Contribution of prostaglandins in hypoxia-induced vasodilatation in isolated rabbit hearts. Relation to adenosine and KATP channels

The mechanism of hypoxia-induced coronary vasodilatation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO₂ (from 520±6 to 103±9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF₁ (from 1.8±0.3 to a maximum of 4.4±0.9 pmol min^–1 g^–1). The cyclooxygenase inhibitor, diclofenac (1 M), blocked the release of PGI₂ and reduced hypoxia-induced vasodilatation (from 47±8% to 25±5%, P<0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K⁺ channel (K_ATP channel) activation in hypoxia-induced vasodilatation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (–48 ±7%) was found to be equivalent to the sum of their respective effects (–24±7 and –19±4%, respectively). Glibenclamide (0.3 M) reduced significantly hypoxia-induced vasodilatation (differential change in CPP of –27±6%) as well as the dilator response to 10 M adenosine and to the stable PGI₂-analogue, iloprost. Forskolin-induced coronary vasodilatation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of K_ATP channels. K_ATP channel activation by prostacyclin and adenosine may involve both cyclic adenosine monophosphate-dependent and independent pathways.     

Early Protective Effects of Iloprost after Experimental Spinal Cord Ischemia in Rabbits

The potential role of Iloprost, a stable analogue of prostocyclin, in treating spinal cord ischemia was investigated in rabbits subjected to aortic occlusion for 15 minutes. Ten adult rabbits weighing 2-2.5 kg received an intravenous infusion of saline (SF) as a control group and 14 rabbits received an intravenous infusion of Iloprost, 25 microg/kg/h. Iloprost infusion was started immediately after clamping of the aorta and continued 60 minutes thereafter. Cortical somatosensorial evoked potentials (CSEP) were recorded during the pre-ischemic period as a baseline and post-ischemic readings were taken at 15, 30 and 60 minutes. There was no statistically significant difference between CSEP of the saline and Iloprost treated groups (p < 0.05). All animals were examined neurologically by using a modification of Tarlov scale and all subjects were then deeply anesthetized and their spinal cords were removed for light and electron microscopic examinations at 24 h after spinal cord ischemia. In order to obtain an accurate comparison of ultrastructural changes between saline treated and Iloprost treated groups, a grading scale was performed. The light microscopic and ultrastructural analysis of the Iloprost treated group revealed that there was moderate protection of the myelin and axons and edema was attenuated. Findings of this study suggest that Iloprost exerts a protective effect on spinal cord ischemia. However, further studies are needed to reveal possible mechanisms of protection provided by Iloprost.     

吸入伊洛前列素对初入高海拔地区青年血流动力学的影响

目的探讨雾化吸入伊洛前列素溶液对初入高海拔地区青年血流动力学的影响。方法将32名受试者随机分为伊洛前列素组(n=16)和对照组(n=16),自海拔1 400 m历时5 d进入5 200 m,从进入海拔5 200 m当天开始,伊洛前列素组4次/d雾化吸入伊洛前列素溶液,连续5 d。对照组用同样的方法吸入生理盐水。于吸入伊洛前列素溶液第5天,用XG-Ⅲ型血液循环功能自动测试仪检测两组受试者的血流动力学。结果伊洛前列素组较对照组P、TPR、ALT、η、BK、PAWP、CCP降低,差异有统计学意义(P<0.05);SV、MAP、BV增高,差异有统计学意义(P<0.05)。结论在高原雾化吸入伊洛前列素溶液对初入高海拔地区青年血流动力学有明显的改善作用。     

Captopril and ramiprilat protect against free radical injury in isolated working rat hearts

The protection of angiotensin converting enzyme (ACE) inhibitors, captopril and ramiprilat, against free radical-mediated myocardial injury were studied in isolated working rat hearts. Free radicals were generated by electrolysis of Krebs-Henseleit solution with 10 mA direct current for 1 min. Both captopril (360 μmol/l) and ramiprilat (12.5 μmol/l) significantly reduced the decrease of left ventricle dP/dt′_max, coronary flow (CF), myocardial superoxide dismutase (SOD) and creatine kinase (CK) activities and the elevation of S-T segment of epicardial ECG as well as the rise of myocardial malondialdehyde (MDA) content caused by electrolysed perfusate. Captopril afforded a dose-dependent protection on cardiac functions with various concentrations of 45, 90, 180 and 360 μmol/l. Iloprost (30 nmol/l), a stable mimetic of prostacyclin, could also alleviate free radical-mediated myocardial injuries. All the beneficial effects of ramiprilat (12.5 μmol/l) were abolished by the administration of indomethacin (5 μmol). In contrast, captopril (90 μmol/l) still exhibited significant protective effects after indomethacin (9 μmol) was administered, though these protective effects were insignificantly weakened. In order to assess the role of sulfhydryl (-SH) group in the effects of captopril, a SH-containing drug S8 and a disulfide DG4, both are deficient in ACE inhibitory properties in vitro, were examined. Data showed that S8 (180 μmol/l) provided a significant protection while DG4 showed no protective effect. It is concluded that ACE inhibitors can protect against free radical-induced myocardial damage. Ramiprilat, a non-SH-containing ACE inhibitor, inhibits free radical-induced damages mainly by stimulation of prostacyclin synthesis and/or release. In addition to this effect, captopril, a SH-containing ACE inhibitor, may exert additional anti-free radical effects by a mechanism which is probably related to the sulfhydryl group.     

The effects of iloprost on colonic anastomotic healing in rats under obstructive ileus conditions

Background

The aim of this study was to investigate the effects of iloprost, on colonic anastomotic healing in rats, under obstructive ileus conditions.

Materials and methods

Eighty male Albino rats were randomized into four groups of 20 animals each. They underwent colonic resection followed by an inverted anastomosis. The rats of group 1 (control) and group 2 (ileus) received 3 mL of saline 0.9% intraperitoneally and those of group 3 (iloprost), and group 4 (ileus + iloprost) iloprost (2 μg/kg of body weight), immediately postoperatively and daily until the day of sacrifice. Each group was further divided into two equal subgroups, depending on the day of sacrifice. The animals of subgroup “a” were sacrificed on the fourth postoperative day, whereas those of “b” on the eighth day. Macroscopic and histologic assessment was performed, whereas anastomotic bursting pressures and the tissue concentrations in hydroxyproline and collagenase I were evaluated.

Results

Means of bursting pressure, neoangiogenesis, fibroblast activity, and hydroxyproline concentration were significantly increased in group 4 compared with group 2. In addition, on the fourth postoperative day, the inflammatory cell infiltration and the collagenase I concentration were significantly decreased in group 4 compared with group 2. Moreover, on the eighth postoperative day, collagen deposition was significantly increased in group 4 compared with group 2.

Conclusions

Iloprost after intraperitoneal administration reverses the negative effect of obstructive ileus. It promotes not only the angiogenic activity but also collagen formation, resulting in increased bursting pressures on the fourth and eighth postoperative days.     

The effects of iloprost on ischemia-reperfusion injury in skeletal muscles in a rodent model

Purpose

The aim of this study was to investigate the effects of iloprost (IL) on ischemia-reperfusion injury in a rodent model.

Materials and methods

Twenty-four Wistar Albino rats were randomized into four groups (n = 6). Laparotomy was performed in all groups under general anesthesia. Only laparotomy was applied in group S (Sham). Ischemia-reperfusion group (group I/R) underwent ischemia and reperfusion performed by clamping and declamping of the infrarenal abdominal aorta for 120 min. The iloprost group (group IL) received intravenous infusion of IL 0.5 ng/kg/min, without I/R. Group I/R + IL received intravenous infusion of IL 0.5 ng/kg/min immediately after 2 h period of ischemia. At the end of the reperfusion period, all rats were killed under anesthesia and skeletal muscle samples of lower extremity were harvested for biochemical and histopathologic analyses.

Results

Tissue levels of endothelial nitric oxide were significantly higher in I/R groups than those in groups S and IL. The heat shock protein 60 levels were higher in group I/R than the other groups. But the heat shock protein 60 levels in group I/R + IL were found to be similar with the groups S and IL. Malondialdehyde levels were significantly higher in group I/R. On the other hand, in group I/R + IL, malondialdehyde levels were higher than those in groups S and IL but lower than those in group I/R. Superoxide dismutase (SOD) enzyme activities were found to be significantly lower in group I/R than the other groups. Also in group I/R/I, the SOD enzyme activities were higher than those in group I/R. But, in group I/R + IL, SOD levels were found to be higher than those in group I/R but lower than those in groups S and IL.

Conclusions

These results indicate that IL has protective effects on I/R injury in skeletal muscle in a rodent model.     

通气侧肺吸入伊洛前列素对肺动脉压和缺氧性肺血管收缩的影响

目的 探讨雾化吸入伊洛前列素对大鼠单肺通气(one-lung ventilation,OLV)期间肺动脉压和缺氧性肺血管收缩(hypoxic pulmonary vasoconstriction,HPV)的影响。方法 雄性SD大鼠30只,随机分为A、B、C三组,每组10只。原位离体肺灌注模型建立后,调整气管导管深度致左侧肺OLV,FiO_2为100%,打开连接于呼吸回路的雾化器,A组吸入生理盐水,B组吸入伊洛前列素0.05μg·kg-1·min-1,C组吸入伊洛前列素0.1μg·kg~(-1)·min~(-1),记录灌注10min(T_1)、雾化吸入10min(T_2)和OLV 1h(T_3)的平均肺动脉压(MPAP)及左心房引流液氧分压(PaO_2)。通过测量T_1、T_2和T_3时的左心房引流液PaO_2计算氧合指数(oxygenation index,OI)。实验结束分别取双侧肺组织进行电镜检查。结果 与T_1时比较,T_2、T_3时三组MPAP明显升高(P0.05);T_2、T_3时B、C组MPAP明显低于A组(P0.05),且C组MPAP明显低于B组(P0.05)。与T_1时比较,T_2、T_3时三组OI明显降低(P0.05);T_2、T_3时C组OI明显高于B组(P0.05)。相对于B、C组通气侧,A组通气侧与A、B、C组非通气侧Ⅱ型肺泡上皮细胞核膜外突内陷,部分板层小体排空。结论 在大鼠原位肺灌注模型中,单肺通气期间雾化吸入伊洛前列素能明显降低平均肺动脉压,减少肺内分流并增加氧合。     

伊洛前列素治疗儿童先天性心脏病并肺动脉高压临床研究

目的 探讨吸人伊洛前列素(万他维)对先天性心脏病(先心病)并肺动脉高压患儿心功能的影响.方法 选择一组先心病患儿术前用口含器或面罩吸入万他维,剂量为25～30 ng·kg-1·min-1,以2 ml0.9%氯化钠溶液稀释后,通过PARI Junior BOY N压缩机压缩雾化吸入,每3小时给药一次,吸入60 min、120 min、180 min后采用连续多普勒超声波技术,测量左右心每搏心排量等血流动力学参数变化.结果 在用药前和后60 min、120 min、180 min,除血流动力学有明显变化,还发现用药后左、右心排血量增加,用药后再行手术的患儿,呼吸机带管时间缩短,术后恢复顺利.结论 吸人伊洛前列素可以增加心输出量,改善心功能,提示该方法治疗先心病并肺动脉高压有效可行.     

Antiplatelet effects of intravenous iloprost in patients with peripheral arterial obliterative disease

Summary The dose-dependent inhibition of platelet aggregation by the chemically stable, prostacyclin-mimetic, iloprost, was studied in patients suffering from stage II–III peripheral arterial obliterative disease (PAOD). The study was designed as a randomized placebo-controlled cross-over trial. Iloprost was administered i.v. to six patients at doses of 0.5, 1.0, 2.0 or 3.0 ng/kg×min for 4 h, with an interval of 2–3 days between the infusions. During iloprost infusion, systolic and diastolic arterial blood pressure, heart rate and blood flow in the affected limb remained unchanged. In contrast, there was a considerable, dose-dependent inhibition of ADP- and thrombin-induced platelet aggregation and secretion ex vivo at doses of 0.5–2.0 ng/kg×min iloprost, indicating that iloprost reduced platelet stimulation by 50%–70%. The antiplatelet action of iloprost remained unchanged during infusion but ceased with 2 h after administration had ended. The agent was tolerated by the patients without unacceptable side-effects at doses up to 2 ng/kg × min. It is concluded that iloprost administered i.v. at doses of 1–2 ng/kg×min in patients with stage II–III PAOD does not involve haemodynamic side-effects and might be considered an effective antiplatelet agent.Abbreviations ADP Adenosinediphosphate - PGI₂ Prostacyclin - PRP platelet rich plasma - TXA₂ Thromboxane A₂ - 12-HPETE 12-hydroperoxy-eicosatetraenoic acid Presented in part as a preliminary report at the II. International Prostaglandin Symposium, Nürnberg-Fürth, 1984     

Acute reversible reduction of PGI2 platelet receptors after iloprost infusion in man

Platelet sensitivity to PGI2 and platelet PGI2 receptors were investigated in eight subjects with peripheral artery disease (stage IV according to Fontaine) treated for 14 consecutive days with six hour iv infusion of Iloprost (Schering, FRG) 2 ng/Kg/min. Platelet studies were performed on the 1st, the 2nd, the 7th and the 14th day of therapy, immediately before infusion (between 8.00 and 9.00 a.m.), at the end and 6 and 18 hours (the following morning) after the end of the infusion. Platelet sensitivity to PGI2 was assessed by determining the PGI2 inhibitory dose 50(ID 50) on platelet aggregation induced by 5 μM ADP. PGI2 platelet receptors were investigated by a direct radioligand binding assay.

PGI2 ID 50 after the infusion was significantly higher than that at baseline(p<0.01) and six hours later the baseline sensitivity was restored. After the six hour Iloprost iv infusion a significant reduction in the number of high affinity PGI2 platelet receptor (HAR) was observed (p<0.005) without any change in their affinity for the ligand. Six hours after the end of the infusion the number of the HAR was still significantly reduced (p<0.05). The following morning the receptor number of HAR was restored. The baseline values of PGI2 HAR, when reassessed after seven and fourteen days of treatment, were not significantly different from those recorded on the first day of therapy. These data indicate that the reduction of platelet PGI2 sensitivity following short-term Iloprost infusion is rapidly reversible and is related to a contemporary down-regulation of PGI2 platelet receptors. However the observed decrease of the number of PGI2 receptors, in the absence of any changes in affinity for the ligand, seems unable to explain the reduced biological effects so that the existence of other post-binding alterations could be postulated.