in rat. In this study, 24 female Wistar-albino female rats were divided into four groups. Ovarian torsion was produced by applying vascular clamps to right ovaries. In Group I, bilateral oophorectomy was performed. In group II, bilateral oophorectomy was performed after a unilateral torsion period of 4h. In group III, bilateral ovaries were removed, following unilateral torsion-detorsion periods each lasted for 4h. Saline was injected i.p. 30 min before detorsion. In group IV, same experimental protocol, which was conducted in group III, was repeated. Iloprost was injected i.p. 30 min before detorsion instead of saline in group IV. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), which are the indicators for oxidative stress were determined and histopathological evaluation was performed in bilateral ovaries in all groups. The MDA and NO levels for ipsilateral ovaries of four groups were compared and no significant difference was found (p>0.05). The same comparison were done for the contralateral sides and no difference was seen either (p>0.05). In histological examination, iloprost produced improvement in I/R-induced alterations in ipsilateral and contralateral ovaries. In conclusion, these results showed that iloprost has beneficial effect on the histological appearances in both the ipsilateral and contralateral rat ovaries after unilateral torsion-detorsion.

Topics: Animals; Disease Models, Animal; Female; Iloprost; Ovarian Diseases; Ovary; Oxidative Stress; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Reperfusion Injury

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Carrageenan; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Hyperalgesia; Ligands; Mice; Molecular Structure; Pain; Peritonitis; Quinazolines; Rats; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship

We investigated the effects of iloprost and pentoxifylline on skeletal muscle ischemia-reperfusion injury in a rabbit model.. Forty New Zealand white rabbits were grouped into four. In Group 1, iloprost was continuously infused starting half an hour before the reperfusion following a 2-hour ischemia formed by abdominal aortic occlusion, and it was continued during the 4-hour reperfusion period. Group 2 was treated with pentoxifylline, and Group 3 received saline solution. Group 4 was the sham group. Malondialdehyde levels and edema scores in gastrocnemius muscle were evaluated.. Edema score was significantly lower in Group 1 when compared with the control group (Group 1 vs Group 3, p=0.040; Group 2 vs Group 3, p=0.145; Group 1 vs Group 2, p=0.580). Malondialdehyde levels of the medicated groups were significantly lower when compared with the control group (Group 1: 60+/-11 nmol/g tissue, Group 2: 74+/-11 nmol/g tissue, Group 3: 95+/-10 nmol/g tissue; Group 1 vs Group 2, p=0.010; Group 1 vs Group 3, p<0.001; Group 2 vs Group 3, p<0.001; Group 1 vs Group 4, p<0.001; Group 2 vs Group 4, p<0.001; Group 3 vs Group 4: p<0.001).. Acute skeletal muscle ischemia is a common problem. We are of the opinion that in the early phase of skeletal muscle ischemia, iloprost and pentoxifylline medication may reduce ischemia-reperfusion injury.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Edema; Female; Humans; Iloprost; Male; Malondialdehyde; Muscle, Skeletal; Pentoxifylline; Platelet Aggregation Inhibitors; Rabbits; Random Allocation; Reperfusion Injury; Treatment Outcome; Vasodilator Agents

The effects of iloprost on ischemia-reperfusion injury have been studied on the skeletal, muscle, liver, myocardium, kidney, and spinal cord. However, no sufficient data exist about effects of levosimendan on renal ischemia-reperfusion injury. The purpose of this experimental study was to investigate and compare effectiveness of levosimendan and iloprost on renal injury induced by ischemia and reperfusion. Fifty rabbits were divided into five groups. Levosimendan was continuously infused starting half an hour before the cross-clamp. Cross-clamp time was one hour. After one hour ischemia, levosimendan was continued for 4 h in Group A whereas Group B took iloprost in the same protocol. Group C was the control group which did not receive any medication. Group D was sham group and Group E was medicated both iloprost and levosimendan. Renal tissues were histologically and biochemically evaluated. The histological scores were obtained according to presence of tubular necrosis and atrophy, regenerative atypia, hydropic degeneration (Group A vs. Group C<0.001, Group B vs. Group C<0.001, Group D vs. Group C<0.01, Group E vs. Group C<0.001). Mean malondialdehyde levels were 114+/-12 nmol/g tissue; in Group A 121+/-13 nmol/g tissue, in Group B 134+/-13 nmol/g tissue, in Group E 130+/-11 nmol/g tissue, in Group D 134+/-11 nmol/g tissue (Group A vs. Group B; P=0.003, Group B vs. Group D; P=0.132, Group A vs. Group E; P=0.132). Malondialdehyde levels and histologic scores of all of the groups were significantly different from the control group. Iloprost and pentoxyfillin reduced renal ischemia-reperfusion injury in rabbit model. There was no significant difference between these two medications.

Topics: Animals; Atrophy; Disease Models, Animal; Female; Hydrazones; Iloprost; Kidney; Kidney Diseases; Lipid Peroxidation; Male; Malondialdehyde; Necrosis; Protective Agents; Pyridazines; Rabbits; Reperfusion Injury; Simendan

The aim of this study was to clarify whether levosimendan could prevent lung tissue injury from limb ischemia/reperfusion.. The common femoral arteries of 50 New Zealand white rabbits, both male and female, each weighing about 3 kg, were clamped and 1 h of ischemia followed by 4 h of reperfusion. In an attempt to decrease reperfusion injury, the rabbits were given levosimendan in Group A. In Group B, iloprost was infused at the same period. A similar value of saline solution was given in the control group, Group C correspondingly. Levosimendan and iloprost were given together the Group E, and Group D was sham group without medication and ischemia. Blood pH, pO2, pCO2, HCO3, Na, K, creatine phosphokinase, lactate dehydrogenase values were determined at the end of the reperfusion period. Malondialdehyde (MDA) was measured in plasma and lung as an indicator of free radicals. Hemodynamics parameters were noted for each group. After the procedure, left lung tissues were taken for histopathologic study.. Blood PO2 and HCO3 levels were significantly higher (P < 0.05) and creatine phosphokinase, lactate dehydrogenase, and MDA levels were significantly lower (P < 0.05) in Groups A, B, D, and E compared with Group C. Similarly, the MDA levels in the lung tissue and plasma levels were significantly lower in the treatment groups compared with the control group (P < 0.05). Lung damage was significantly higher in Group C. There was no significant difference between groups in other parameters.. The results suggest that levosimendan and iloprost are useful for attenuating oxidative lung damage occurring after a period of limb ischemia/reperfusion.

Topics: Animals; Disease Models, Animal; Extremities; Female; Hydrazones; Iloprost; Lung; Male; Malondialdehyde; Pyridazines; Rabbits; Reperfusion Injury; Simendan

The rapid desensitization of the human prostacyclin (IP) in response to agonist binding has been shown in cell culture. Phosphorylation of the IP receptor by protein kinase C (PKC) has been suggested to be involved in this process.. In this study we investigated the vasodilatory effects of iloprost, a stable prostacyclin analogue, in perfused rabbit lungs. Continuous infusion of the thromboxane mimetic U46619 was employed to establish stable pulmonary hypertension. A complete loss of the vasodilatory response to iloprost was observed in experiments with continuous iloprost perfusion, maintaining the intravascular concentration of this prostanoid over a 180 min period. When lungs under chronic iloprost infusion were acutely challenged with inhaled iloprost, a corresponding complete loss of vasoreactivity was observed. This desensitization was not dependent on upregulation of cAMP-specific phosphodiesterases or changes in adenylate cyclase activity, as suggested by unaltered dose-response curves to agents directly affecting these enzymes. Application of a prostaglandin E1 receptor antagonist 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH 6809) or the PKC inhibitor bisindolylmaleimide I (BIM) enhanced the vasodilatory response to infused iloprost and partially prevented tachyphylaxis.. A three-hour infusion of iloprost in pulmonary hypertensive rabbit lungs results in complete loss of the lung vasodilatory response to this prostanoid. This rapid desensitization is apparently not linked to changes in adenylate cyclase and phosphodiesterase activation, but may involve PKC function and co-stimulation of the EP1 receptor in addition to the IP receptor by this prostacyclin analogue.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Cell Culture Techniques; Colforsin; Cyclic AMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Female; Hypertension, Pulmonary; Iloprost; Infusions, Parenteral; Lung; Male; Myocytes, Smooth Muscle; Rabbits; Receptors, Epoprostenol; Vasodilator Agents

Inhalation of iloprost, a stable prostacyclin (PGI(2)) analog, is a well-accepted and safe treatment for pulmonary arterial hypertension. Although iloprost mainly acts as a vasodilator by binding to the I prostanoid (IP) receptor, recent evidence suggests that signaling via this receptor also has antiinflammatory effects through unclear mechanisms. Here we show in a murine model of asthma that iloprost inhalation suppressed the cardinal features of asthma when given during the priming or challenge phase. As a mechanism of action, iloprost interfered with the function of lung myeloid DCs, critical antigen-presenting cells of the airways. Iloprost treatment inhibited the maturation and migration of lung DCs to the mediastinal LNs, thereby abolishing the induction of an allergen-specific Th2 response in these nodes. The effect of iloprost was DC autonomous, as iloprost-treated DCs no longer induced Th2 differentiation from naive T cells or boosted effector cytokine production in primed Th2 cells. These data should pave the way for a clinical effectiveness study using inhaled iloprost for the treatment of asthma.

Topics: Administration, Inhalation; Animals; Anti-Asthmatic Agents; Asthma; Cell Differentiation; Dendritic Cells; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Iloprost; Lung; Mice; Mice, Inbred BALB C; Mice, Transgenic; Ovalbumin; Th2 Cells

The aim of this study was to investigate whether iloprost injected intraperitoneally immediately after colon resection can improve anastomotic healing on the fifth and eighth postoperative days.. Forty Wistar rats were randomised into 2 equal groups. After the resection of a 1 cm segment of transverse colon, an end to end sutured anastomosis was generated. From the day of the operation, group 1 (control) received intraperitoneal 3 cc saline solution once daily until sacrifice, while group 2 (iloprost) received iloprost in a dose of 2 mg/kg body weight intraperitoneally once daily until sacrifice. Each group was further randomly divided into 2 equal subgroups and animals were sacrificed on the fifth (subgroup A), and eighth (subgroup B) postoperative days. After sacrifice, anastomoses were examined macroscopically and were measured for bursting pressures and tissue hydroxyproline levels while anastomotic healing process was evaluated histopathologically.. None of the rats exhibited any clinical evidence of leakage and there were no instances of peri-anastomotic abscess or peritonitis. Bursting pressure on the fifth postoperative day was significantly higher in the iloprost group than in the control group (P<0.001), while on the eighth postoperative day, bursting pressure was higher in the iloprost group but not significantly different (P=0.165). On both the fifth and eighth postoperative days rats in the iloprost group developed significantly more marked neo-angiogenesis and, in parallel with this, there was a trend showing a higher inflammatory cell infiltration.. The intraperitoneal administration of iloprost promoted neo-angiogenesis and enhanced colonic healing on the fifth postoperative day.

Topics: Anastomosis, Surgical; Angiogenesis Inducing Agents; Animals; Colon; Disease Models, Animal; Epoprostenol; Iloprost; Injections, Intraperitoneal; Random Allocation; Rats; Rats, Wistar; Wound Healing

The objectives of this study were to compare the protective effects of ascorbic acid and iloprost on lung injury caused by ischemia reperfusion (I/R) of the lower extremities of rats. Wistar albino rats (n = 34) were divided into five groups. In the I/R group (n = 6), the aorta was cross-clamped for 3 hr, followed by 1 hr of reperfusion. In the vitamin C group (n = 8), animals were pretreated with 100 mg/kg ascorbic acid via the left jugular vein before aortic cross-clamping. In the iloprost group (n = 8), animals were pretreated with 20 ng/(kg x min) iloprost by constant intravenous infusion via the left jugular venous cannula. In the sham group (n = 6), the abdomen was left open at the same period and a juguler venous line was established. In the control group (n = 6), lungs were removed and blood samples taken immediately after sternotomy. No treatment was given in this group. After both lungs were removed, biochemical parameters were measured and histopathological evaluation was made. Although the arterial blood pO2 and HCO3 levels were statistically significantly high in both the vitamin C and iloprost groups compared to the I/R group, plasma malondialdehyde (MDA) levels were significantly low. Meanwhile, the MDA levels in the lung tissue were significantly low in the vitamin C group compared to the I/R group. The MDA level in the lung tissue in the iloprost group was also low compared to the I/R group, but it was not statistically significant. The lungs of the I/R group displayed intense interstitial leukocytic infiltration in histopathological examination compared to the other groups. Pretreatment of animals with iloprost and vitamin C significantly decreased the pulmonary injury characterized by decreased plasma leukocyte sequestration. The results suggest that both vitamin C and iloprost are useful agents for attenuating the lung injury caused by increased oxidative stress and neutrophil accumulation after a period of I/R of the lower extremities.

Topics: Animals; Aorta, Abdominal; Ascorbic Acid; Constriction; Disease Models, Animal; Free Radical Scavengers; Iloprost; Lipid Peroxidation; Lung; Neutrophils; Platelet Aggregation Inhibitors; Pulmonary Edema; Rats; Rats, Wistar; Reperfusion Injury

In ischemia-reperfusion, Iloprost decreases neutrophil activation and aggregation besides inhibition of oxygen-free radical production. Pentoxifylline (Ptx) attenuates reperfusion-associated membrane injury and tissue edema, suppresses leukocyte adhesion and improves hindlimb blood flow during the reperfusion period. The primary hypothesis in this study was that Iloprost could present better protection than pentoxyfillin on renal ischemia-reperfusion in rabbit model.. Forty rabbits were grouped into four. Iloprost was continuously infused starting half an hour before the reperfusion after 2 hours ischemia and during the 4 hours reperfusion period in Group 1 whereas the Group 2 was treated with pentoxyfillin. Group 3 was the control group which didn't receive any medication. Forth group was sham group. Renal tissues were histologically and biochemically evaluated.. The histologic scores were obtained according to presence of tubuler necrosis and atrophy, regenerative atypia, hydropic degeneration (Group 1 vs Group 3; p<0.001, Group 2 vs Group 3; p = 0.001, Group 1 vs Group 2; p = 0.331). Malondialdehyde levels of the medicated groups were 109 +/- 11 nmol/gr tissue in Group 1, 119 +/- 15 nmol / gr tissue in Group 2 and 132 +/- 14 nmol / gr tissue in Group 3 (Group 1 vs Group 2; p = 0.130, Group 1 vs Group 3, p = 0.002, Group 2 vs Group 3; p = 0.045). Malondialdehyde levels and histologic scores of all of the groups were significantly different from the sham group.. Iloprost and pentoxyfillin reduced renal ischemia-reperfusion injury in rabbit model. There was not a significant difference between these two medications.

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Female; Iloprost; Kidney; Kidney Cortex; Kidney Tubules; Lipid Peroxidation; Male; Malondialdehyde; Pentoxifylline; Platelet Aggregation Inhibitors; Rabbits; Reperfusion Injury; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

Pulmonary hypertension, and consequently right ventricular failure, complicates several congenital heart defects. Although intervention in the prostacyclin-thromboxane ratio is known to improve outcome, the underlying mechanism is not clear. Therefore, effects of acetyl salicylic acid and iloprost are studied in an animal model for flow-associated pulmonary hypertension. Male Wistar rats with flow-associated pulmonary hypertension, an aortocaval shunt in addition to monocrotaline induced pulmonary hypertension, were treated with low-dose aspirin (25 mg/kg/day) or iloprost (72 microg/kg/day). Effects on pulmonary hemodynamics and pulmonary vascular remodeling as well as right ventricular hemodynamics and remodeling were evaluated. Ninety percent (n=7/8) of the untreated pulmonary hypertensive rats developed dyspnea and pleural fluid, whereas this was seen in 50% (n=4/8, ns) and 10% (n=1/8, P<0.05 vs. untreated animals) of the aspirin and iloprost-treated rats, respectively. This could not be attributed to changes in pulmonary artery pressure, wall-lumen ratio of the pulmonary vasculature or right ventricular hypertrophy. However, both therapies restored reduced right ventricular capillary to myocyte ratio in pulmonary hypertensive rats (0.95+/-0.10 in untreated rats vs. 1.38+/-0.18 in control animals; P<0.05, and 1.32+/-0.11 in aspirin-treated and 1.29+/-0.9 in iloprost-treated rats; both P<0.05 vs. non-treated animals), which was associated with improved right ventricular contractility (iloprost). Thus, interventions in the prostacyclin-thromboxane metabolism improve outcome in rats with flow-associated pulmonary hypertension. However, these effects may be attributed to effects on cardiac rather than on pulmonary vascular remodeling.

Topics: Animals; Arachidonic Acid; Aspirin; Blood Pressure; Capillaries; Disease Models, Animal; Echocardiography; Gene Expression; Heart Ventricles; Hypertension, Pulmonary; Iloprost; Lung; Male; Myocardium; Organ Size; Platelet Aggregation Inhibitors; Pulmonary Artery; Pulmonary Circulation; Rats; Rats, Wistar; Receptors, Vascular Endothelial Growth Factor; Survival Rate; Vascular Endothelial Growth Factor A; Ventricular Remodeling

The optimal strategy for pulmonary graft preservation remains elusive. Experimental work and initial clinical experience support low-potassium dextran solutions as lung perfusates. We have previously shown a protective effect of prostaglandin E 1 on ischemia-reperfusion injury in lung transplantation by a shift from proinflammatory to anti-inflammatory cytokines in a rat lung transplantation model. In this study, we tested the hypothesis that the addition of a prostacyclin analog (iloprost) to low-potassium dextran might lead to improved surfactant and ultimately graft function.. In a randomized, blinded study with a porcine left single-lung transplantation model, donor lungs were flushed with 1 L of either low-potassium dextran solution or low-potassium dextran solution modified by the addition of 250 microg iloprost (n = 6 in each group). Grafts were stored at 4 degrees C for 24 hours. After transplantation, the right bronchus and pulmonary artery were clamped, and the animals remained dependent on the graft. Posttransplantation graft function was assessed throughout a 7-hour observation period by measuring oxygenation (30-minute intervals), different pulmonary and systemic hemodynamic parameters, and wet/dry lung weight ratios. Bronchoalveolar lavage fluid was obtained before and 2 hours after reperfusion. Surfactant function was measured from bronchoalveolar lavage fluid with a pulsating bubble surfactometer. Neutrophil sequestration was assessed by a myeloperoxidase assay performed on lung tissue specimens taken at the end of the observation period.. Pulmonary vascular resistance remained lower in the iloprost group than in the control group (P < .05). Tissue water content after 7 hours of reperfusion remained lower in the iloprost group (P < .05). In addition, significantly reduced myeloperoxidase tissue activity was observed in the iloprost group (P < .05). Although there was no difference in degradation of surface active surfactant large aggregates to small aggregates, the surface tension measured at minimal bubble diameter was lower in the iloprost group (P < .05).. Modification of low-potassium dextran solution with the prostacyclin analog iloprost resulted in a significant amelioration of ischemia-reperfusion injury and improved preservation of surfactant function in transplanted lungs. This intriguing approach merits further evaluation with respect to the mechanisms involved and, ultimately, potential introduction into clinical lung transplantation.

Topics: Animals; Disease Models, Animal; Female; Graft Rejection; Graft Survival; Iloprost; Lung Transplantation; Male; Organ Preservation; Organ Preservation Solutions; Peroxidase; Probability; Pulmonary Surfactants; Random Allocation; Reference Values; Reperfusion Injury; Sensitivity and Specificity; Surface Tension; Swine

Iloprost, a prostacyclin analogue with a prolonged plasma half-life has beneficial effects in chronic pulmonary hypertension, whereas the effects in acute lung injury (ALI) are unknown. The present study was performed to evaluate the cardiopulmonary effects of iloprost in experimental ALI. ALI was induced in 18 pigs by repeated lung lavage. Animals were randomised to controls, i.v. or inhaled iloprost for 15 min. Haemodynamics, gas exchange and ventilation-perfusion distribution were measured at the end of iloprost application and after 1 and 2 h. As a short-term effect, both i.v. and inhaled iloprost significantly decreased pulmonary artery pressure without major effects on gas exchange or systemic haemodynamics. After 1 and 2 h, a reduction of pulmonary hypertension was no longer present. As a long-term effect, inhaled, but not i.v., iloprost decreased pulmonary shunt and significantly improved gas exchange after 1 and 2 h. In conclusion, the single application of iloprost revealed short-term pulmonary vasodilation without other major cardiopulmonary effects. However, inhaled iloprost improved gas exchange due to a decrease of pulmonary shunt as a long-term effect, possibly as a result of a reduction of lung oedema formation.

Topics: Acute Disease; Administration, Inhalation; Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Lung Diseases; Lung Injury; Probability; Pulmonary Circulation; Pulmonary Gas Exchange; Random Allocation; Swine

Spinal cord ischemia may develop into paraplegia in some cases during operation of the thoracoabdominal aorta. This is attributable to the vulnerability of spinal motor neurons to ischemia. In this study, iloprost was used as an agent to decrease the severity of ischemia and reperfusion injury to the spinal cord motor neurons. Twenty-one rabbits were randomized into three groups of seven animals each: group A (iloprost not administered), group B (25 ng/kg per minute iloprost), and group S (sham-operated). The spinal cord ischemia model was created by a 15-min occlusion of the aorta just caudal to the renal artery with a balloon catheter. Administration of iloprost began 10 min before occlusion of the aorta, and continued thereafter for 60 min. The pre- and postocclusion arterial pressure and heart rate recordings, results of blood gas analyses, and hematocrit and glucose levels were recorded. The spinal cords were removed after 8-h monitoring of neurologic function. Viable and nonviable motor neurons in the anterior horn of the spinal cord were counted under light microscopy. Any significant alteration in hemodynamics, blood gases, and other physiologic parameters could not be detected within the groups. Iloprost had a moderately hypotensive effect. Neurologic function in terms of Johnson scoring was significantly better in the iloprost group (P<0.05). The number of viable cells was higher, whereas the number of nonviable cells was lower in iloprost group, when compared with the control group (P<0.05). Higher numbers of viable motor neurons were consistent with the neurological findings. As a result of this study we concluded that iloprost infused during clamping of the aorta mitigates the spinal cord injury due to ischemia and reperfusion, and has a significant protective effect.

Topics: Animals; Blood Gas Analysis; Blood Pressure; Cell Survival; Disease Models, Animal; Heart Rate; Iloprost; Motor Neurons; Neurologic Examination; Neuroprotective Agents; Rabbits; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Time Factors

Ischemia-reperfusion injury accounts for one-third of early deaths after lung transplantation. To expand the limited donor pool, lung retrieval from non-heart beating donors (NHBD) has been introduced recently. However, because of potentially deleterious effects of warm ischemia on microvascular integrity, use of NHBD lungs is limited by short tolerable time periods before preservation. After intravenous prostanoids are routinely used to ameliorate reperfusion injury, the latest evidence suggests similar efficacy of inhaled prostacyclin. Therefore, the impact of donor pretreatment with the prostacyclin analogue iloprost on postischemic NHBD lung function and preservation quality was evaluated.. Asystolic pigs (5 per group) were ventilated for 180 minutes of warm ischemia (Group 2). In Group 3, 100 microg iloprost was aerosolized during the final 30 minutes of ventilation with a novel mobile ultrasonic nebulizer. Lungs were then retrogradely preserved with Perfadex and stored for 3 hours. After left lung transplantation and contralateral lung exclusion, hemodynamics, rO2/FiO2, and dynamic compliance were monitored for 6 hours and compared with sham-operated controls (Group 1). Pulmonary edema was determined both stereologically and by wet-to-dry weight ratio (W/D). Statistics comprised analysis of variance with repeated measures and Mann-Whitney test.. Flush preservation pressures, dynamic compliance, inspiratory pressures, and W/D were significantly superior in iloprost-treated lungs, and oxygenation and pulmonary hemodynamics were comparable between groups. Stereology revealed a trend toward lower intraalveolar edema formation in iloprost-treated lungs compared with untreated grafts.. Alveolar deposition of Iloprost and NHBD lungs before preservation ameliorates postischemic edema and significantly improves lung compliance. This easily applicable innovation approach, which uses a mobile ultrasonic nebulizer, offers an important strategy for improvement of pulmonary preservation quality and might expand the pool of donor lungs.

Topics: Aerosols; Animals; Disease Models, Animal; Epoprostenol; Female; Heart Arrest, Induced; Iloprost; Injections, Intravenous; Lung Compliance; Lung Transplantation; Organ Preservation; Organ Size; Prostaglandins; Random Allocation; Reperfusion Injury; Swine; Tissue Donors; Vasodilator Agents

We attempted to determine whether activation of the sensory neuron contributes to reduction of endotoxin-induced hypotension by inhibiting tumor necrosis factor (TNF)-alpha production via calcitonin gene-related peptide (CGRP) release in rats.. Prospective, randomized, controlled study.. Research laboratory at a university medical center.. Wistar rats weighing 220-280 g.. Mean arterial blood pressure was measured in rats administered endotoxin intravenously. Animals were pretreated with capsazepine (a vanilloid receptor antagonist), CGRP(8-37) (a CGRP receptor antagonist), and indomethacin before endotoxin administration. Levels of CGRP, 6-keto-prostaglandin F1alpha, TNF-alpha, and cytokine-induced neutrophil chemoattractant (CINC) were measured by enzyme immunoassay methods. The concentration of NO2/NO3 was measured using the Griess reagent. Tissue levels of messenger RNA of the inducible form of nitric oxide synthase (iNOS) and TNF-alpha were determined by reverse transcription polymerase chain reaction.. Both lung levels of CGRP and plasma levels of 6-keto-prostaglandin F1alpha were increased after intravenous administration of endotoxin (5 mg/kg), peaking at 90 mins after endotoxin administration. Increases in plasma levels of 6-keto-prostaglandin F1alpha at 90 mins after endotoxin administration (766 +/- 134 pg/mL) were inhibited by pretreatment with capsazepine (373 +/- 44 pg/mL, p < .05), CGRP(8-37) (406 +/- 64 pg/mL, p < .05), and indomethacin (154 +/- 40 pg/mL, p < .05). Although none of the pretreatments affected a series of endotoxin-induced responses, including increases in lung tissue levels of TNF-alpha, CINC, and iNOS and the resultant hypotension in animals given 5 mg/kg endotoxin, such pretreatments enhanced these pathologic responses in animals given a smaller dose of endotoxin (1 mg/kg) to the same extent as those induced by 5 mg/kg of endotoxin, suggesting that shock responses induced by 5 mg/kg endotoxin are maximum responses and activation of sensory neurons in endotoxin-treated rats is essentially a reparative response.. Activation of sensory neurons might contribute to reduction of endotoxin-induced hypotension by releasing CGRP, which is capable of promoting endothelial production of prostacyclin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Calcitonin Gene-Related Peptide; Capsaicin; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxins; Hypotension; Iloprost; Indomethacin; Interleukin-16; Lung; Neurons, Afferent; Nitric Oxide Synthase; Prospective Studies; Rats; Rats, Wistar; Reference Values; Tumor Necrosis Factor-alpha; Vasodilator Agents

Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH.. The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats.. Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline.. After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed.. We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Hypertension, Pulmonary; Iloprost; Monocrotaline; Pulmonary Artery; Rats; Rats, Wistar; Vasodilator Agents; Ventricular Pressure

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of PPA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Drug Combinations; Drug Synergism; Female; Hypertension, Pulmonary; Iloprost; Lung; Male; Phosphodiesterase Inhibitors; Rabbits; Treatment Outcome; Vasodilation

Recent studies on prostanoids showed that some of prostanoid receptors are expressed in rat dorsal root ganglion (DRG) neurons. These facts suggest that prostanoid receptors might be involved in the excitation mechanism of DRG neurons. In the present study, PCR experiments revealed that one of prostanoid receptor, prostacyclin receptor (IP receptor) was expressed in L6 and S1 rat DRG neurons and that the expression of IP receptor was not changed in DRG neurons obtained from the cyclophosphamide (CYP)-induced cystitis rat. We examined the functional role of IP receptor agonist and other prostanoids by measuring cyclic AMP (cAMP) accumulation and substance P (SP) release in primary cultured DRG neurons. The pretreatment of DRG neurons with prostanoid agonists such as iloprost (IP), butaprost (EP(2)), misoprostol (EP(2-4)), PGE(2) (EP(1-4)) or PGD(2) (DP and CRTH2) sensitized the DRG neurons and hence potentiated the lys-bradykinin-induced SP release. The increase of SP release by lys-BK plus prostanoid agonists was proportion to cAMP accumulation. Iloprost was the most potent agonist to induce cAMP accumulation and SP release among prostanoid agonists evaluated in this study and its effect is mediated by IP receptor. Moreover, capsaicin-, ATP- and KCl-induced SP release was also enhanced by iloprost although iloprost did not change intracellular Ca(2+) and membrane depolarization induced by these chemical stimuli. These results strongly indicate that IP receptor play an important role in the sensitization of rat sensory neuron.

Topics: Animals; Animals, Newborn; Capsaicin; Cells, Cultured; Cyclic AMP; Cystitis, Interstitial; Disease Models, Animal; Female; Ganglia, Spinal; Iloprost; Inflammation Mediators; Membrane Potentials; Neurons, Afferent; Nociceptors; Pain; Potassium Chloride; Prostaglandins; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Substance P; Vasodilator Agents

The effects of stable prostacyclin analogue iloprost on the trypsinogen activation, labilization of lysosomal membranes, lipolytic enzymes activities, histopathological and ultrastructural changes in the pancreas of rats with severe, taurocholate acute pancreatitis (AP), preceded for 6 h by acute ethanol intake have been investigated. Iloprost (1 microg/kg b.w., i.p.) was applied every 6 hours after inducing of taurocholate AP. The antecedent intragastric 40% ethanol intake (5 g/kg b.w.) increased an index of trypsinogen activation in AP lasting 18 h. Treatment with iloprost prevented this increase in the rats with AP given earlier alcohol, and limited the labilization of lysosomal membranes in nonalcoholized rats with AP. Phospholipase A2 and lipase activities were reduced by iloprost only in the rats not given ethanol. The additional damaging effect of acute ethanol abuse prior to AP could be dependent on augmented activation of trypsinogen. The protective effect of iloprost in AP seems to be dependent on the attenuation of trypsinogen activation, decrease of total potential trypsin and the decrease of lysosomal membranes labilization. Its protective effect could be limited in taurocholate acute pancreatitis preceded by acute ethanol intake as evidenced by the differences in the cathepsin B, phospholipase A2 and lipase activities and by histopathological and ultrastructural examination.

Topics: Acute Disease; Animals; Disease Models, Animal; Ethanol; Iloprost; Intracellular Membranes; Lipase; Lysosomes; Male; Pancreas; Pancreatitis; Phospholipases A; Phospholipases A2; Rats; Rats, Wistar; Taurocholic Acid; Trypsinogen

Ischemia-reperfusion (I/R) injury of the lung involves increased pulmonary vascular resistance. Prostaglandins are thought to have a beneficial effect in lung transplantation, but their mechanism in I/R injury is unknown. We investigated whether iloprost, a stable prostacyclin analogue, prevents I/R-associated pulmonary vascular dysfunction and whether it affects endothelin-1 (ET-1) balance.. In an isolated blood-perfusion model, we subjected lungs of Lewis rats to 45 minutes of ischemia at 37 degrees C and randomly allocated the lungs to 3 groups (n = 6 each): iloprost (33.3 nmol/liter) added to the perfusate before ischemia and reperfusion (ILO+IR), iloprost (33.3 nmol/liter) given only before reperfusion (ILO+R), and controls without iloprost treatment (ILO-).. Reperfusion induced marked pulmonary edema in non-treated controls (ILO-), which was attenuated in ILO+R lungs and completely prevented in ILO+IR lungs. At 60 minutes reperfusion, arterial oxygen tension was significantly greater in both ILO+R and ILO+IR lungs compared with ILO- controls. Mean pulmonary artery pressure and pulmonary vascular resistance were slightly decreased in the ILO+R and significantly decreased in the ILO+IR group compared with the ILO- controls. Plasma levels of big ET-1, measured in both afferent and efferent blood, showed that I/R results in increased pulmonary venous levels of big ET-1. Interestingly, the increased venoarterial ET-1 gradient in ILO- lungs decreased significantly in the ILO+IR group.. We demonstrated in an isolated lung perfusion model that iloprost ameliorates post-ischemic lung reperfusion injury and maintains an appropriate pulmonary ET-1 balance.

Topics: Animals; Body Weight; Disease Models, Animal; Endothelin-1; Iloprost; Lung; Male; Models, Cardiovascular; Oxygen; Pulmonary Circulation; Pulmonary Edema; Pulmonary Gas Exchange; Pulmonary Wedge Pressure; Rats; Rats, Inbred Lew; Reperfusion Injury; Respiratory Distress Syndrome; Severity of Illness Index; Statistics as Topic; Vascular Resistance; Vasodilator Agents

In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Inhalation; Animals; Antihypertensive Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Epoprostenol; Female; Iloprost; Infusions, Intravenous; Male; Phosphodiesterase Inhibitors; Pyridazines; Rabbits; Respiratory Distress Syndrome; Vasodilator Agents

Lipoxins and 15-epi-lipoxins are counter-regulatory lipid mediators that modulate leukocyte trafficking and promote the resolution of inflammation. To assess the potential of lipoxins as novel anti-inflammatory agents, a stable 15-epi-lipoxin A(4) analog, 15-epi-16-p-fluorophenoxy-lipoxin A(4) methyl ester (ATLa), was synthesized by total organic synthesis and examined for efficacy relative to a potent leukotriene B(4) (LTB(4)) receptor antagonist (LTB(4)R-Ant) and the clinically used topical glucocorticoid methylprednisolone aceponate. In vitro, ATLa was 100-fold more potent than LTB(4)R-Ant for inhibiting neutrophil chemotaxis and trans-epithelial cell migration induced by fMLP, but was approximately 10-fold less potent than the LTB(4)R-Ant in blocking responses to LTB(4). A broad panel of cutaneous inflammation models that display pathological aspects of psoriasis, atopic dermatitis, and allergic contact dermatitis was used to directly compare the topical efficacy of ATLa with that of LTB(4)R-Ant and methylprednisolone aceponate. ATLa was efficacious in all models tested: LTB(4)/Iloprost-, calcium ionophore-, croton oil-, and mezerein-induced inflammation and trimellitic anhydride-induced allergic delayed-type hypersensitivity. ATLa was efficacious in mouse and guinea pig skin inflammation models, exhibiting dose-dependent effects on edema, neutrophil or eosinophil infiltration, and epidermal hyperproliferation. We conclude that the LXA(4) and aspirin-triggered LXA(4) pathways play key anti-inflammatory roles in vivo. Moreover, these results suggest that ATLa and related LXA(4) analogs may have broad therapeutic potential in inflammatory disorders and could provide an alternative to corticosteroids in certain clinical settings.

Topics: Administration, Cutaneous; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Calcimycin; Cell Movement; Chemotaxis, Leukocyte; Croton Oil; Disease Models, Animal; Diterpenes; Female; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Hypersensitivity, Delayed; Iloprost; Inflammation; Leukotriene B4; Lipoxins; Mice; Phthalic Anhydrides; Skin; Terpenes

We conducted this study to analyze endothelial cell function within intact thoracic aorta of the systemic sclerosis murine model, the heterozygous tight-skin mice 1: (i) assessing the distribution and activation intensity of endothelial cells, responsive to endothelium-dependent vasodilators (acetylcholine, adenosine triphosphate, bradykinin, and substance P) and Iloprost, using laser line confocal microscopy in combination with two Ca2+ fluorescent dyes; (ii) evaluating en-dothelium-dependent vasodilator- and Iloprostinduced relaxation, using isometric tension measurement; and (iii) investigating the role of nitric oxide in mediating relaxation to acetylcholine and adenosine triphosphate. The number of activated endothelial cells was significantly lower in heterozygous tight-skin mice 1, compared with controls, for adenosine triphosphate and Iloprost. Maximal increase of Ca2+ fluorescence intensity ratio in activated endothelial cells was decreased for adenosine triphosphate, bradykinin, and Iloprost, in heterozygous tight-skin mice 1. Adenosine triphosphate- and Iloprost-mediated aortic relaxation was further impaired in heterozygous tight-skin mice 1. Finally, aortic relaxation to acetylcholine and adenosine triphosphate was markedly decreased by nitric oxide synthase inhibitor in heterozygous tight-skin mice 1. This study suggests that endothelial cell receptors for endothelium-dependent vasodilators and Iloprost may not be homogeneously distributed or continuously expressed in thoracic aorta of heterozygous tight-skin mice 1, resulting in endothelium-dependent vasodilatation dysfunction. Moreover, because endothelium-dependent relaxation was highly dependent on nitric oxide release in heterozygous tight-skin mice 1, endothelium-dependent relaxation may differ from that of controls by increased production of nitric oxide. In turn, in heterozygous tight-skin mice 1, the resulting elevated nitric oxide levels may contribute to nitric oxide-mediated free radical endothelial cytotoxicity, although endothelium impairment may be related to other factors, particularly: Fbn-1 gene mutation and transforming growth factor-beta.

Topics: Acetylcholine; Adenosine Triphosphate; Animals; Aorta, Thoracic; Bradykinin; Calcium; Disease Models, Animal; Endothelium, Vascular; Iloprost; In Vitro Techniques; Isometric Contraction; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Confocal; Nitric Oxide; Nitric Oxide Synthase; Scleroderma, Systemic; Skin; Substance P; Vasodilation; Vasodilator Agents

To compare the effects of a 12 h continuous infusion of iloprost, a stable prostacyclin analogue, on hepatic blood flow (Qliv), O2 exchange, and energy metabolism during a 24 h hyperdynamic, porcine endotoxemia with volume resuscitation alone.. Prospective, randomized, experimental study with repeated measures.. Investigational animal laboratory.. Twenty-eight domestic pigs: 16 animals during endotoxemia with volume resuscitation alone (ETX), 12 with endotoxemia, volume resuscitation, and treatment with iloprost (ILO).. Endotoxemia was initiated by continuous infusion of E. coli lipopolysaccharide. Animals were resuscitated with hetastarch, aimed at maintaining a MAP of > 60 mmHg. After 12 h of endotoxemia, iloprost was administered for 12 h in the treatment group, titrated to avoid pharmacologically induced hypotension (MAP < 60 mmHg).. Iloprost significantly increased Qliv, with no effect on hepatic O2 delivery. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface, as well as HbScO2 frequency distributions--a measure of microcirculatory O2 availability--remained unchanged. Treatment with iloprost, however, significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased endogenous glucose production (EGP) rate, iloprost restored EGP to normal at the end of the experiment.. Thus, in a clinically relevant model of human sepsis, iloprost did not produce potential adverse effects but rather ameliorated hepatic metabolic disturbances and, thereby, hepatic energy balance.

Topics: Animals; Blood Gas Analysis; Disease Models, Animal; Drug Evaluation, Preclinical; Endotoxemia; Energy Metabolism; Escherichia coli; Escherichia coli Infections; Female; Fluid Therapy; Hemodynamics; Hemoglobins; Iloprost; Lactic Acid; Lipopolysaccharides; Liver; Male; Microcirculation; Oxygen Consumption; Prospective Studies; Pyruvic Acid; Random Allocation; Resuscitation; Swine; Time Factors; Vasodilator Agents

We investigated whether antithrombin (AT) can reduce ischemia/reperfusion (I/R)-induced injury of rat liver by promoting prostacyclin release from endothelial cells. Although intravenous administration of AT (250 U/kg) markedly reduced hepatic injury, neither dansyl-Glu-Gly-Arg-chloromethyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Hepatic levels of 6-keto-PGF1, a stable prostacyclin (PGI2) metabolite, were increased significantly after I/R of the rat liver. AT significantly increased the hepatic level of 6-keto-PGF1, whereas neither DEGR-Xa nor Trp49-modified AT increased it. Hepatic tissue blood flow was markedly reduced after I/R. Although AT significantly increased the hepatic tissue blood flow after I/R, neither DEGR-Xa nor Trp49-modified AT increased the blood flow. Hepatic levels of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO) were significantly increased after hepatic I/R. The levels of these two indicators were reduced by AT but were unaffected by either DEGR-Xa or Trp49-modified AT. Pretreatment of animals with indomethacin (IM) completely inhibited the protective effects of AT on the I/R-induced hepatic damage and the leukocyte activation as well as the AT-induced increase in hepatic 6-keto-PGF1 levels after I/R. Iloprost, a stable analog of PGI2, exhibited effects similar to those of AT and also significantly inhibited the exacerbation of liver injury, the decrease in hepatic tissue blood flow, and the increases in hepatic CINC and MPO levels seen in rats subjected to I/R but pretreated with IM. These findings suggest that AT may prevent I/R-induced hepatic injury by increasing the hepatic levels of PGI2 through the interaction of AT with cell-surface glycosaminoglycans, thus increasing hepatic tissue blood flow and inhibiting leukocyte activation in animals subjected to I/R.

Topics: 6-Ketoprostaglandin F1 alpha; Amino Acid Chloromethyl Ketones; Animals; Antithrombin III; Disease Models, Animal; Epoprostenol; Factor Xa; Iloprost; Indomethacin; Injections, Intravenous; Liver; Male; Rats; Rats, Wistar; Reperfusion Injury; Sulfonium Compounds; Tryptophan

This study was designed to determine the effects of cyclooxygenase inhibition and prostacyclin agonists on the hypertension induced by nitric oxide synthase blockade in a previously characterized rat model of preeclampsia.. A condition similar to preeclampsia was induced by infusing pregnant rats with the nitric oxide synthase inhibitor N G -nitro- L -arginine methyl ester through subcutaneously implanted osmotic minipumps. Blood pressure was measured with the tail cuff method. In the first experiment the rats received either vehicle alone (control group), N G -nitro- L -arginine methyl ester (50 mg/d), indomethacin (0.1 mg/d), or N G -nitro- L -arginine methyl ester plus indomethacin beginning on day 17 of pregnancy. In the second experiment the rats received vehicle alone (control group), N G -nitro- L -arginine methyl ester (50 mg/d), or N G -nitro- L -arginine methyl ester plus iloprost (31 microgram/d). In a third experiment cicaprost (15 microgram/d) was substituted for iloprost.. Except for an increase on the day after insertion of the pump indomethacin had no significant effect on the hypertension induced by N G -nitro- L -arginine methyl ester. Both prostacyclin agonists (iloprost and cicaprost), however, attenuated the rise in blood pressure usually seen after N G -nitro- L -arginine methyl ester administration.. Nonselective inhibition of the cyclooxygenase enzymatic system does not influence the hypertension seen in the rat preeclampsia model induced by chronic nitric oxide deficiency. The hypertension in this model can be partially reversed with prostacyclin analogs.

Topics: Animals; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Female; Gestational Age; Iloprost; Indomethacin; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pre-Eclampsia; Pregnancy; Prostaglandins, Synthetic; Rats

The effects of ZK-118.182, a stable analogue of PGD2, were evaluated in an endothelin-1-induced cerebral ischemia rabbit model. Ischemia was induced by endothelin-1 injection (0.25 ng bolus) into subcavian artery and ischemic changes were assessed histologically by the number of ischemic neurons in the brain stem. ZK-118.182 (2 micrograms/kg, bolus into subclavian artery) reduced the number of ischemic neurons when injected 20 min after endothelin-1 injection, Iloprost, a stable analogue of PGI2, was also effective in reducing the number of ischemic neurons in a dose of 0.5 microgram/kg (bolus into subclavian artery). The results suggested that ZK-118.182 has a potent antiischemic effect which is comparable to that of iloprost in rabbits.

Topics: Animals; Brain Ischemia; Dinoprost; Disease Models, Animal; Endothelin-1; Iloprost; Neurons; Platelet Aggregation Inhibitors; Rabbits

The aim of this study was to investigate the cytoprotective effect of Iloprost on the liver against carbon tetrachloride induced necrosis. The serum histamine-like activity was found to be increased when compared with that of controls after treatment with carbon tetrachloride for 18 weeks while prostaglandin E2- and leukotriene C4-like activities were unchanged. After pretreatment with Iloprost for 18 weeks the increased activity of histamine was found to be unchanged while prostaglandin E2-like activity was increased. It is concluded that Iloprost protects the liver against carbon tetrachloride-induced damage and reduces the level of histamine that has a role in the pathogenesis of portal hypertension.

Topics: Animals; Carbon Tetrachloride; Dinoprostone; Disease Models, Animal; Female; Histamine; Hypertension, Portal; Iloprost; Injections, Subcutaneous; Leukotriene C4; Liver; Liver Cirrhosis, Experimental; Male; Platelet Aggregation Inhibitors; Rats; Vasodilator Agents

The effects of iloprost infusion (100 ng/kg/min for 75 min) alone and in combination with aspirin (3 mg/kg IV bolus) were compared in a canine model of myocardial reperfusion injury. Regional ischemia of 40 min was produced by temporary occlusion of the left anterior descending coronary artery, after which the myocardium was reperfused for a period of 3 hours. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LVdP/dtmax and negative (-) LVdP/dtmax were monitored. Rate pressure product and (-) dP/dt/Pmax were also derived from the above. Myocardial tissue levels of adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate were estimated. Following reperfusion in the saline treated group, there was a significant fall in (i) MAP, (ii) (+) LVdP/dtmax and (iii) (-) LVdP/dtmax. LVEDP was corrected about 2 hours after reperfusion. Despite correction of lactate accumulation, ATP and glycogen were not restored although the CP store was replenished. The hemodynamic profiles in both iloprost and in combination treated groups were similar; (i) depressed MAP (particularly during iloprost infusion) without any significant change in HR (ii) no significant depression in (+) LVdP/dtmax (iii) depression in (-) LVdP/dtmax but not when corrected for lower Pmax and (iv) a significant reduction in the incidence of reperfusion arrhythmias. Similarly, in both the drug/s treated groups, ATP, CP and lactate were normalised although glycogen store was not restored. The results of this study indicate (i) cardioprotective effect of iloprost even when administered prior to reperfusion and (ii) no additional protective effect of combining iloprost and aspirin.

Topics: Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Dogs; Drug Synergism; Drug Therapy, Combination; Glycogen; Heart Rate; Iloprost; Lactic Acid; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Ventricular Pressure

In this study, the time-dependent ulcerogenic effects of restraint-cold stress and indomethacin on the gastric mucosa and the temporal variation in the protective effect of iloprost, a synthetic stable analog of prostacyclin, were investigated in rats synchronized to 12h light and 12h darkness, lights on at 08:00. The severity of gastric ulceration produced by either stress or indomethacin showed marked circadian variation; it was greatest at 11 HALO (hours after lights on) for restraint-cold stress and at 23 HALO for indomethacin. The severity of the induced ulcerogenesis was least at 7 HALO for both stimuli. The protective effect of iloprost against restraint-cold stress was most prominent at 15 HALO and 19 HALO with an approximately 80% protection score. On the other hand, pretreatment with iloprost reduced the indomethacin-induced mucosal injury only at 23 HALO. The circadian variation in the effect of iloprost and in the rhythmic modalities of these two experimental ulcer models are indicative of differences in their underlying mechanisms. In experimental models of ulceration, the circadian time of application of the ulcerogenic stimulus must be considered as an important experimental factor. Moreover, the protective effectiveness of antiulcer drugs can express time-dependent differences and must also be taken into account in investigative research.

Topics: Animals; Anti-Ulcer Agents; Circadian Rhythm; Cold Temperature; Disease Models, Animal; Drug Administration Schedule; Female; Gastric Mucosa; Iloprost; Indomethacin; Male; Rats; Restraint, Physical; Stomach Ulcer; Stress, Physiological

Isolated lungs from male Wistar rats (250-350 g) were perfused at a constant flow rate (10 ml/min, non-recirculating) with Krebs-Ringer-bicarbonate buffer containing 4.5 % bovine serum albumin, and were ventilated at a positive pressure (60 breaths/min). Pulmonary arterial pressure and lung weight (as a measure of edema formation) were recorded continuously. After an equilibration period of 20 minutes the various test compounds were added to the perfusion fluid and experimental recording was continued for another 60 minutes. The effects of the stable PGI2-mimetic, iloprost, of PGE1, and of the biologically active PGE1-metabolite, 13,14-dihydro-PGE1, were evaluated in this model (n = 6). Iloprost showed slight, but not significant vasodilation; however, lung weight remained unchanged. PGE1 and 13, 14-dihydro-PGE1 also caused slight vasodilation, but in contrast to iloprost these compounds induced distinct pulmonary edema. The lung weight gain was discernible at concentrations of 2.8 x 10(-6) mol/l (significant at 2.8 x 10(-5) mol/l; p < or = 0.05) and was accompanied by increases in the wet-weight to dry-weight ratios. These findings were duplicated in a second set of experiments (n = 6) from which the same results were obtained. The results indicate that at high concentrations PGE1 (and 13,14-dihydro-PGE1), but not iloprost, can induce pulmonary edema in rats probably by increasing the permeability of the pulmonary vasculature.

Topics: Alprostadil; Animals; Blood Pressure; Disease Models, Animal; Iloprost; In Vitro Techniques; Male; Organ Size; Perfusion; Pulmonary Artery; Pulmonary Edema; Rats; Rats, Wistar; Reproducibility of Results; Vasodilator Agents

A chemically stable prostacyclin analog, KP-10614 [(4Z,16S)-4, 5, 18, 18, 19, 19-hexadehydro-16,20-dimethyl-delta 6(9 alpha)-9(O)-methano-prostaglandin I1], was synthesized to increase the cytoprotective activity and to decrease the hypotensive activity. We have reported that KP-10614, infused i.v. at a dose of 3 ng/kg/min for 4 hr, inhibited platelet functions and reduced the experimental cardiac infarct size significantly, but did not change hemodynamic parameters and the ischemic area of the heart induced by ligation of the left descending coronary artery in rats. Accordingly, we thought that myocardial protective effects of KP-10614 might be based on the inhibition of platelet functions and cellular metabolism produced by platelets at the site of tissue injury. KP-10614 suppressed leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes, which was enhanced by thrombin-treated platelets in a concentration-dependent manner, even though KP-10614 did not suppress leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes separately in vitro. Moreover in in vivo studies, KP-10614, which was infused at a dose of 3 ng/kg/min for 4 hr, suppressed leukotriene B4 content, myeroperoxidase activity and polymorphonuclear leukocyte counts in myocardial tissues that were infarcted by ligation of the left descending coronary artery for 4 hr in rats. These data supported the hypothesis that KP-10614, a new prostacyclin analog, had protective effects on myocardial infarction in rats by suppressing the platelet-polymorphonuclear leukocyte interaction at the site of tissue injury in vivo.

Topics: Animals; Blood Platelets; Cell Communication; Cells, Cultured; Disease Models, Animal; Epoprostenol; Fibrinolytic Agents; Iloprost; Leukotriene B4; Male; Myocardial Infarction; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Rabbits; Rats; Rats, Sprague-Dawley

An existing arterio-venous shunt thrombosis model in the rat has been modified to increase its usefulness for the testing of anti-thrombotic agents and characterised using morphological and radiometric techniques. The thrombus formed on the cotton thread held in the shunt was found to be composed of platelet aggregates surrounded by red thrombus. After 30 min of blood flow there was a 15-fold increase in the platelet content of the thrombus and a 4-fold increase in the fibrin(ogen) content compared with an equivalent weight of whole blood. Use of the anticoagulants recombinant desulphatohirudin (CGP 39393, 4 mg/kg, s.c.) and unfractionated heparin (800 IU/kg, s.c.) showed that approx. 90% inhibition of thrombus weight and approx. 80% inhibition of fibrin(ogen) content could be achieved without significant effect on the platelet content. Conversely, using the platelet inhibitor Iloprost (1 microgram kg-1 min-1), a reduction in thrombus weight of 50% was associated with 75% inhibition of platelet content and only 20% inhibition of fibrin(ogen). These observations suggest that the growth of this type of thrombus is largely the result of continued fibrin formation rather than continued platelet recruitment and activation.

Topics: Animals; Arteriovenous Shunt, Surgical; Disease Models, Animal; Fibrinolytic Agents; Hematologic Tests; Heparin; Hirudin Therapy; Hirudins; Iloprost; Male; Radiometry; Rats; Rats, Inbred Strains; Recombinant Proteins; Thrombosis

In this study we attempted to determine whether administration of iloprost (ZK 36374), a chemically stable prostacyclin analogue, would reduce infarct size after experimental coronary artery occlusion and reperfusion. One hour of coronary artery occlusion was performed in 28 open-chest, anesthetized rabbits++, followed by 5 hours of reperfusion. Two minutes after occlusion, 99mTc-labeled albumin microspheres were injected into the left atrium for later assessment of the area at risk of infarction. Fifteen minutes after occlusion animals were randomly assigned to either the treatment group (iloprost, 1.2 micrograms/kg/min intravenously for 6 hours; n = 14) or the control group (n = 14). In vitro platelet aggregation was inhibited in rabbits receiving iloprost. In 10 rabbits (five treated and five control) regional myocardial blood flow was also measured by means of differentially labeled radioactive microspheres. Infarct size was significantly smaller in treated rabbits (53.6 +/- 4.1% of the risk zone vs 89.4 +/- 3.8% in control rabbits; p less than 0.001). Flow to the nonischemic myocardium was higher in treated animals, that is, 1.87 +/- 0.20 ml/min/gm of tissue 50 minutes after occlusion and 1.90 +/- 0.20 ml/min/gm of tissue 4 hours after reperfusion, compared with 1.54 +/- 0.20 and 1.64 +/- 0.30 ml/min/gm of tissue, respectively, in control rabbits (p less than 0.01). Collateral flow to the ischemic region was not affected by the drug. Mean arterial blood pressure, heart rate, and pressure-rate product in treated rabbits were not significantly different from values in control rabbits. In conclusion, administration of iloprost reduced myocardial infarct size in this model of myocardial ischemia and reperfusion in absence of major hemodynamic effects.

Topics: Animals; Cardiovascular Agents; Coronary Circulation; Coronary Disease; Disease Models, Animal; Drug Administration Schedule; Epoprostenol; Hemodynamics; Iloprost; Male; Myocardial Infarction; Platelet Aggregation; Rabbits; Random Allocation

A new stable analogue of prostacyclin, iloprost, was tested on the basilar artery of anaesthetized rabbits constricted by electrical stimulation and intracisternal injection of autologous blood. The vasospasm induced by these stimuli was effectively relieved (about 100%) by topical application of iloprost, a stable analogue of prostacyclin (PGI2), and no constriction occurred on further stimulation within one hour. The mechanisms of the action of iloprost and its possible therapeutic value in subarachnoid haemorrhage are discussed.

Topics: Animals; Basilar Artery; Disease Models, Animal; Epoprostenol; Female; Iloprost; Ischemic Attack, Transient; Male; Rabbits

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Alprostadil; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Iloprost; Lupus Nephritis; Mice; Mice, Inbred NZB; Mice, Inbred Strains; Nephritis; Proteinuria; Thromboxane B2; Vasodilator Agents

The thromboxane (TX) synthetase inhibitor dazoxiben (80 micrograms/kg X min) and the prostacyclin analogue iloprost (0.6 micrograms/kg X min) were investigated in a cat model of acute myocardial ischaemia (MI) plus reperfusion. The agents were i.v. infused starting 30 min after LAD occlusion until the end of the observation period (5h). Dazoxiben significantly reduced the MI-induced increase in TXB2 and platelet ATP secretion. Dazoxiben did not influence the MI-induced depression in platelet count (PC), the fall in CK-specific activity or the ECG alterations associated with reperfusion whereas iloprost resulted in a nearly complete recovery of these parameters. These data suggest an efficacy of PGI2 administration but not of TX synthetase inhibition in preserving the myocardium from reperfusion injury. These data indicate that reperfusion-induced tissue damage appears not to be a thromboxane-dependent phenomenon.

Topics: Adenosine Triphosphate; Animals; Blood Platelets; Cardiovascular Agents; Cats; Collagen; Disease Models, Animal; Epoprostenol; Iloprost; Imidazoles; Infusions, Parenteral; Myocardial Infarction; Oxidoreductases; Platelet Count; Thromboxane-A Synthase

The hemodynamic and antithrombotic action of ZK 36374, a stable carbacyclin derivative of prostacyclin, was studied during electrically-induced coronary artery thrombosis in the open chest anesthetized pig. Infusion of ZK 36374 (100 ng/kg/min, n = 6) had no effect on heart rate and cardiac output, but caused a 20% reduction in mean arterial blood pressure by peripheral vasodilation. In animals receiving solvent or no drug prior to thrombosis induction, the time to occlusive coronary artery thrombosis (TOT) was 30 +/- 2 minutes (mean +/- SEM, n = 17). Pretreatment with an i.v. infusion of ZK 36374 (100 ng/kg/min) prolonged TOT by 50% to 47 +/- 7 minutes (p less than 0.005, n = 6). This prolongation of TOT was not due to the lower blood pressure in the ZK 36374 group, as dihydralazine in a dose that lowered arterial blood pressure to the same extent had no effect on TOT (32 +/- 4 minutes, n = 4). The results indicate that ZK 36374 may be useful in delaying (or preventing) occlusive coronary artery thrombi.

Topics: Animals; Arterial Occlusive Diseases; Cardiotonic Agents; Coronary Disease; Disease Models, Animal; Epoprostenol; Fibrinolytic Agents; Hemodynamics; Iloprost; Platelet Aggregation; Swine