Alprostadil attenuates myocardial ischemia/reperfusion injury by promoting antioxidant activity and eNOS activation in rats

Abstract Purpose: To investigate the effect of alprostadil on myocardial ischemia/reperfusion (I/R) in rats. Methods: Rats were subjected to myocardial ischemia for 30 min followed by 24h reperfusion. Alprostadil (4 or 8 μg/kg) was intravenously administered at the time of reperfusion and myocardial infarct size, levels of troponin T, and the activity of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were measured. Antioxidative parameters, nitric oxide (NO) content and phosphorylated endothelial nitric oxide synthase 3 (p-eNOS) expression in the left ventricles were also measured. Histopathological examinations of the left ventricles were also performed. Results: Alprostadil treatment significantly reduced myocardial infarct size, serum troponin T levels, and CK-MB and LDH activity (P<0.05). Furthermore, treatment with alprostadil significantly decreased malondialdehyde (MDA) content (P<0.05) and markedly reduced myonecrosis, edema and infiltration of inflammatory cells. Superoxide dismutase and catalase activities (P<0.05), NO level (P<0.01) and p-eNOS (P<0.05) were significantly increased in rats treated with alprostadil compared with control rats. Conclusion: These results indicate that alprostadil protects against myocardial I/R injury and that these protective effects are achieved, at least in part, via the promotion of antioxidant activity and activation of eNOS.

The protective effect of Papaverine and Alprostadil in rat testes after ischemia and reperfusion injury

ABSTRACT Objective: To investigate the effect of papaverine and alprostadil on testicular torsion-detorsion injury in rats. Materials and Methods: A total of 40 male Wistar-Albino rats were used in this study. Four hours of right testicular torsion was applied to each group, excluding sham oper- ated group. The torsion-detorsion (T/D), T/D + papaverine and T/D + alprostadil groups received saline, papaverine and alprostadil at the same time as surgical detorsion, respectively. At 14 days after the surgical detorsion, ischaemic changes and the degree of damage were evaluated with Cosentino scoring and the Johnson tubular biopsy score (JTBS). Results: JTBS was determined as 8.8±2.7 in the Sham group, 5.08±1.9 in the T/D+papaverine group, 5.29±2.3 in the T/D +alprostadil group and 2.86±1.9 in the TD group. The JTBS was determined to be statistically significantly high in both the T/D + papaverine group and the T/D + alprostadil group compared to the T/D group (p=0.01, p=0.009). In the T/D + papaverine group, 3 (43%) testes were classified as Cosentino 2, 3 (43%) as Cosentino 3 and 1 (14%) as Cosentino 4. In the T/D +alprostadil group, 5 (50 %) testes were classified as Cosentino 2, 3 (30 %) as Cosentino 3 and 2 (20%) as Cosentino 4. Conclusion: The present study indicated that spermatic cord administration of alprostadil and papaverine showed a protective effect against ischemia/reperfusion injury after right-side testes torsion and histological changes were decreased after testicular ischemia reperfusion injury.

Pentoxifylline and prostaglandin E1 action on ischemia and reperfusion of small intestine tissue in rats. An immunohistochemical study

PURPOSE: To investigate the action of pentoxifylline (PTX) and prostaglandin E1 (PGE1) on ischemia and reperfusion of small intestine tissue in rats, using immunohistochemical analysis. METHODS: Thirty-five Wistar rats were distributed as follows: group A (n=10): subjected to intestinal ischemia and reperfusion for 60 min, with no drugs; group B (n=10): PTX given during tissue ischemia and reperfusion; group C (n=10): PGE1 given during tissue ischemia and reperfusion; group D (n=5): sham. A segment of the small intestine was excised from each euthanized animal and subjected to immunohistochemical examination. RESULTS: Mean number of cells expressing anti-FAS ligand in the crypts was highest in Group A (78.9 ± 17.3), followed by groups B (16.7 ± 2.8), C (11.3 ± 1.8), and D (2.5 ± 0.9), with very significant differences between groups (p<0.0001). CONCLUSIONS: The use of pentoxifylline or prostaglandin E1 proved beneficial during tissue reperfusion. The immunohistochemical results demonstrated a decrease in apoptotic cells, while protecting other intestinal epithelium cells against death after reperfusion, allowing these cells to renew the epithelial tissue. .

Alprostadil attenuates inflammatory aspects and leucocytes adhesion on renal ischemia and reperfusion injury in rats

PURPOSE: To evaluate the effects of alprostadil in an experimental model of ischemia and reperfusion injury (IRI) in rat renal tissue. METHODS: Adult male Wistar rats were randomized into three groups Vehicle-treated group(Veh), Alprostadil-treated(Al), and sham(Sh) group. Veh and Al groups had suprarenal aorta occluded for 30 minutes and reperfused for 60 minutes. Saline or 20 µg/kg of Alprostadil was intravenously infused immediately before declamping. Sh group animals underwent similar procedure without aortic occlusion. Left nephrectomy and blood sampling were performed after 60 minutes of reperfusion. Renal ICAM-1 expression and histological analysis were performed to estimate inflammatory response and tissue disarrangement. Serum biochemical markers for IRI were also measured. Kruskal-Wallis test was used to assess differences between the groups. RESULTS: There was lower expression of ICAM-1 in groups Veh and Sh. On histologically evaluation, inflammation and necrosis in the Veh group was significantly higher (grades III/IV) than Al group (Veh>Al=Sh; p = 0.025), as well as CPK levels (Veh>Al=Sh; p = 0.03). CONCLUSION: Alprostadil attenuates the immunohistochemical and histological repercussions in the renal tissue of rats submitted to a post-ischemic reperfusion with supra-renal aortic clamping. .

Ischemia and reperfusion of rat small intestine using pentoxyfilline and prostaglandin E1

PURPOSE: To investigate the small intestinal tissue alterations in rats submitted to ischemia and tissue reperfusion using pentoxyfilline or prostaglandin E1. METHODS: Thirty five Wistar rats were used, distributed into group control (A) n=10 were submitted to intestinal ischemia and reperfusion during 60 minutes and no one drug have been utilized. In the group pentoxyfilline (B) n=10 have been utilized during tissue ischemia and reperfusion as well as prostaglandin E1 (C) n=10, but separately. In the group sham (D) n=5, the animals were submitted to surgical. After euthanasia of the animals, a segment of the small intestine was cut, stained by hematoxilin-eosin and histological analysis according to Chiu criteria. RESULTS: Histological results showed that using pentoxyflline or prostaglandin E1 the results during tissue reperfusion were better, since the levels of criteria from Chiu that predominated were level 2 and 3, indicating less tissue damage in comparison to the control group (group A) that showed levels 4 and 5, what means more severe histological tissue alterations. CONCLUSION: Use of pentoxyfilline or prostaglandin E1 promoted a beneficial effect during intestinal reperfusion, demonstrated by less severe histological lesions in the small intestine mucosa of rats submitted to ischemia and tissue reperfusion when helped by the drugs.

Study of rat hepatocytes in primary culture submitted to hypoxia and reoxygenation: action of the cytoprotectors prostaglandin E1, superoxide dismutase, allopurinol and verapamil / Estudo de hepatócitos de rato em cultura primária submetidos a hipóxia e reoxigenação: ação dos citoprotetores prostaglandina E1, superóxido dismutase, alopurinol e verapamil

Context: Exposure of hepatocytes to pathological conditions in a microenvironment of hypoxia and reoxygenation is very frequent in hepatic diseases. Several substances present perspectives for cytoprotective action on hepatocyte submitted to reoxygenation after hypoxia and simple hypoxia. Objective: We research therapeutic options for hepatocytes submitted to hypoxia and hypoxia + reoxygenation injury. Methods: Primary culture of rat hepatocytes was submitted to hypoxia (2 hours) plus reoxygenation (2 hours) and simple hypoxia (4 hours) in the presence or the absence of cytoprotectors. The hepatocyte lesion was evaluated by functional criteria through percentage of lactate dehydrogenase released and cell viability. The effects of the cytoprotectors prostaglandin E1 3 ηg/mL, superoxide dismutase 80 μg/mL, allopurinol 20 μM and verapamil 10-4 M were studied in this model of injury. Results: Reoxygenation after hypoxia induced more significant lesion in cultured hepatocytes compared to simple hypoxia, detected by analysis of functional criteria. There was a significant reduction of percentage of lactate dehydrogenase released and a significant increase of percentage of cell viability in the hypoxia + reoxygenation + cytoprotectors groups compared to hypoxia + reoxygenation groups. Prostaglandin E1, superoxide dismutase and verapamil also protected the group submitted to simple hypoxia, when evaluated by functional criteria. Conclusions: We conclude that reoxygenation after hypoxia significantly increased the lesion of cultured rat hepatocytes when compared to simple hypoxia. Prostaglandin E1, superoxide dismutase, allopurinol and verapamil acted as cytoprotectors to the rat cultured hepatocytes submitted to hypoxia + reoxygenation in vitro. The substances prostaglandin E1, superoxide dismutase and verapamil protected hepatocytes submitted to simple hypoxia on the basis of all the criteria studied in this experimental model.

Contexto: A exposição dos hepatócitos a condições patológicas em que ocorram microambientes de hipóxia e reoxigenação são muito frequentes em doenças hepáticas. Várias substâncias apresentam perspectivas de ação citoprotetora para hepatócitos submetidos a reoxigenação após hipóxia e hipóxia simples. Objetivo: Pesquisaram-se opções terapêuticas para o dano dos hepatócitos submetidos a hipóxia e hipóxia + reoxigenação. Métodos: Hepatócitos de rato em cultura primária foram submetidos a hipóxia (2 horas) mais reoxigenação (2 horas) e hipóxia simples (4 horas), na presença ou ausência dos citoprotetores. A lesão dos hepatócitos foi avaliada por critérios funcionais através da percentagem liberada de desidrogenase láctica e da viabilidade celular. Os efeitos dos citoprotetores prostaglandina E1 3 ηg/mL, superóxido dismutase 80 μg/mL, alopurinol 20 μM e verapamil 10-4M, foram estudados neste modelo de injúria celular. Resultados: A reoxigenação após hipóxia induziu lesão mais significativa nos hepatócitos cultivados comparado com hipóxia simples, conforme demonstrado pela análise dos critérios funcionais. Houve significativa redução da porcentagem liberada de desidrogenase láctica e aumento significativo da percentagem de viabilidade celular nos grupos hipóxia + reoxigenação + citoprotetores em comparação com o grupo hipóxia + reoxigenação. Prostaglandina E1, superóxido dismutase e verapamil também protegeram o grupo hipóxia simples, quando avaliado pelos critérios funcionais. Conclusões: Conclui-se que a reoxigenação após hipóxia aumentou significativamente a lesão dos hepatócitos de rato cultivados, em comparação com a hipóxia simples. Prostaglandina E1, superóxido dismutase, alopurinol e verapamil foram citoprotetores para os hepatócitos de rato submetidos a hipóxia + reoxigenação in vitro. As substâncias prostaglandina E1, superóxido dismutase e verapamil protegeram os hepatócitos submetidos a hipóxia simples com base em...

Influência do alprostadil na cicatrização da anastomose de esôfago cervical: estudo em cães / Alprostadil and it's healing on cervical esophageal anastomosis in dogs

Nas operações do esôfago deiscências nas anastomoses correpondem à graves complicações. Anastomoses esôfago-esofágicas cervicais demonstram altas taxas de deiscências. Muitos fatores podem estar envolvidos nelas tais como a tensão na anastomose, distribuição do suprimento sanguíneo, trauma local, obstrução e infecção...

Cervical esophageal anastomosis has high dehiscences rates and mortality. Many factors can be involved on it, such as anastomotic tension, impared blood supply, local trauma, blockage and infection...

Soluble P-and E- selectins and ultrastructural evaluation of canine liver after reperfusion with methylprednisolone and prostaglandin E 1

Ischemia reperfusion injury [IRI] is a multifactorial process that may be the main underlying factor in critical phases faced during and after liver transplantation. This work evaluates the effect of methylprednisolone [MP] and prostaglandin El [PGE1] on IRI of the liver of dogs at the ultrastructural level together with the assessment of soluble P-and E- selectin levels. Three groups of dogs [9 each] were subjected to 60 min ischemia followed by 30 min reperfusion with the appropriate solution according to the group. Group I, the control untreated group was flushed with Ringer's solution, group II was administered 10 mg/kg MP 24 hours before the procedure and with induction of anaesthesia, and group III was flushed with PGE1 in Ringer's solution at a rate of 0.02 microg/kg/min. Liver specimens were collected before ischemia, after ischemia and after reperfusion and were processed for the preparation of ultrathin sections for electron microscopic examination. Corresponding venous blood samples were harvested, centrifuged and serum was processed for the estimation of soluble P-and E- selectins by enzyme immunoassay, together with alanine and aspartate aminotransferases. Electron microscopic [EM] examination of liver ultrathin sections revealed that the morphological structure of hepatocytes and endothelial lining of hepatic sinusoids were well preserved in the group treated with PGE1. Hepatic ultrastructure was much altered in MP treated group showing necrotic and degenerative changes. The control untreated group disclosed bleb formation of hepatocytic membrane with increased leukocyte infiltration. Soluble P-and E- selectin levels were significantly elevated in the control group, near to pre-ischemic level in PGE1 group and showed a persistent elevation in MP group. Serum transaminases [AST and ALT] were significantly elevated in both control and MP groups as compared to their corresponding pre-ischemic levels. Yet, in PGE1 group, their values were comparable to the pre-ischemic ones. This work confirms the hepatoprotective effect of PGE1 in IR injury. The PGE1 impact on preserving the subcellular structure of hepatic sinusoids is crucial and may be mainly attributed to its biological properties. We presume that P-and E- selectins are greatly implicated in the mechanism of IR and may be an important therapeutic target by specific monoclonal antibodies

effects of PGE1 and indomethacin on orthodontic tooth movement in rat

Prostaglandin E1 [PGE1] and indomethacin, a nonstroidal antiinflammatory drug, were separately administered during orthodontic tooth movement in rats. At the beginning, an orthodontic appliance was placed and activated in male albinus rats. In the first examination, the experimental group received submucosal injections of PGE1 [10 mg/kg/day] near the first maxillary right molars, and alcohol was injected to control group animals as a vehicle similarly. In the second examination, indomethacin [10 mg/kg/day] and methyl cellulose subcutaneously injected to experimental and control groups respectively. Tooth movement was measured at 1,3,5,7,9 and 11 days. In PGE1 group, tooth movement increased significantly at the beginning of seven days as compared to the vehicle injected group and the number of osteoclast and Howship's lacunae were markedly increased. A significant inhibition of tooth movement occurred beginning at seven days in the indomethacin group compared to the control group

Prostaglandin E1 in infants with congenital heart disease: Indian experience.

BACKGROUND: E-type prostaglandins (PGE1) can effectively maintain the patency of the ductus arteriosus in neonates. Its use, therefore and be life saving in infants born with ductus dependent congenital heart disease. Although PGE1 is available for over two decade in western world, it has been introduced in India only since April, 1995. OBJECTIVE: To assess the efficacy of PGE1 at our center. SETTING: Hospital based. METHOD: 65 infants with ductus dependent congenital heart disease were included. Age at time of starting PGE1 infusion ranged from 18 hours to 39 days. Forty two of these were more than a week of age, 19 were more than 14 days, and two were above one month. PGE1 was started in an initial dose of 0.05 microgram/kg/min, decreased to 0.005-0.01 microgram/kg/min for maintenance. The indications for use of PGE1 were to increase pulmonary blood flow in 33 cases with pulmonary atresia, tricuspid atresia or critical pulmonic stenosis (Group I); to increase systemic blood flow in 15 cases with coarctation of aorta, hypoplastic left heart and interruption of aortic arch (Group II); to improve mixing in 13 cases of transposition of great arteries (Group III) and for improving the left ventricular volumes by keeping the duct open in 4 cases of transposition of great arteries with intact ventricular septum (Group IV). The efficacy of the drug was assessed by a rise on PaO2 and SaO2% determined for Group I & III, and by appearance of lower limbs pulses in Group II. Left ventricular volumes were serially measured by echocardiography in Group IV cases. RESULTS: The drug was successful in 62 of the 65 cases. There were two failures. One was a 39 days old baby with Ebstein's anomaly of tricuspid valve and pulmonary atresia and other was an eight days old baby with coarctation of aorta and renal failure. In addition, PGE1 could not be continued in another baby due to development of a linear skin rash locally. Side effects included apnea in 5 (9%) of 56 spontaneously breathing patients. Necrotizing enterocolitis, hyperpyrexia and jitteriness was sent in one case each. Six patients died. Two were related to PGE1, one due to failure, another due to its side effects. Definitive procedure were performed in 51 cases electively. PGE1 was used upto 13 days with sustained benefit. CONCLUSIONS: PGE1 is an effective drug for keeping the ductus open in infants with ductus dependent congenital heart disease. It can be used for neonates beyond the first week of life with efficacy. Apnea is a major side effect and close monitoring is essential.

Tratamiento de la impotencia post traumática con alprostadil intracavernoso / Treatment of the post-traumatic impotence with intracavernous alprostadil

Con el fin de tratar la impotencia sexual post-traumática se inició en 1995, el tratamiento con alprostadil intracavernoso. Se realizó diagnóstico con doppler de arteria cavernosa, potenciales evocados del nervio cavernoso y test de tumescencia peneana nocturna. Aquellos pacientes con impotencia orgánica se realizó una titulación progresiva; una vez conocida la dósis óptima se instruyó al paciente para la autoinyección. Un total de 15 pacientes entraron a este protocolo, con un seguimiento promedio de 12 meses. Después del análisis de los resultados, podemos concluir, que el tratamiento con alprostadil en este tipo de pacientes resulta ser eficiente; seguro y con gran satisfacción para los enfermos

Circulaçäo portal esplâncnica: reforço da intensidade da imagem radiológica e aumento da visibilizaçäo de colaterais com emprego da prostaglandina E1 / Splanchnic portal circulation: enhancement of the radiologic image intensity and of the visibility of collateral branches with the use of prostaglandin E1

Säo apresentados os resultados da comparaçäo entre mesentérico-portografias realizadas com e sem prostaglandina E1 (PGE1) injetada na artéria mesentérica superior como adjuvante à realizaçäo do exame angiográfico. Foram estudados 28 pacientes com variadas doenças hepáticas e biliopancreáticas nos quais, após cateterismo da artéria mesentérica superior, realizaram duas séries de arterio-mesentérico-portografias: a primeira só com contraste e a segunda com injeçäo prévia de 50 mug de prostaglandina E1 na forma de "bolus". Avaliaram-se, em cada série, a presença, a intensidade de opacificaçäo dos vários componentes do sistema portal e o tempo decorrido desde o início da injeçäo até o máximo da opacificaçäo. Observou-se que, com o uso da PGE1, houve opacificaçäo regular, acentuada e precoce da veia mesentérica superior, veia porta e ramos intra-hepáticos em todos os pacientes que apresentavam o eixo mesentérico-portal pérvio e/ou circulaçäo hepatópeta. Notou-se, também, a reduçäo significativa do tempo necessário para opacificar o sistema mesentérico-portal. Além disso, houve com o uso do fármaco, contrastaçäo das vias de circulaçäo colateral em maior número de doentes e aumento da sua intensidade. Devido aos bons resultados obtidos, à fugacidade da açäo do fármaco, à ausência de reaçöes colaterais cardiocirculatórias e/ou gerais é recomendado seu uso sistemático para estudo do sistema venoso portal esplâncnico.

Tratamento contemporâneo de disfunçäo erétil através de injeçäo intracavernosa / Contemporary treatment of erectile dysfunction through intracavernous injection

Desde 1970 o tratamento da impotência sexual tem sofrido inúmeras modificaçoes. Isto se deu graças ao profundo conhecimento adquirido, através de inúmeras pesquisas, da fisiofarmacologia envolvida na ereçao. A descoberta de que substâncias vasoativas injetadas dentro dos corpos cavernosos poderiam produzir uma ereçao fisiológica trouxe nova luz ao tratamento de tal moléstia. Esta nova modalidade terapêutica, doravante denominada auto-injeçao intracavernosa, é sem dúvida o tratamento de primeira escolha para o paciente com disfunçao erétil de qualquer etiologia em 1994. Neste artigo os autores descrevem as principais drogas utilizadas nesta modalidade terapêutica, assim como o seu mecanismo de açao e complicaçoes.

Mechanism of aspirin induced neural tube defect in chick embryo.

The effect of acetyl salicylic acid (aspirin) on neural tube development in chick embryo was studied, using the chick embryo blastoderm model. Aspirin was injected in four different doses sub-blastodermally into fresh embryonated eggs. The role of PGE1 and PGE2 alpha in the defect induced by aspirin on neural tube development in chick embryo was studied. PGE1 (5 micrograms) given after aspirin (30 micrograms) treatment was found to produce greater defect in development. All the four doses of aspirin used (i.e., 6, 30, 60 and 120 micrograms/embryo) produced significant changes (P < 0.01) in the neural tube development of chick embryo. Pre-treatment with PGE1 did not modify the defect induced by aspirin, whereas pre-treatment with PGF2 alpha prevented neural tube defects induced by aspirin. It appears that aspirin (in the doses used) affects neural tube formation by decreasing PGF2 alpha synthesis in chick embryo blastoderm.

Is asparagine-linked protein glycosylation an obligatory requirement for angiogenesis?

Dependence of protein N-glycosylation on capillary endothelial cell proliferation has been studied. Amphomycin, a potent N-glycosylation inhibitor, inhibited capillary endothelial cell proliferation in a dose-dependent manner. beta-Agonist isoproterenol as well as other intracellular cAMP enhancing agents, viz. cholera toxin, prostaglandin E1 and 8Br-cAMP, also enhanced capillary endothelial cell proliferation. In addition to cell proliferation, isoproterenol also enhanced protein glycosylation in these cells. Isoproterenol effect was mediated by beta-adrenoreceptors, as it got reduced on pre-treatment of cells with either atenolol or ICI 118, 551 or propranolol. Furthermore, isoproterenol stimulation of protein glycosylation by exogenous dolichyl monophosphate and its inhibition by tunicamycin (GlcNAc-1P transferase inhibitor) supported the concept that isoproterenol specifically stimulated protein N-glycosylation event(s) in the cell.

Further studies on the influence of dibutyryl cAMP, theophylline and prostaglandin E1 on composition and biosynthesis of phospholipids in Microsporum gypseum.

Exogenous supplementation of dibutyryl cAMP and cAMP modulators like theophylline and prostaglandin E1 in the growth medium of Microsporum gypseum lead to increase in the levels of phosphatidylcholine and lysophosphatidylcholine and thereby in total phospholipid content. These observations were further confirmed by the increased incorporation of [32P]orthophosphoric acid into total phospholipid and [14C]choline into phosphatidylcholine and lysophosphatidylcholine. The activity of sn-glycerol-3-phosphate acyltransferase, the enzyme involved in phospholipid synthesis, was stimulated in the presence of dibutyryl cAMP, theophylline and PGE1 supporting the increased synthesis of phospholipids.

Prostaglandin E1 (PGE1): effect on the human fibrinolytic system.

The in vitro effect of prostaglandin E1 on the fibrinolytic process was assessed in 30 patients with acute myocardial infarction (MI) using Thrombin Time (TT) and Euglobulin Clot Lysis time (ECLT) as parameters. Thrombin time was shortened and ECLT was prolonged (p less than 0.001) in acute MI as compared to thirty age and sex matched controls. In both groups, preincubation of sera with PGE1 (3.3 micrograms/ml) produced prolongation of TT and shortening of ECLT (p less than 0.001). Thus PGE1, which is a naturally occurring vasodilator and antiplatelet agent, also appears to have fibrinolytic activity.

Gastric cytoprotection induced by prostaglandin-dopaminergic mechanism

Se estudió el efecto citoprotector sobre la mucosa gástrica de la Bromcriptina ante la injuria del etanol absoluto, donde dio citoprotección gástrica similar al Misoprostol. Pretratamiento con SCH 23390 (un antagonista de los receptores dopaminérgicos vasculares periféricos) y Domperidona ( un antagonista de los receptores dopaminérgicos neurales periféricos), mostró que Misoprostol fue dependiente de los receptores dopaminérgicos periféricos en su mecanismo citoprotector; así como Bromocriptina fue un agonista dopaminérgico neuronal periférico en su mecanismo citoprotector. Pretratamiento con Indometacina, mostró que los receptores dopaminérgicos periféricos fueron dependientes de las prostaglandinas endógenas en su mecanismo citoprotector. En conclusión, fue postulado un mecanismo prostaglandino-dopaminérgico periférico en la citoprotección de la mucosa gástrica