Effects Of Iloprost Research Articles

Gene expression profiling in circulating endothelial cells from systemic sclerosis patients shows an altered control of apoptosis and angiogenesis that is modified by iloprost infusion

IntroductionCirculating endothelial cells are increased in patients affected by systemic sclerosis (SSc) and their number strongly correlates with vascular damage. The effects of iloprost in systemic sclerosis are only partially known. We aimed at studying the gene expression profile of circulating endothelial cells and the effects of iloprost infusion and gene expression in patients with systemic sclerosis.MethodsWe enrolled 50 patients affected by systemic sclerosis, 37 patients without and 13 patients with digital ulcers. Blood samples were collected from all patients before and 72 hours after either a single day or five days eight hours iloprost infusion. Blood samples were also collected from 50 sex- and age-matched healthy controls. Circulating endothelial cells and endothelial progenitors cells were detected in the peripheral blood of patients with systemic sclerosis by flow cytometry with a four-colour panel of antibodies. Statistical analysis was performed with the SPSS 16 statistical package.Circulating endothelial cells were then isolated from peripheral blood by immunomagnetic CD45 negative selection for the gene array study.ResultsThe number of both circulating endothelial cells and progenitors was significantly higher in patients affected by systemic sclerosis than in controls and among patients in those with digital ulcers than in patients without them. Circulating endothelial cells and progenitors number increased after iloprost infusion. Gene array analysis of endothelial cells showed a different transcriptional profile in patients compared to controls. Indeed, patients displayed an altered expression of genes involved in the control of apoptosis and angiogenesis. Iloprost infusion had a profound impact on endothelial cells gene expression since the treatment was able to modulate a very high number of transcripts.ConclusionsWe report here that circulating endothelial cells in patients with systemic sclerosis show an altered expression of genes involved in the control of apoptosis and angiogenesis. Moreover we describe that iloprost infusion has a strong effect on endothelial cells and progenitors since it is able to modulate both their number and their gene expression profile.

Comparison of anti-edema effects of iloprost and diclofenac sodium on traumatic rat paw edema

The aim of this study was to compare the anti-edema effects of a stable prostacyclin analogue, iloprost, with parenteral and local forms of a non-steroidal anti-inflammatory drug, diclofenac sodium, on traumatic soft tissue edema. Thirty-two adult male rats were randomly divided into 4 equal groups. Traumatic edema in one paw of each rat was produced by established protocol. Different drugs were then administered to each group: intraperitoneal (i.p.) saline (group 1, control group), topical diclofenac gel (group 2), i.p. diclofenac sodium (group 3), and i.p. iloprost (group 4). The volume of the paws was measured at baseline (before trauma) and at 1 hour, 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours after trauma. The anti-edema effects of these 3 drugs (diclofenac gel, diclofenac sodium i.p., iloprost i.p.) were compared to each other and to the control group. The greatest increase in paw edema in the first, second and fourth hours was seen in the control and iloprost groups. At the 4-hour measurement, edema levels were all equal except control group. Following 4- and 8-hour measurements, edema began to decrease in all groups. After 8 and 24 hours, the fastest decrease in edema was in iloprost group, with complete resolution of edema by 72 hours. The next fastest decrease in paw volume was seen with i.p. diclofenac sodium, followed by diclofenac gel. Iloprost has experimentally higher anti-edema effect than diclofenac sodium for the conservative treatment of the traumatic soft tissue edema.

Prostacyclin Inhibits IFN-γ-Stimulated Cytokine Expression by Reduced Recruitment of CBP/p300 to STAT1 in a SOCS-1-Independent Manner

Increasing evidence indicates that pulmonary arterial hypertension is a vascular inflammatory disease. Prostacyclin (PGI(2)) is widely used to treat pulmonary arterial hypertension and is believed to benefit patients largely through vasodilatory effects. PGI(2) is also increasingly believed to have anti-inflammatory effects, including decreasing leukocyte cytokine production, yet few mechanistic details exist to explain how these effects are mediated at the transcriptional level. Because activated monocytes are critical sources of MCP-1 and other cytokines in cardiovascular inflammation, we examined the effects of iloprost on IFN-gamma- and IL-6-stimulated cytokine production in human monocytes. We found that iloprost inhibited IFN-gamma- and IL-6-induced MCP-1, IL-8, RANTES, and TNF-alpha production in monocytes, indicating wide-ranging anti-inflammatory action. We found that activation of STAT1 was critical for IFN-gamma-induced MCP-1 production and demonstrated that iloprost inhibited STAT1 activation by several actions as follows: 1) iloprost inhibited the phosphorylation of STAT1-S727 in the transactivation domain, thereby reducing recruitment of the histone acetylase and coactivator CBP/p300 to STAT1; 2) iloprost selectively inhibited activation of JAK2 but not JAK1, both responsible for activation of STAT1 via phosphorylation of STAT1-Y701, resulting in reduced nuclear recruitment and activation of STAT1; and 3) SOCS-1, which normally terminates IFN-gamma-signaling, was not involved in iloprost-mediated inhibition of STAT1, indicating divergence from the classical pathway for terminating IFN-gamma-signaling. We conclude that PGI(2) exerts anti-inflammatory action by inhibiting STAT1-induced cytokine production, in part by targeting the transactivation domain-induced recruitment of the histone acetylase CBP/p300.

THE EFFECT OF ILOPROST ON RENAL DYSFUNCTION AFTER RENAL I/R USING CYSTATIN C AND β2-MICROGLOBULIN MONITORING

The purpose of this study was to investigate the effect of iloprost, a cytoprotective prostacyclin analog, on renal injury during unilateral renal I/R in rats and to determine whether the levels of serum cystatin C (CyC) and beta2-microglobulin (B2M), as markers of glomerular function, might denote this injury. Thirty-two Wistar rats were randomized into four groups (n = 8) as follows: control (sham laparotomy), renal I/R (60-min left renal ischemia and 120-min reperfusion), renal I/R + iloprost (20 ng kg(-1) min(-1) infusion during renal I/R period, i.v.), and control + iloprost. Blood and kidney tissue samples were obtained for biochemical and histological analysis from all rats. Serum urea, creatinine, CyC, and B2M levels were evaluated for biochemical analysis. Histopathological changes in renal structure were examined for histological analysis. Serum urea, creatinine, and CyC levels were significantly increased in the renal I/R group. Iloprost treatment decreased these three markers in the renal I/R + iloprost group. beta2-Microglobulin levels were not significantly changed in any group. Histological analyses showed that renal I/R elicited significant renal injury, whereas iloprost significantly decreased I/R-induced renal injury. Serum CyC level is one of the good indicators of acute renal damage due to I/R produced by renal artery occlusion. In contrast, we have shown that there are no significant changes in the levels of serum B2M levels that would make it an accurate diagnostic tool for detecting acute changes in renal injury subject to renal I/R in rats.

Rap1 mediates protective effects of iloprost against ventilator-induced lung injury

Prostaglandin I(2) (PGI(2)) has been shown to attenuate vascular constriction, hyperpermeability, inflammation, and acute lung injury. However, molecular mechanisms of PGI(2) protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of cAMP-activated Epac-Rap1 pathway in the barrier protective effects of PGI(2) analog iloprost in the murine model of ventilator-induced lung injury. Mice were treated with iloprost (2 microg/kg) after onset of high tidal volume ventilation (30 ml/kg, 4 h). Bronchoalveolar lavage, histological analysis, and measurements of Evans blue accumulation were performed. In vitro, microvascular EC barrier function was assessed by morphological analysis of agonist-induced gap formation and monitoring of Rho pathway activation and EC permeability. Iloprost reduced bronchoalveolar lavage protein content, neutrophil accumulation, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation. Small-interfering RNA-based Rap1 knockdown inhibited protective effects of iloprost. In vitro, iloprost increased barrier properties of lung microvascular endothelium and alleviated thrombin-induced EC barrier disruption. In line with in vivo results, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data describe for the first time protective effects for Rap1-dependent signaling against ventilator-induced lung injury and pulmonary endothelial barrier dysfunction.

Lung endothelial barrier protection by iloprost in the 2-hit models of ventilator-induced lung injury (VILI) involves inhibition of Rho signaling

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.

Iloprost Improves Gas Exchange and Exercise Tolerance in Patients with Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease

Background: Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained. Objectives: To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH. Methods: Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 µg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (V_E/VO₂) and carbon dioxide (V_E/VCO₂) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose. Results: Mean differences in V_E/VCO₂ and V_E/VO₂ were –13.3 (95% CI –36.5 to –2.7; p = 0.002) and –15.0 (95% CI –36.7 to –0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was –3.7 mm Hg (95% CI –6.1 to –1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen. Conclusions: Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance.

Randomized Comparison of Vasodilator Effects of Iloprost versus Diltiazem on Flow and Pathologic Changes in Radial Arteries: Mid-term Angiographic Control Study of the Comparison of Vasodilators on Radial Artery Vasospasm

The increasing prevalence of routine radial artery (RA) use in coronary artery bypass grafting (CABG) has rendered the pharmacologic prevention of spasm of this artery a critical consideration in the early postoperative period and in the long-term outcome. In this study, we compared the effects of iloprost and diltiazem on vasospasm. Seventy patients who underwent CABG with the RA were randomized into 2 groups, and the vasodilator effects of iloprost and diltiazem were studied prospectively. RA flow was measured with Doppler ultrasonography. Following harvesting, a 5-mm piece was removed from the RA distally for pathologic examination. In group B, diltiazem was infused before removing the RA, whereas in group A, iloprost infusion was initiated 5 days before surgery. At the end of a 2-year follow-up, each patient underwent coronary angiography. Doppler flow measurements made during harvesting revealed a statistically significant reduction in flow, and a pathologic examination of the RAs revealed significant luminal narrowing in group B. A 2-year angiographic follow-up revealed all of the RA grafts in group A to be patent. Our evaluation of the results revealed the superior efficacy of iloprost over diltiazem in preventing RA spasm in the early period, and the 2-year angiographic findings showed that the use of iloprost produced superior mid-term patency.

The effects of iloprost, a prostacyclin analogue, in experimental ischaemia/reperfusion injury in rat ovaries

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 4 h. In group III, bilateral ovaries were removed, following unilateral torsion–detorsion periods each lasted for 4 h. 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 appearences in both the ipsilateral and contralateral rat ovaries after unilateral torsion–detorsion.

The transport of high amounts of vascular endothelial growth factor by blood platelets underlines their potential contribution in systemic sclerosis angiogenesis

Altered angiogenesis is a characteristic feature in SSc and remains ill-understood. VEGF is believed to play a central role. Serum VEGF is elevated in SSc patients but questions remain concerning the source of circulating VEGF. Here we investigated platelet activation and the role of platelets as a source of VEGF and other angiogenic mediators in this disease. A cohort of 40 patients with SSc was included. Age- and sex-matched healthy subjects and subjects presenting a primary RP were included as controls. Platelets were isolated, activated with thrombin and the secretion of VEGF, platelet derived growth factor, homodimeric form BB (PDGF-BB), TGF-beta1 and angiopoietins-1 and -2 measured. Plasma concentrations of these mediators and the functionality of platelet-derived VEGF were also studied. Platelet activation was assayed by measuring plasma beta-thromboglobulin and expression of P-selectin on platelets. The effect of iloprost on VEGF secretion by platelets was studied. Platelets from SSc patients, in contrast to controls, secreted large amounts of VEGF when activated, but not PDGF-BB, TGF-beta1 or angiopoietins. Increased expression of membrane P-selectin confirmed platelet activation in the patients. Iloprost inhibited VEGF secretion by platelets both in vivo and in vitro, through inhibition of platelet activation. Platelets transport high levels of VEGF in SSc. They may contribute to circulating VEGF because of ongoing activation in the course of the disease. If activated at the contact of injured endothelium, platelets may be important in the altered angiogenesis associated with the disease through the secretion of high levels of VEGF.

Therapeutic effect of inhaled Iloprost on pediatric pulmonary hypertension after congenital heart disease operation

Objective To study the therapeutic effects of inhaled iloprost on pediatric pulmonary hypertension after congenital heart disease operation and to investigate the mechanisms of iloprost.Methods Thirteen 10 min every time,every 4 hours for 48 h after the surgery.We used the 24 h cardiac monitoring and ultrasonic cardiography for hemodynamical monitoring.We examined the blood cAMP and cGMP by ELISA assay.Results The patients were(17.88±12.56) months old with average weight of(9.29±3.59) kg.The right atrial pressure,systolic pulmonary arterial pressure,systolic pulmonary arterial pressure/systolic blood pressure were(11.5±1.41)mm Hg,(61.64±13.6) mm Hg and 0.66±0.16 before the treatment and they were(9.88±1.88) mm Hg,(47.67±12.18) mm Hg and 0.52±0.15 at the time point of 20 min after the treatment.For all the three parameters,there were significant differences before and after treatment.The effect of iloprost continues to 120 min later.The cAMP level was(335.75±127.31) μg/L before iloprost inhalation and increased to(519.68±148.54)μg/L at the time point of 20 min after inhaling iloprost,showing a significant difference(P＜0.01).Blood pressure,cGMP level and ventilator parameters showed no notable difference before and after the treatment.Conclusion Inhaled iloprost significantly improves pulmonary hemodynamics in children with pulmonary hypertension after congenital heart disease operation,which might be achieved by increasing the blood cAMP.However,systemic blood pressure and respiratory function keep unaffected after iloprost inhalation. Key words: Congenital heart disease; Inhaled iloprost; Blood cAMP; Child

Iloprost, a prostacyclin (PGI2) analogue, reduces liver injury in hepatic ischemiareperfusion in rats

To evaluate the effects of iloprost a prostacyclin analogue on the hepatic IR injury in rats. Forty male Sprague-Dawley rats (250-300 g) were divided into four groups each containing 10 rats;(1)--controls: data from unmanipulated animals; (2) sham group: rats subjected to the surgical procedure, except for liver I/R, and given saline; (3) I/R group: rats that underwent liver ischemia for 45 min followed by reperfusion for 45 min; (4) IR/ Iloprost group: rats pretreated with iloprost (10 microg kg-1, i.v). Liver tissues were taken to determine SOD, CAT, GSH, and MDA levels and for biochemical and histological evaluation. The plasma ALT and AST levels were increased in group 3 than in group 4. MDA values and the liver injury score decreased, while the SOD, CAT, and GSH values increased in group 4 compared to group 3. In group 3, hepatocytes were swollen with marked vacuolization. In group 4, there were regular sinusoidal structures with normal morphology without any signs of congestion. We demonstrated hepatoprotective effects of iloprost against severe ischemia and reperfusion injury in rat liver.

Iloprost preserves renal oxygenation and restores kidney function in endotoxemia-related acute renal failure in the rat

To investigate that exogenous prostacyclin would counterbalance an endotoxemia-induced intrarenal vasoconstriction and would therefore have beneficial effects on kidney function. Prospective, randomized, controlled study. University medical center research laboratory. Eighteen male Wistar rats. In anesthetized and ventilated animals, arterial blood pressure (mean arterial blood pressure [MAP]) and renal blood flow (RBF) were recorded. Renal microvascular Po2 (muPo2) and renal venous Po2 were continuously measured by phosphorescence lifetime technique. All animals received a 30-minute infusion of lipopolysaccharide (LPS) (2.5 mg/kg) to induce endotoxemia. One group of rats was not resuscitated. A second group received fluid resuscitation 90 minutes after stop of LPS infusion. In a third group of rats, the prostacyclin analogue iloprost (100 ng/kg/min) was continuously infused in addition to fluid resuscitation. Furthermore, in all the animals, plasma NOx levels, renal inducible nitric-oxide synthase (iNOS) messenger RNA (mRNA) expression, and creatinine clearance were determined. During LPS infusion, MAP and RBF progressively dropped to 50% of baseline at 120 minutes. After an initial increase in MAP and RBF, start of fluid resuscitation with iloprost resulted in the stabilization of both parameters. All animals became anuric during endotoxemia. Only in animals receiving iloprost was creatinine clearance totally restored at the end of the experiment. Iloprost had no significant effects on average muPo2, but prevented the occurrence of cortical microcirculatory hypoxic areas. NOx levels and iNOS mRNA expression were significantly increased in all animals receiving LPS after 5 hours. There was no difference in NOx concentration between the different groups. In animals receiving iloprost, iNOS mRNA expression was significantly suppressed in the inner medulla. Iloprost significantly restored kidney function of endotoxemic rats to baseline values. This beneficial effect of iloprost on renal function might be addressed to an improvement in intrarenal oxygenation.

Rap1 mediates protective effects of iloprost against lung endothelial dysfunction and vascular leak

Prostaglandin I2 has been implicated in the regulation of vascular function, inflammation, and acute lung injury. However molecular mechanisms of prostaglandin I2 protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of novel cAMP‐activated Epac‐Rap1 pathway in barrier protective effects of synthetic analogue of prostaglandin I2 iloprost using in vivo and in vitro models of lung vascular leak. Iloprost dramatically reduced bronchoalveolar lavage (BAL) protein content, neutrophil accumulation in BAL and lung tissue, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation (HTV, 30 ml/kg, 4 hrs). SiRNA‐based Rap1 knockdown inhibited protective effects of iloprost against HTV‐induced lung injury. In vitro, iloprost induced sustained TER increase in lung microvascular endothelium, enhanced intercellular junctions and formation of actin cortical rim, and attenuated thrombin‐induced EC barrier disruption. Consistent with in vivo experiments, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data demonstrate that Rap1‐dependent signaling is a major contributor to protective effects of iloprost against lung endothelial barrier dysfunction and vascular leak.HL87823, HL58064

Involvement of prostacyclin/IP receptors in decreased acid response of damaged stomachs — Mediation by somatostatin/SST2 receptors

Aims We examined the effect of a prostacyclin (PGI 2) analog iloprost on histamine-induced acid secretion and investigated how endogenous PGI 2 mediated the decreased secretory response in the damaged stomach after exposure to taurocholate (TC). Main methods Male C57BL/6 mice, both wild-type (WT) and IP receptor knockout (IP-KO) animals, were used after 18 h of fasting. Under urethane anesthesia, the abdomen was incised, and an acute fistula was provided in the stomach. Key findings Acid secretion in WT and IP-KO mice was similarly and dose-dependently increased by histamine. Iloprost decreased the histamine-stimulated secretion in WT but not IP-KO mice. The inhibitory effect of iloprost in WT mice was totally abrogated by the prior administration of CYN154806, a selective somatostatin SST2 receptor antagonist. On the other hand, the acid secretion in WT mice was decreased after exposure of the stomach to 20 mM TC for 20 min, with an increase in mucosal PGI 2 content, but the decrease was significantly less marked in IP-KO mice. The decreased acid response to TC in WT mice was totally prevented by the prior administration of CYN154806 as well as indomethacin. Somatostatin contents in the stomach were reduced after the administration of iloprost or the mucosal exposure to TC, while the blood levels increased. Significance Somatostatin/SST2 receptors are involved in the decreased acid response of the damaged stomach, in addition to PGI 2/IP receptors. It is assumed that PGI 2 releases somatostatin from D cells, which in turn decreases acid secretion via the activation of SST2 receptors.

Effects of Iloprost on Calvarial Sutures

Premature fusion of calvarial sutures is the result of a long and complex reaction, and several growth factors including transforming growth factor beta and basic fibroblast growth factor have important role in this event. Several prostaglandins have important functions in local bone modeling and remodeling by autocrine and paracrine mechanisms. Although effects of prostaglandins on long bones were studied both experimentally and clinically, there are limited data about cranial bones and sutures. In this study, we investigated the effect of iloprost-a stable prostacyclin analogue, which is widely used for the treatment of pulmonary arterial hypertension even in early pregnancy, to rat calvarial sutures. In 2 study groups, iloprost was injected intraperitoneally 10 and 15 microg kg d, respectively. In the third group, dexamethasone 2 mg kg d + iloprost 15 microg kg d was injected intraperitoneally to antagonize the effects of iloprost. In every group, 4 rats were killed at the postoperative 15, 30, and 45 days, and specimens including the sagittal and frontal sutures were excised immediately. Routine histological and immunohistological staining were performed on the specimens. Morphological measurements were performed on the skulls, also. In histological evaluation, bone formation in the both frontal and sagittal suture area was increased and accelerated in iloprost groups. Dexamethasone inhibited the effects of iloprost on the third group. Expressions of transforming growth factor beta and basic fibroblast growth factor were also increased in immunohistological staining. In morphological measurements, statistically significant differences were found between control and study groups. Iloprost did not fused the rat calvarial sutures prematurely, but it narrowed the sagittal and frontal sutures especially after the second week of the study. This situation might effect the sutures of the babies of the pregnant patients with pulmonary arterial hypertension treated with iloprost. Cranial sutures, calvarial bones, and cranial shape of the babies of the pregnant patients who were treated with iloprost should be monitored to clarify the topic.

Superoxide from NADPH oxidase upregulates type 5 phosphodiesterase in human vascular smooth muscle cells: inhibition with iloprost and NONOate

To determine whether there is an association between vascular NADPH oxidase (NOX), superoxide, the small GTPase Rac(1) and PDE type 5 (PDE5) in human vascular smooth muscle cell (hVSMCs). hVSMCs were incubated with xanthine-xanthine oxidase (X-XO; a superoxide generating system) or the thromboxane A(2) analogue, U46619 (+/-superoxide dismutase (SOD) or apocynin) for 16 h. The expression of PDE5 and NOX-1 was assessed using Western blotting and superoxide measured. The role of Rac(1) in superoxide generation was assessed by overexpressing either the dominant-negative or constitutively active Rac isoforms. The effects of iloprost, DETA-NONOate and the Rho-kinase inhibitor, Y27632, on PDE5 and NOX-1 expression were also studied. Following 16 h incubation, U46619 and X-XO promoted the expression of PDE5 and NOX-1, an effect blocked by SOD or apocynin when co-incubated over the same time course. X-XO and U46619 both promoted the formation of superoxide. Overexpression of dominant-negative Rac(1) or addition of iloprost, DETA-NONOate or Y27632 completely blocked both superoxide release and PDE5 protein expression and activity. These data demonstrate that superoxide derived from NOX upregulates the expression of PDE5 in human VSMCs. As PDE5 hydrolyses cyclic GMP, this effect may blunt the vasculoprotective actions of NO.

Iloprost Downregulates Expression of Adhesion Molecules and Reduces Renal Injury Induced by Abdominal Aortic Ischemia-Reperfusion

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.

Iloprost, ein stabiles Prostacyclinderivat, bei arterieller Verschlußkrankheit im Stadium IV: Eine placebo-kontrollierte Multizenterstudie

The effectiveness of iloprost, a prostacyclin derivative, was assessed in a placebo-controlled multicentre trial on 101 patients with chronic arterial disease, stage IV. All patients were on a basic local treatment, 53 randomly being assigned to the iloprost group, 48 to the placebo one. Both groups received identical saline infusions, one with the other without iloprost. Infusions were given on 28 consecutive days, iloprost being added at a dose of up to 2 ng/kg.min over six hours. At the end of the treatment period, 32 of 52 patients (61.5%) of the iloprost group and eight of the 47 in the placebo group (17%) had partial or complete healing of ulcers (P less than 0.05), the treatment effect persisting in both groups for a mean duration of at least one year. Iloprost was well tolerated, once individual dosages had been appropriately adjusted. Facial flushes, headache and nausea were the most common side effects. Heart rate and blood-pressure variations did not differ between the two groups.

Effect of iloprost on the microcirculation and liver function after orthotopic liver transplantation

Iloprost, a prostacyclin analogon, can probably improve the microcirculation in various tissues. It may have a positive effect on perfusion and function of the liver, especially in patients after liver transplantation. We therefore estimated liver function with the indocyanine green (ICG) plasma disappearance rate (PDR). We also evaluated iloprost effects on microcirculation in the oral mucosal tissue.