beraprost and Body-Weight

The prostacyclin analog, beraprost sodium (BPS), was examined for its potential to improve the symptoms of obesity-type diabetes (i.e., hyperglycemia, hyperinsulinemia, dyslipidemia, histopathologic changes, and diabetic complications).. Obese Zucker rats, an experimental model of genetic obesity-induced type 2 diabetes, were repeatedly administered BPS at oral doses of 0.2 or 0.6 mg x kg(-1) x day(-1) b.i.d. for 12 weeks, and serum chemistry, urinalysis, and histopathologic examination were performed.. BPS dose-dependently suppressed serum glucose, insulin, triglyceride, and cholesterol levels in obese animals. In oral glucose tolerance test, BPS suppressed the post-glucose-loading elevation of serum glucose in a dose-dependent manner. Urinary N-acetyl-beta-D-glucosaminidase was significantly lower in BPS-treated obese animals compared with control animals, although no significant differences were observed in urinary protein levels between the BPS-treated groups and the control group. In addition, histopathologic examination revealed significant protective effects of BPS against renal disorder in obese animals. Histopathologically, BPS also inhibited the progression of hepatic steatosis, hypertrophy of adipose tissue, and pancreatic fibrosis. Furthermore, thermographic analysis of the hind limb sole skin surface indicated a significant increase in temperature in BPS-treated animals, compared with control animals, which was likely due to improved blood circulation by administration of BPS.. BPS suppressed the pathogenesis and development of diabetes and its complication, nephropathy, which was presumably accompanied by improving glucose intolerance and insulin resistance in obese Zucker rats.

Topics: Adipose Tissue; Animals; Blood Glucose; Blood Pressure; Body Weight; Cholesterol; Cryoprotective Agents; Epoprostenol; Glycated Hemoglobin; Insulin; Kidney; Liver; Male; Metabolic Syndrome; Obesity; Pancreas; Rats; Rats, Zucker; Skin Temperature; Triglycerides

Effects of beraprost sodium, a chemically stable prostacyclin analogue, on renal dysfunction in an experimental rat model of glomerulonephritis were investigated. Beraprost sodium (30, 100 and 300 microg/kg) was orally given twice daily from the late stage of nephritis in which renal dysfunction was already developed. Beraprost sodium treatment inhibited the increase in urinary protein, serum creatinine and blood urea nitrogen, and the decrease in creatinine clearance. The elevation of serum creatinine was also inhibited by predonisolone (1 mg/kg). However, captopril (25, 50 and 100 mg/kg) and dipyridamole (20 and 60 mg/kg) failed to inhibit the elevation of serum creatinine. In the beraprost sodium-treated nephritic rats, the increase in mRNA levels for monocyte chemoattractant protein-1 (MCP-1) and collagen in the kidney was inhibited. These results suggest that beraprost sodium ameliorates developed renal dysfunction and is possibly an effective agent for the treatment of human glomerulonephritis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Blood Pressure; Blood Urea Nitrogen; Body Weight; Captopril; Chemokine CCL2; Creatinine; Dipyridamole; Epoprostenol; Glomerulonephritis; Kidney; Kidney Function Tests; Kidney Glomerulus; Male; Platelet Aggregation Inhibitors; Prednisolone; Proteinuria; Rabbits; Rats; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To clarify the function of polymorphonuclear leukocytes (PMN) in spontaneously hypertensive rats (SHR) and the effect of beraprost sodium (BS) on these functions, we examined superoxide anion (O2-) production and adherent activity by PMN, as well as modification of these functions by BS ex vivo and in vitro. In study 1, we measured PMN functions in 4-week-old SHR and Wistar-Kyoto (WKY) rats. In study 2 (ex vivo), 14-week-old SHR received vehicle (n = 6) and BS (30 microg/kg/day [n = 6] and 100 microg/kg/day [n = 7]) once daily for 4 weeks. In study 3 (in vitro), PMN from 18-week-old SHR were incubated with BS (0.1 and 1 micromol/L) and theophylline (200 micromol/L), which is reported to inhibit the PMN O2- production. Systolic blood pressure, platelet counts, and PMN O2- production stimulated by phorbol ester myristate acetate were significantly elevated in 4-week-old SHR compared with WKY (P < .05). Beraprost sodium decreased the ex vivo PMN O2- production, serum superoxide dismutase activity, and platelet counts (P < .05); however, BS did not reduce the in vitro PMN O2- production. These data support our hypothesis that the enhanced PMN function contributes to the cardiovascular damages during the early phase of SHR, and that BS has merit for preventing the O2- related organ damages in this model.

Topics: Animals; Anti-Inflammatory Agents; Blood Pressure; Body Weight; Epoprostenol; Hypertension; Male; Neutrophils; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Superoxides

The effects of beraprost sodium (BPS), a stable prostacyclin analogue, on the tail flick (TF) latency were investigated in streptozotocin-induced (STZ;55mg/kg, i.p.) diabetic male Sprague-Dawley (SD) rats and in spontaneously diabetic WBN/Kob rats. The SD rats were divided into 5 groups, i.e., (I) normal, (II) diabetic control, diabetic treated with (III) BPS (10 micrograms/kg/day), (IV) BPS (30 micrograms/kg/ day), and (V) aldose reductase inhibitor (ARI; epalrestat, 50 micrograms/kg/day). The drugs were administered orally. At 12 weeks, TF latency was significantly longer in untreated diabetic rats than in normal rats. After 4 weeks treatment, BPS significantly improved the abnormality in TF latency dose-dependently. But ARI did not normalize the response. The 45 weeks male WBN/Kob rats were divided into 2 groups: diabetic control and diabetic treated with BPS at 30 micrograms/kg/day, p.o., respectively. Untreated, age-matched wistar rats were served as the normal group. At 61 weeks, TF latency was significantly longer in control WBN/Kob rats than in normal wistar rats in time-dependent manner. After 16 weeks treatment, BPS significantly normalized the prolongation in TF latency. In in vivo experiments, BPS significantly increased the cyclic AMP (cAMP) content in sciatic nerves from normal rats dose-dependently. In STZ-induced diabetic rats, cAMP content in sciatic nerves were significantly reduced, and 4 weeks treatment of BPS significantly restored this reduced cAMP content. It was suggested that BPS may be effective on diabetic neuropathy by, at least in part, maintenance of cAMP contents in the nerves.

Topics: Animals; Blood Glucose; Body Weight; Cyclic AMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dose-Response Relationship, Drug; Epoprostenol; Male; Pain; Rats; Rats, Mutant Strains; Rats, Sprague-Dawley; Sciatic Nerve; Time Factors; Vasodilator Agents

A study of albuminuria, creatinine clearance (CCr) and blood pressure of streptozotocin (STZ)-induced diabetic rats with or without treatment by a prostacyclin (PGI2) analog, beraprost sodium (BPS), is described. Glomerular prostanoid synthesis was measured by gas chromatography (GC) mass spectrometry. Renal specimens stained with hematoxylin and eosin and periodic acid-Schiff were examined by light microscopy. Mean values of albuminuria in BPS-treated diabetic rats were significantly decreased compared with those in nontreated diabetic rats. The ratio of kidney to body weight in the BPS-treated diabetic rats was significantly lower than that in the nontreated diabetic rats. Levels of CCr and blood pressure were decreased in diabetic rats after the treatment with BPS. GC mass spectrometry showed that BPS did not influence the glomerular synthesis of PGI2 and TXB2. No histologic injury in the renal tissues was observed in the diabetic rats with or without BPS treatment. We concluded that BPS (PGI2 analog) might decrease the levels of urinary albumin excretion and CCr due to its vasodilating effects in the early phase of STZ-induced diabetes in rats.

Topics: Albuminuria; Animals; Blood Pressure; Body Weight; Creatinine; Diabetes Mellitus, Experimental; Epoprostenol; Gas Chromatography-Mass Spectrometry; Kidney Glomerulus; Male; Organ Size; Prostaglandins; Rats; Rats, Sprague-Dawley

We examined whether beraprost sodium (beraprost), a stable prostacyclin analogue, prevented cardiomyopathy in diabetic rats in vivo. Diabetes was induced by a bolus injection of streptozotocin in rat-tail vein. Four weeks after the induction of diabetes, the animals were treated with beraprost (30 micrograms/kg/day, p.o.) for 4 weeks until they were used for the measurement of hemodynamics, electrocardiogram (ECG), and plasma creatine phosphokinase (CK) activity. Nontreated diabetic rats have lower mean blood pressure, heart rate, left ventricular systolic pressure, and peak positive dP/dt at basal levels compared to age-matched normal rats. All of these changes were not improved in beraprost-treated rats. The left ventricular end-diastolic pressure and ST/R ratio in the ECG were significantly increased in diabetic rats. These parameters were significantly improved by beraprost compared with nontreated diabetic rats. Additionally, beraprost significantly suppressed the elevation of plasma CK activity as compared with that in non-treated diabetic rats. Changes in peak positive dP/dt in response to isoproterenol were attenuated in nontreated diabetic rats as compared with age-matched normal rats and beraprost-treated diabetic rats. These results suggest that beraprost is capable of preventing diabetic cardiomyopathy without affecting hyperglycemic condition.

Topics: Administration, Oral; Animals; Blood Glucose; Blood Pressure; Body Weight; Cardiomyopathies; Creatine Kinase; Diabetes Mellitus, Experimental; Electrocardiography; Epoprostenol; Heart Rate; Male; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Streptozocin; Ventricular Function, Left

We evaluated the effects of beraprost Na (Sodium (+-)-(1R*,2R*, 3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3- hyd roxy-4-methyl-1- octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butylate, beraprost), a stable and orally active prostacyclin (PGI2) analog with potent antiplatelet and vasodilating properties, on two stroke models, namely sudden death induced by arachidonate (AA) in rabbits and spontaneous stroke in stroke-prone spontaneously hypertensive rats (SHRSP). In the AA-induced sudden death model, 30 min after beraprost administration (1 or 3 mg/kg, po), AA was injected into the rabbit internal carotid artery, and incidence of convulsion and sudden death were assessed. Beraprost decreased both incidence of convulsion and mortality of rabbits. In SHRSP, orally administered beraprost (100 micrograms/kg, twice a day from 56-385 d of age) improved survival rate and decreased incidence of stroke. Preventive effects of beraprost on the two stroke models may have been caused mainly by the improvement of cerebral circulation. These results indicate that beraprost may have potential in the treatment and/or prevention of the cerebral circulatory disorders.

Topics: Animals; Arachidonic Acid; Blood Pressure; Body Weight; Cerebrovascular Circulation; Cerebrovascular Disorders; Death, Sudden; Diltiazem; Epoprostenol; Male; Platelet Aggregation Inhibitors; Rabbits; Rats; Rats, Inbred SHR; Ticlopidine