beraprost and Disease-Models--Animal

In this study, the liver sinusoidal endothelial cells (LSECs)-protective effects of beraprost sodium (BPS) were investigated using mice with monocrotaline (MCT)-induced sinusoidal obstruction syndrome (SOS).. The mice were divided into BPS, placebo and control groups. They were killed 48 h after MCT administration, and blood samples and liver tissues were evaluated. Immunostaining was performed using anti-SE-1 and anti-CD42b antibodies, whereas plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS) levels were evaluated using western blot or real-time RT-PCR.. On pathological examination, SOS-related findings were observed in zone 3 in the placebo group; however, these were significantly suppressed in the BPS group. SE-1 staining showed a consistent number of LSECs in the BPS group compared with that in the placebo group, while CD42b staining showed a significant decrease in the number of extravasated platelet aggregation (EPA) in the BPS group. PAI-1 expression was significantly lower in the BPS group than in the placebo group; however, eNOS expression was significantly higher in the BPS group than in the placebo group.. Prophylactic administration of BPS is useful for suppressing the development of SOS through the protective effects of LSEC.

Topics: Animals; Biomarkers; Biopsy; Disease Models, Animal; Endothelial Cells; Epoprostenol; Female; Hepatic Veno-Occlusive Disease; Immunohistochemistry; Liver Transplantation; Mice; Symptom Assessment; Vasodilator Agents

Beraprost sodium (BPS), as a prostacyclin analog, plays a significant role in various diseases based on its antiplatelet and vasodilation functions. However, its regulation and role in chronic kidney disease (CKD) still remain elusive. Here, we determined whether BPS could alleviate renal interstitial fibrosis, and improve the renal function and its therapeutic mechanism. In vitro, BPS increased angiogenesis in the HUVECs incubated with BPS detected by tube formation assay and repair damaged endothelial cell-cell junctions induced by hypoxia. In vivo, mice were randomly assigned to a sham-operation group (sham), a unilateral ureteral obstruction group (UUO), and a BPS intragastrical administration group (BPS), and sacrificed at days 3 and 7 post-surgery (six in each group). In UUO model, tissue hypoxia, renal inflammation, oxidative stress, and fibrotic lesions were detected by q-PCR and Western blot techniques and peritubular capillaries (PTCs) injury was detected by a novel technique of fluorescent microangiography (FMA) and analyzed by MATLAB software. Meanwhile, we identified cells undergoing endothelial cell-to-myofibroblast transition by the coexpression of endothelial cell (CD31) and myofibroblast (a-SMA) markers in the obstructed kidney. In contrast, BPS protected against interstitial fibrosis and substantially reduced the number of endothelial cell-to-myofibroblast transition cells. In conclusion, our data indicate the potent therapeutic of BPS in mitigating fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT) progression after inhibiting inflammatory and oxidative stress effects. KEY MESSAGES: BPS could improve renal recovery through anti-inflammatory and anti-oxidative pathways. BPS could mitigate fibrosis through repairing renal microvessels and suppressing endothelial-mesenchymal transition (EndMT).

Topics: Adult; Animals; Chemokine CCL2; Disease Models, Animal; Epoprostenol; Fibrosis; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-6; Kidney; Kidney Function Tests; Male; Mice, Inbred C57BL; Microvessels; Neovascularization, Physiologic; Regeneration; Transforming Growth Factor beta; Tyrosine; Uncoupling Protein 2; Ureteral Obstruction; Vascular Endothelial Growth Factor A

The reduced expression and function of voltage-dependent potassium (KV) channels have been involved in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH), leading to pulmonary vasoconstriction and vascular remodeling, while the upregulation of KV channels is of therapeutic significance for pulmonary hypertension. Beraprost sodium (BPS) has been shown to be effective in patients with pulmonary hypertension. However, the effect of BPS on O2-sensitive KV channels in pulmonary artery smooth muscle cells (PASMCs) remains unclear. In the present study, the effect of BPS on rats with HPH was observed, and the influence of BPS on the expression and function of O2-sensitive KV channels in PASMCs was investigated. The results revealed that BPS reduced mean pulmonary artery pressure, suppressed right ventricular hypertrophy, and attenuated the remodeling of pulmonary arteries in rats exposed to discontinuous hypoxia for 4 weeks (8 h/day). This was accompanied with the significantly upregulated expression of KV channel α-subunits (KV1.2, KV1.5 and KV2.1) and O2-sensitive voltage-gated K+ (KV) channel current (IK(V)) in small pulmonary arteries in HPH model rats, as well as in hypoxia-induced PASMCs. Furthermore, in vitrostudies have revealed that the upregulation of BPS on O2-sensitive KV channels was significantly inhibited after treatment with prostaglandin E2 receptor subtype EP4 antagonist GW627368X. Taken together, these results suggest that BPS attenuates the development of HPH through the upregulation of O2-sensitive KV channels, which was probably via the EP4 receptor-related pathway.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Cells, Cultured; Disease Models, Animal; Epoprostenol; Hypoxia; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxygen; Potassium Channels, Voltage-Gated; Pulmonary Arterial Hypertension; Pulmonary Artery; Rats, Sprague-Dawley; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Up-Regulation; Vascular Remodeling; Vasodilator Agents; Ventricular Function, Right

The goal of this study was to determine the effects of beraprost sodium (BPS) preconditioning on hepatic ischemia-reperfusion (IR) injury and its underlying mechanisms of action.. Mice were randomly divided into sham, IR, IR+BPS (50 µg/kg), and IR+BPS (100 µg/kg) groups. Saline or BPS was given to the mice by daily gavage for 1 week before the hepatic IR model was established. Liver tissues and orbital blood were collected at 2, 8, and 24 hours after reperfusion for the determination of liver enzymes, inflammatory mediators, apoptosis- and autophagy-related proteins, key proteins in P38 and c-Jun N-terminal kinase (JNK) cascades, and evaluation of liver histopathology.. BPS preconditioning effectively reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, improved pathological damage, ameliorated production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and affected expressions of Bax, Bcl-2, Caspase-3, Caspase-8, and Caspase-9, microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and P62. The protective effects of BPS preconditioning were associated with reduced P38 and JNK phosphorylation.. BPS preconditioning ameliorated hepatic IR injury by suppressing inflammation, apoptosis, and autophagy, partially via inhibiting activation of the P38 and JNK cascades.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Autophagy-Related Proteins; Cytoprotection; Disease Models, Animal; Drug Administration Schedule; Epoprostenol; Hepatitis; Inflammation Mediators; JNK Mitogen-Activated Protein Kinases; Liver; Male; Mice, Inbred BALB C; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reperfusion Injury; Signal Transduction; Time Factors

Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs.

Topics: Adolescent; Adult; Animals; Cell Hypoxia; Cell Proliferation; Child; Disease Models, Animal; Drug Delivery Systems; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Myocytes, Smooth Muscle; Nanoparticles; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Time Factors; Young Adult

Prostaglandin I2 (PGI2) and its analogues (such as beraprost sodium, BPS) are beneficial for the treatment of pulmonary arterial hypertension (PAH). The encapsulation of BPS in nanoparticles to provide sustained release and targeting abilities would improve both the therapeutic effect of BPS on PAH and the quality of life of patients treated with this drug. BPS was encapsulated into nanoparticles prepared from a poly(lactic acid) homopolymer and monomethoxy poly(ethyleneglycol)-poly(lactide) block copolymer. The accumulation of nanoparticles in damaged pulmonary arteries was examined using fluorescence-emitting rhodamine S-encapsulated nanoparticles. The monocrotaline-induced PAH rat model and the hypoxia-induced mouse model were used to examine the pharmacological activity of BPS-encapsulated nanoparticles. A nanoparticle, named BPS-NP, was selected among various types of BPS-encapsulated nanoparticles tested; this was based on the sustained release profile in vitro and blood clearance profile in vivo. Fluorescence-emitting rhodamine S-encapsulated nanoparticles were prepared in a similar manner to that of BPS-NP, and showed accumulation and prolonged residence in monocrotaline-damaged pulmonary peripheral arteries. Intravenous administration of BPS-NP (once per week, 20μg/kg) protected against monocrotaline-induced pulmonary arterial remodeling and right ventricular hypertrophy. The extent of this protection was similar to that observed with oral administration (once per day, 100μg/kg) of BPS alone. The once per week intravenous administration of BPS-NP (20μg/kg) also exhibited an ameliorative effect on hypoxia-induced pulmonary arterial remodeling and right ventricular hypertrophy. The beneficial effects of BPS-NP on PAH animal models seem to be mediated by its sustained release and tissue targeting profiles. BPS-NP may be useful for the treatment of PAH patients due to reduced dosages and frequency of BPS administration.

Topics: Animals; Capillary Permeability; Delayed-Action Preparations; Disease Models, Animal; Drug Carriers; Epoprostenol; Hypertension, Pulmonary; Lactic Acid; Male; Mice, Inbred C57BL; Monocrotaline; Nanoparticles; Polyesters; Polyethylene Glycols; Polymers; Pulmonary Artery; Rats, Wistar; Rhodamines

We have previously demonstrated that renoprotective effects of a prostacyclin analog, beraprost sodium, on the kidney of anti-glomerular basement membrane glomerulonephritis (GN) rats. The aim of this study is to address the renoprotection mechanism of beraprost sodium, especially in the terminal stage of GN. Beraprost sodium was orally administrated from 2 to 7 weeks after induction of GN, and renal function, morphology, protein and mRNA levels were analyzed. We found the beraprost sodium treatment suppressed the structural regression of renal microvascular network and decline of renal blood flow occurred in the kidney of GN rats. To address the mechanism of the structural maintenance, we focused on apoptosis because the increased number of apoptotic renal microvascular endothelial cells and tubular epithelial cells was observed in the kidneys of GN rats as compared with normal and beraprost sodium treated rats. Protein and mRNA analyses demonstrated that mitochondria-dependent apoptotic pathway was activated in the kidneys of GN rats, and beraprost sodium suppressed the activation by modulating the expression patterns of pro- and anti-apoptotic factors. These results suggest that inhibition of mitochondria-dependent apoptosis of renal cells in GN kidney and consequent maintenance of renal functional structures, including microvascular network might contribute to the renoprotective effect of beraprost sodium in GN.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Capillaries; Caspases; Disease Models, Animal; Epoprostenol; Glomerular Basement Membrane; Glomerulonephritis; Immune Sera; Inhibitor of Apoptosis Proteins; Kidney; Male; Microscopy, Electron, Scanning; Microvessels; Mitochondria; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred WKY; RNA, Messenger

ONO-1301 is a novel drug that acts as a prostacyclin agonist with thromboxane A(2) (TxA(2)) synthase inhibitory activity. We investigated the effect of ONO-1301 on development of airway allergic inflammation.. Mice sensitized and challenged to ovalbumin (OVA) received ONO-1301, OKY-046 (TxA(2) synthase inhibitor), beraprost, a prostacyclin receptor (IP) agonist, ONO-1301 plus CAY10449 (selective IP antagonist) or vehicle during the challenge period. Twenty-four hours after the OVA challenge, airway hyperresponsiveness (AHR) to methacholine was assessed and bronchoalveolar lavage was performed. Lung specimens were excised for goblet cell staining and analysis of lung dendritic cells (DCs). Bone marrow-derived dendritic cells (BMDCs) were generated, in the presence or absence of drugs, for analysis of DC function.. Mice that received ONO-1301 showed significantly lower AHR, airway eosinophilia, T-helper type 2 cytokine levels, mucus production and lung DCs numbers than vehicle-treated mice. These effects of ONO-1301 were mostly reversed by CAY10449. BMDCs treated with ONO-1301 alone showed lower DC functions, such as expression of costimulatory factors or stimulation to spleen T cells.. These data suggest that ONO-1301 may suppress AHR and airway allergic inflammation through modulation of DCs, mainly mediated through the IP receptor. This agent may be effective as an anti-inflammatory drug in the treatment of asthma.

Topics: Animals; Bronchial Hyperreactivity; Dendritic Cells; Disease Models, Animal; Epoprostenol; Female; Inflammation; Methacrylates; Mice; Mice, Inbred BALB C; Ovalbumin; Pyridines; Thromboxane-A Synthase; Thromboxanes

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI2 analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.

Topics: Adaptation, Physiological; Aldehydes; Animals; Capsaicin; Cytoprotection; Denervation; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Gastric Mucosa; Heme Oxygenase (Decyclizing); Hydrochloric Acid; Lipid Peroxidation; Macrophages; Male; NF-E2-Related Factor 2; Oxidative Stress; Protoporphyrins; Rats; Rats, Wistar; Signal Transduction; Stomach Ulcer

Studies of the molecular and cellular mechanisms of concanavalin A (ConA)-induced liver injury have provided important knowledge on the pathogenesis of many liver diseases involving hepatic inflammation. However, studies identifying hepato-protective factors based on the mechanistic understanding of this model are lacking. Evidence suggests that certain prostaglandin (PG) products of cyclooxygenase (COX)-1 and COX-2 provide important anti-inflammatory and cytoprotective functions in some pathophysiological states. In the present study, we demonstrate a protective role of COX-2 derived PGs in ConA-induced liver injury. COX-2(-/-) mice developed much more severe liver damage upon ConA treatment compared with wild-type and COX-1(-/-) mice. Treatment of COX-2(-/-) mice with misoprostol (a PGE(1/2) analog) or beraprost (a PGI(2) analog) significantly decreased ConA-induced liver injury. Data from both in vivo and in vitro experiments demonstrated that misoprostol and beraprost acted directly on hepatic leukocytes, including natural killer (NK)T and T cells, and down-regulated their production of interferon (IFN)-gamma, which are critical in mediating ConA-induced tissue damage. Collectively, the results provide strong evidence that the protective effects of COX-2 within the liver are mediated through the production of PGE(2) and PGI(2), which exert anti-inflammatory functions. These findings suggest that COX-2-derived PGs may have great therapeutic potentials in treating patients with inflammatory liver diseases.

Topics: Animals; Chemical and Drug Induced Liver Injury; Concanavalin A; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Down-Regulation; Epoprostenol; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Inflammation; Interferon-gamma; Liver Diseases; Male; Mice; Mice, Knockout; Misoprostol; Mitogens

The role of inducible cAMP early repressor (ICER), a transcriptional repressor, in the vascular remodeling process has not been determined. We examined whether ICER affects growth of vascular smooth muscle cells (VSMCs).. Semi-quantitative RT-PCR and Western blot analysis showed that expression of ICER was increased in beraprost (a prostaglandin I2 analogue)-stimulated VSMCs in a time- and dose-dependent manner. The induction of ICER was inhibited by pretreatment with H89, a protein kinase A (PKA) inhibitor, suggesting that PKA mediates the induction of ICER expression. Beraprost suppressed platelet-derived growth factor-induced thymidine incorporation in VSMCs, which was reversed by transfection of short interfering RNA for ICER, not by scramble RNA. Overexpression of ICER by an adenovirus vector attenuated neointimal formation (intima/media ratio) by 50% compared with overexpression of LacZ. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive cells was increased and the number of Ki-67-positive cells was decreased in ICER-transduced artery.. These results suggest that ICER induces apoptosis and inhibits proliferation of VSMCs, and plays a critical role in beraprost-mediated suppression of VSMC proliferation. ICER may be an important endogenous inhibitor of vascular proliferation.

Topics: Analysis of Variance; Animals; Aorta, Thoracic; Apoptosis; Blotting, Western; Cell Proliferation; Cells, Cultured; Cyclic AMP Response Element Modulator; Disease Models, Animal; Epoprostenol; In Situ Nick-End Labeling; Male; Muscle, Smooth, Vascular; Probability; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity

Pulmonary hypertension (PH) is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells, and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have previously demonstrated that long-term inhibition of Rho-kinase, an effector of the small GTPase Rho, ameliorates monocrotaline-induced PH in rats and hypoxia-induced PH in mice. We also have reported that prostacyclin and its oral analogue, beraprost sodium (BPS), may lack direct inhibitory effect on Rho-kinase in vitro, suggesting that combination therapy with a Rho-kinase inhibitor and BPS is effective for the treatment of PH. In this study, we addressed this point in monocrotaline-induced PH model in rats. Male Sprague-Dawley rats were given a subcutaneous injection of monocrotaline (60 mg/kg). They were maintained with or without the treatment with a Rho-kinase inhibitor, fasudil (30 mg/kg/day), BPS (200 microg/kg/day), or a combination of both drugs for 3 weeks. The combination therapy, when compared with each monotherapy, showed significantly more improvement in PH, right ventricular hypertrophy, and pulmonary medial thickness without any adverse effects. Plasma concentrations of fasudil were not affected by BPS. These results suggest that combination therapy with a Rho-kinase inhibitor and prostacyclin exerts further beneficial effects on PH.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Protein Kinase Inhibitors; Pulmonary Artery; Random Allocation; Rats; Rats, Sprague-Dawley; Vasodilator Agents

Implantation of autologous bone marrow (BM) mononuclear cells (MNCs) has been shown to augment neovascular formation in ischemic tissues in experimental animals and in humans. Prostaglandin derivatives improve the symptoms of patients with critical limb ischemia, possibly by their vasodilating and antiplatelet actions. We therefore examined whether therapeutic angiogenesis by implantation of autologous BM-MNCs would be enhanced by beraprost sodium (BPS), using a rabbit ischemic hindlimb model. Ischemia was induced by surgical resection of the left femoral artery. Twenty-five New Zealand white rabbits were divided into four groups. The first group (BM group, n = 4) received autologous BM-MNCs (2 x 10(6)/animal) implanted into the ischemic tissue 1 week after limb ischemia. The second group (BM+BPS group, n = 8) received BPS injected into the dorsal skin (300 microg/kg daily) starting 1 week before limb surgery. This group received BM-MNC implantation 1 week after surgery. Daily injection of BPS was continued until the end of the protocol. The third group (BPS group, n = 8) received BPS injected into the dorsal skin (600 microg/kg daily) starting 1 week before limb surgery. The fourth group received saline as a control (n = 4). The extent of angiogenesis in the ischemic hindlimb was assessed using the angiographic score (AS), ischemic/normal limb calf blood pressure ratio (CBPR), and tissue capillary density. Four weeks after limb ischemia, the ischemic/normal CBPR was highest in the BM+BPS group, followed by the BPS, BM, and control groups (0.56 +/- 0.16, 0.51 +/- 0.25, 0.44 +/- 0.15, and 0.30 +/- 0.10, respectively). The AS was also the greatest in the BM+BP group, followed by the BM, BP, and S group (1.63 +/-0.21, 1.31 +/- 0.25, 1.26 +/- 0.21 and 0.80 +/- 0.10, respectively). The TCD was greatest in the BM+BP group, followed in by the BM, BP, and S group? (46 +/- 4.1, 34 +/- 0.7, 33 +/- 6.9, and 19 +/- 1.8 per field, respectively). BP treatment is an effective means to enhance the efficacy of therapeutic angiogenesis induced by autologous BM-MNCs implantation in ischemic hindlimb tissues.

Topics: Angiogenesis Inducing Agents; Animals; Blood Pressure; Bone Marrow Transplantation; Capillaries; Collateral Circulation; Disease Models, Animal; Epoprostenol; Hindlimb; Ischemia; Male; Muscle, Skeletal; Neovascularization, Physiologic; Rabbits; Radiography; Time Factors; Transplantation, Autologous

Sildenafil, an oral phosphodiesterase type-5 inhibitor, has vasodilatory effects through a cyclic guanosine 3', 5'-monophosphate-dependent mechanism, whereas beraprost, an oral prostacyclin analog, induces vasorelaxation through a cAMP-dependent mechanism. We investigated whether the combination of oral sildenafil and beraprost is superior to each drug alone in the treatment of pulmonary hypertension. Rats were randomized to receive repeated administration of saline, sildenafil, beraprost, or both of these drugs twice a day for 3 weeks. Three weeks after monocrotaline (MCT) injection, there was significant development of pulmonary hypertension. The increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight were significantly attenuated in the Sildenafil and Beraprost groups. Combination therapy with sildenafil and beraprost had additive effects on increases in plasma cAMP and cyclic guanosine 3', 5'-monophosphate levels, resulting in further improvement in pulmonary hemodynamics compared with treatment with each drug alone. Unlike MCT rats given saline, sildenafil, or beraprost alone, all rats treated with both drugs remained alive during 6-week follow-up. These results suggest that combination therapy with oral sildenafil and beraprost attenuates the development of MCT-induced pulmonary hypertension compared with treatment with each drug alone.

Topics: Administration, Oral; Analysis of Variance; Animals; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Epoprostenol; Hemodynamics; Hypertension, Pulmonary; Male; Piperazines; Probability; Purines; Random Allocation; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Survival Rate; Vascular Patency; Vasodilator Agents

Topics: Animals; Disease Models, Animal; Drug Therapy, Combination; Epoprostenol; Hypertension, Pulmonary; Male; Piperazines; Purines; Random Allocation; Rats; Rats, Wistar; Reference Values; Sensitivity and Specificity; Sildenafil Citrate; Sulfones; Treatment Outcome

Acute hemodynamic effects of beraprost sodium were tested in a canine vasoconstrictive pulmonary hypertension model induced by the continuous infusion of U-46619, a thromboxane A(2)mimetic. The effects of beraprost were compared with those of prostaglandin E(1), nitroglycerin and nifedipine. Beraprost and nitroglycerin decreased pulmonary arterial pressure. On the other hand, prostaglandin E(1)and nifedipine increased pulmonary arterial pressure. All drugs except nitroglycerin increased cardiac output and decreased pulmonary vascular resistance. Beraprost was selective to pulmonary circulation, while nitroglycerin, prostaglandin E(1), and nifedipine showed poor selectivity for the pulmonary vasculature. These results suggest that the vasodilative effect of beraprost is the most selective for the pulmonary circulation among these four vasodilators.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alprostadil; Animals; Antihypertensive Agents; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypertension, Pulmonary; Male; Nifedipine; Nitroglycerin; Oxygen; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents

1. The effect of the potassium channel opener KRN4884 on the peripheral arterial occlusion model induced by laurate was examined and compared with that of beraprost sodium and nilvadipine. 2. KRN4884 or beraprost sodium prevented macroscopic changes in the paw after the injection of laurate. In contrast, nilvadipine did not improve the lesions. 3. KRN4884 produced a dose-dependent increase in gastrocnemius blood flow in the chronic femoral artery-ligated rats. The effect of KRN4884 on the blood flow was stronger in the hypoxic muscle than in the normal muscle. 4. KRN4884 did not have a direct antiplatelet aggregation activity. 5. These findings suggest that KRN4884 is useful for the therapy of peripheral arterial occlusive disease and that the effect of KRN4884 is associated with an increase in blood flow in ischemic skeletal muscle.

Topics: Animals; Arterial Occlusive Diseases; Arteriosclerosis Obliterans; Constriction; Disease Models, Animal; Epoprostenol; Femoral Artery; Male; Muscle, Skeletal; Potassium Channels; Pyridines; Rats; Rats, Wistar; Regional Blood Flow; Thromboangiitis Obliterans

Stress ulcers still have a high mortality in critically burned patients and the pathophysiology remains relatively unknown. Impaired gastric mucosal perfusion is one of the factors contributing to gastric mucosal ulceration. Burn injury causes thrombosis and vascular occlusion by increasing the blood viscosity, resulting in decreased organ perfusion. Reduced blood flow is one of the most important factors in gastric mucosal ulceration. Beraprost sodium is a chemically stable prostaglandin I2 (PGI2) analogue with antiplatelet, vasodilator and cytoprotective actions. In the present study, we examined the effects of a PGI2 analogue, beraprost sodium (Procylin, Kaken Pharmaceutical Company, Tokyo, Japan) on burn-induced gastric mucosal changes in rats. Twenty male Sprague-Dawley rats weighing an average of 400 g were burned with hot water (90 degree C) and then divided into two groups of 10 animals. One group received 0.015 mg of beraprost sodium intraperitoneally immediately after burn injury, while the control group received the same volume of saline. Gastric mucosal blood flow was measured with a laser Doppler flowmeter and the area of mucosal necrosis was also determined macroscopically and histologically. Gastric mucosal damage was significantly reduced in the beraprost sodium-treated rats and gastric mucosal blood flow was significantly improved (p < 0.05). These findings demonstrate that PGI2 plays a very important role in the pathophysiology of burn-induced Curling's ulcer and that beraprost sodium can improve gastric mucosal blood flow and reduce mucosal damage.

Topics: Animals; Blood Flow Velocity; Burns; Disease Models, Animal; Epoprostenol; Gastric Mucosa; Laser-Doppler Flowmetry; Male; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Stress, Physiological; Vasodilator Agents

The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on motor nerve conduction velocity and nerve blood flow of the sciatic nerve were investigated in streptozotocin-induced diabetic rats, and they were compared with the effects of epalrestat (aldose reductase inhibitor). Treatment with BPS for 4 weeks significantly inhibited the decrease in motor nerve conduction velocity and nerve blood flow dose-dependently, but epalrestat had no effect on nerve blood flow. Morphological changes of the myelinated fibers of the sciatic nerve were observed macroscopically. The mean axonal area and the mean circularity index of diabetic control rats were significantly less than that of normal rats, while after 6 weeks of BPS treatment, these decreases of the axonal area and the circularity index were inhibited. The enlargement of the mean lumen area of microvessels in the diabetic rats was significantly inhibited after 6 weeks of BPS treatment. Additionally, augmentation of the washed platelet aggregation in diabetic rats was significantly normalized by BPS. It was suggested that BPS is effective on diabetic neuropathy via amelioration of the decrease of blood supply to the structure. The effects of BPS on platelets might also contribute to the improvement of neuronal circulatory deficiency.

Topics: Animals; Blood Flow Velocity; Diabetic Neuropathies; Disease Models, Animal; Epoprostenol; Male; Neural Conduction; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Streptozocin

Beraprost sodium is a chemically stable prostaglandin I2 analogue with antiplatelet and vasodilator actions. Burn injury causes thrombosis and vessel occlusion by increasing the blood viscosity and by thermal damage to the vascular network in the dermis. A vascular response also occurs in the uninjured dermis surrounding the site of injury. Diminished blood flow and spreading tissue oedema lead to progressive ischaemia and necrosis around the burn site (zone of stasis), with the final necrotic tissue area being larger than the initial one. If blood flow could be restored in the zone of stasis, secondary tissue damage would be minimized. In this study, we examined the effects of a prostaglandin I2 analogue, beraprost sodium (Procylin, Kaken Pharmaceutical Company, Tokyo, Japan) on burn injury in rats. Twenty male Sprague-Dawley rats weighing an average of 450 g were burned with a comb-shaped brass probe that produced a row of three burns measuring 10 x 30 mm each and two intervening unburned areas measuring 5 x 30 mm each. The rats were divided into two groups of 10 animals. One group received 0.015 mg of beraprost sodium intraperitoneally immediately after burn injury, while the control group received the same volume of saline. Skin blood flow was measured with a laser Doppler flowmeter, and the development of oedema as well as the area of necrotic tissue were also determined. The extent of skin necrosis and oedema were significantly reduced in the beraprost sodium-treated rats, and blood flow in the zone of stasis was increased. These findings demonstrate that prostaglandin I2 plays an important role in burn injury and that beraprost sodium can reduce secondary necrosis in the zone of stasis.

Topics: Animals; Biopsy, Needle; Burns; Disease Models, Animal; Dose-Response Relationship, Drug; Epoprostenol; Hemodynamics; Injections, Intraperitoneal; Male; Necrosis; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Reference Values; Regional Blood Flow; Skin; Treatment Outcome

We examined the effect of beraprost sodium (BPS), a stable prostaglandin I2 (PGI2) analogue, on restenosis after balloon angioplasty in the atherosclerotic artery in rabbits. Regional atherosclerosis was induced in the femoral artery of New Zealand white rabbits by balloon deendothelialization and 2% cholesterol diet. After establishment of atheroma in the femoral artery, angioplasty was performed. In all, 65 rabbits were assigned to the following six subcutaneous drug treatment groups: control group (n = 13, saline 0.25 ml/kg); BPS low-dose group (n = 11, BPS 50 micrograms/kg twice daily); BPS high-dose group (n = 12, BPS 100 micrograms/kg twice daily); 2-day BPS high-dose group (n = 11, BPS 100 micrograms/kg twice daily for 2 days after angioplasty); aspirin (ASA) group (n = 10, ASA 30 mg once daily); and BPS+ASA group (n = 8, BPS 50 micrograms/kg twice daily plus ASA 30 mg once daily). Administration of each drug was started 30 min before balloon angioplasty and was continued until 4 weeks thereafter, except in the 2-day BPS high-dose group. Re-examination 4 weeks after the angioplasty showed significant (p < 0.05) preservation of the luminal diameter in the BPS high-dose and 2-day BPS high-dose groups (1.30 +/- 0.15 and 1.25 +/- 0.09 mm, respectively) as compared with that in the control group (0.83 +/- 0.10 mm); however, the luminal diameter in the BPS low-dose, ASA, and BPS+ASA groups (0.94 +/- 0.18, 1.06 +/- 0.11, and 1.05 +/- 0.15 mm, respectively) was not significantly different from that in the control group.

Topics: Administration, Oral; Angioplasty, Balloon; Animals; Arteriosclerosis; Aspirin; Cholesterol, Dietary; Disease Models, Animal; Drug Synergism; Epoprostenol; Femoral Artery; Iliac Artery; Injections, Subcutaneous; Male; Platelet Aggregation Inhibitors; Rabbits; Random Allocation; Recurrence

1. The effects of beraprost sodium (beraprost) on myocardial infarct size in an anesthetized open-chest canine model of regional myocardial ischemia and reperfusion were investigated. 2. Administration of beraprost (300 ng/kg/min, intravenously) to dogs 45 min after left circumflex coronary artery occlusion until 105 min after reperfusion resulted in a significant reduction in infarct size. 3. The values of control and beraprost treated infarct size expressed as a percentage of the total left ventricle were 15 +/- 3% and 4 +/- 2%, respectively. 4. Reperfusion arrhythmia, plasma creatine phosphokinase (CK) and lactate dehydrogenase (LDH) level were significantly suppressed by treatment with beraprost. 5. By histological examination, beraprost proved to reduce neutrophil migration in the ischemic myocardium after 5 h reperfusion. 6. Therefore, it is suggested that the cytoprotective effect of beraprost during myocardial ischemia and reperfusion may be the consequence of the inhibition of neutrophil migration.

Topics: Animals; Arrhythmias, Cardiac; Chemotaxis, Leukocyte; Disease Models, Animal; Dogs; Epoprostenol; Female; Hemodynamics; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; Platelet Aggregation Inhibitors