The effect of Intraportal PGE1 on Warm Ischemic Liver Damage

To determine the most effective route of administering prostaglandin E₁ (PGE₁) to inhibit warm ischemic liver damage, 90-min warm ischemia was established in a canine model. The dogs were divided into three groups according to the treatment given. Thus, group A (n = 10) was the control group which received no treatment, group B (n = 7) was administered PGE₁ intravenously, and group C (n = 7) was administered PGE₁ intraportally. PGE₁ was continuously administered before and after the ischemia at a rate of 0.02⦰/min. The branched-chain amino acid to aromatic amino acid ratio in the hepatic vein, and the arterial ketone body ratio of acetoacetic acid to -hydroxybutyric acid, were examined to observe the metabolism of each amino acid and the oxidation-reduction ability of hepatocytes. Both ratios were maintained only in the group C dogs, three of which survived for over 3 days, whereas in groups A and B, all the dogs died within 24h. The results of this study imply that the intraportal administration of PGEI was more effective against warm ischemic liver damage than the intravenous administration of PGE₁.     

A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases

Prostaglandin E₂ (PGE₂) is generally accepted to be an immunosuppressant produced by cancer cells and their surrounding macrophages. Although several investigators have reported detecting high concentrations of PGE₂ in the portal veins of patients with colorectal cancer, the relationship between these high concentrations of PGE₂ in the portal vein and liver-associated immunity remains unclear. In this study, we attempted to determine if the portal administration of PGE₂ suppresses the immune function of the liver in a rat model. Donryu rats were administered PGE₂ via the portal vein for 7 days, following which the cytotoxic activity of hepatic sinusoidal lymphocytes (HSL) against natural killer (NK)-sensitive YAC-1 and rat syngeneic AH60C tumor cells was assessed. Purified HSL are spontaneously cytolytic; however, the continuous administration of PGE₂ dramatically suppressed the cytotoxic activity of HSLs in a dose-dependent fashion. Flow cytometric analysis showed that the large granular lymphocyte (LGL) fraction, hepatic natural killer (pit) cells, and CD4^–8⁺ killer/suppressor T cells were mainly reduced in number in the HSLs following PGE₂ infusion. In this rat AH60C metastasis model, the continuous administration of PGE₂ increased the number and size of metastatic tumor nodules in the liver, suggesting that high concentrations of PGE₂ in the portal vein suppress liver-associated immunity and promote the formation of hepatic metastasis.     

Comparative hemodynamic effects of hypotension induced by CGRP and PGE1 in dogs

Calcitonin gene-related peptide (CGRP) produces vasodilation, hypotension, and tachycardia. We compared the hemodynamic effects of CGRP-induced hypotension with the effects of prostaglandin E₁ (PGE₁), which is currently used as a hypotensive agent during anesthesia. Eighteen mongrel dogs were anesthetized with pentobarbital (25 mg·kg⁻¹), and 0.87% halothane in oxygen (1MAC). Measurements of hemodynamic variables were made before, during, and after induced hypotension. The mean arterial pressure (MAP) was lowered to 60 mmHg by the infusion of either CGRP (n=10) or PGE₁ (n=8). This decrease in MAP was appoximately 50% of the baseline value. The CGRP- and PGE₁-induced hypotension resulted in 61% and 51% maximum reductions (P<0.01, respectively) in systemic vascular resistance associated with a significant increase in stroke volume index; the two treatments, however produced inconsistent changes in cardiac index (CI). With CGRP, a maximum increase of 144% (P< 0.01) in CI was observed during induced hypotension. In contrast, PGE₁-induced hypotension caused no significant changes in CI throughout the observation period. Left ventricular maximum dP/dt decreased (P<0.01) during the hypotensive period with PGE₁, whereas it remained un-changes during CGRP-induced hypotension. The different results for changes in CI and cardiac contractility during the CGRP- and PGE₁-induced hypotension were probably due to differences in ventricular filling pressure. Hypotension induced by PGE₁ was associated with a significant decrease in heart rate (HR), whereas CGRP did not affect HR. This study shows that both CGRP and PGE₁ are effective in decreasing afterload and in inducing hypotension; the results suggest that CGRP is a useful vasodilator for inducing hypotension during halothane anesthesia. This study was presented, in part, at the Annual Meeting of the American Society of Anesthesiologists, October, 1993, Washington DC, and at the 41st Annual Meeting of the Japan Society of Anesthesiology, April, 1994, Tokyo This study was supported by a Grant-in-Aid (No 04807115) for Scientific Research (C) from the Ministry of Education, Science, Sports, and Culture, Japan     

Enhanced hepatic portal blood flow induced by prostaglandin E1 following liver transplantation in pigs

Portal venous blood flow (PVF), hepatic arterial blood flow (HAF), and systemic arterial pressure (SAP) were examined after prostaglandin E₁ (PGE₁) was injected into the vena cava superior (VCS) of liver-transplanted pigs. The injection of PGE₁ at 0.2 g/kg/min for 2 min on the day of transplantation and 3 days later produced an increase in PVF without causing any change in HAF or SAP, the response in PVF being dose-dependent. However, no reliable change in PVF, HAF, or SAP was seen when the same dose of PGE₁ was administered 7 days after transplantation. Furthermore, no significant difference was noted among the values for PVF and total hepatic blood flow (THF) during the experimented days, although the HAF value had increased markedly 3 days after transplantation. These findings suggest that PGE₁ is effective in increasing PVF in the liver transplanted condition; however, the hepatic circulatory improvement attributed to this agent would be limited to the first few days following transplantation.     

The effect of prostaglandin E1 on the increase of serum lactate and plasma granulocyte elastase activity during radical surgery for esophageal cancer

Serum lactate concentrations and the lactate/pyruvate (L/P) ratio were measured in two groups of patients undergoing radical esophagectomy, as an indicator of tissue hypoxia, and β-glucuronidase and granulocyte elastase as indicators of tissue damage. One group received prostaglandin E₁ (PGE₁) and the other group received nothing. Serum lactate concentrations and the L/P ratio increased significantly 30 min after starting thoracotomy in the patients who were not treated with PGE₁. On the contrary, intravenous drip infusion of PGE₁ (0.04 μg·kg⁻¹·min⁻¹) suppressed the increases in serum lactate concentratons and L/P ratios. Plasma granulocyte elastase activity increased significantly at the end of surgery in both groups. There was no change in serum β-glucuronidase activity in both groups. This study suggests that low doses of PGE₁ maintain organ blood flow without affecting blood pressure. However, these low doses of PGE₁ could not suppress granulocyte elastase release.     

Inhibitory effect of prostaglandin E1 on gastric secretion during general anesthesia in humans

The present study was undertaken to clarify the effects of prostaglandin E₁ (PGE₁) on gastric secretion during general anesthesia. Thirty-three patients, 16 with (PGE₁ group) and 17 without (control group) PGE₁ administration, scheduled for selective surgery were studied during general anesthesia with nitrous oxide (67%) and enflurane (1%–2% inspired). PGE₁ was administered at a rate of 50–200 ng·kg⁻¹·min⁻¹ when hypotensive medication was required. In the PGE₁ group, gastric juice was collected serially three times before and during administration and 60 min after discontinuation of PGE₁. In the control group, it was collected three times corresponding to those in the PGE₁ group. The pH of gastric juice increased significantly, and the acidity and pepsin activity decreased after the beginning of the administration of PGE₁, and these changes were observed even 1h after discontinuation. There was significant differences in the pH, acidity, and pepsin activity between the two groups after administration of PGE₁. The results indicate that PGE₁ inhibits gastric secretion at doses that produce a sufficient hypotensive effect under general anesthesia.     

Effect of prostaglandin E1 on preservation injury of canine liver grafts preserved in UW solution

This study investigated whether prostaglandin E₁ (PGE₁) could reduce hepatic injury to the liver graft caused by harvesting and 24-h preservation in University of Wisconsin (UW) solution in a canine model. The PGE₁-treated group was intravenously administered 0.5 g/kg per minute of PGE₁ for 30 min before harvesting, as well as a concentration of 1 mg/l PGE₁ in the washout and UW solutions. In both the PGE₁-treated and the control group, all recipients survived for 1 week or more after transplantation. Arterial ketone body ratio (AKBR) remained over 1.0 in the early postoperative period. The PGE₁ group showed significant reductions in guanase, GOT, and LDH during the early postoperative period compared to the untreated control group. Histological examination disclosed partial mitochondrial swelling, hepatocyte vacuolation, and necrosis in the control group, while such abnormalities were rarely seen in the PGE₁ group. These results suggest that PGE₁ can effectively reduce hepatic injury to liver grafts preserved in UW solution prior to transplantation.     

Effect of prostaglandin E1 on arterial ketone body ratio in hepatectomy

We evaluated the effect of prostaglandin E₁ (PGE₁) administration during hepatectomy on arterial ketone body ratio (AKBR), which is an indicator of liver function, and on other liver functions in the postoperative period. Eighteen patients were divided into two groups: Continuous intravenous administration of PGE₁ (0.02 μg·kg⁻¹·h⁻¹) was started immediately before hepatic resection and ceased at the end of operation in nine patients (PGE₁ group); the other nine did not receive PGE₁ (control group). After hepatic resection, a significant increase in AKBR was observed in the PGE₁ group. However, no change was observed in the control group. In the PGE₁ group, total bilirubin and SGOT recovered more rapidly to the preoperative level than in the control group. These findings suggested that PGE₁ might have a protective effect on the liver.     

Prostaglandin E1 improves survival rate after 95% hepatectomy in rats

BACKGROUND/AIM: Prostaglandin E1 (PGE1) has a wide-ranging effect on cytoprotection. Overproduction of heat shock protein 70 (HSP70) in the liver protects hepatocytes under various pathologic conditions. In this study, we examined the effect of a nontoxic HSP-inducer, PGE1, on acute liver failure after 95% hepatectomy in rats. METHODS: PGE1 or vehicle was intravenously administered to rats 30 min before and during hepatectomy. RESULTS: Nine of 30 rats pretreated with PGE1 survived, whereas all 20 rats pretreated with vehicle died within 96 h after operation. During the 24-h postoperative period, PGE1 significantly suppressed the release of alanine aminotransferase and elevation of hyaluronic acid. Histological examination showed that the vacuolized hepatocytes and round hepatocytes with pyknotic nuclei are frequently seen in rats pretreated with vehicle, whereas active regeneration is seen in rats pretreated with PGE1. During the first 24 h after surgery, HSP70 induction was absent in the residual livers of vehicle-treated rats. In contrast, PGE1 stimulated the HSP accumulation within 24 h, and viable hepatocytes contained abundant HSP70 in their nuclei. CONCLUSION: Our results suggest that PGE1 may prevent acute liver failure after massive hepatectomy, at least in part, by enhancing HSP70 production in the residual liver.     

The protective effect of thromboxane A2 synthetase inhibitor against ischemic liver injury

To evaluate the role of thromboxane A₂ (TXA₂) in ischemic liver injury, the serum changes in thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F₁ alpha (6-K-PGF₁) following warm ischemia of the total canine liver were examined, and the protective effect of a TXA₂ synthetase inhibitor was assessed. Total liver ischemia was performed for 60 min on two groups of dogs: a control group, in which ischemia alone was performed, and an OKY-046 group, which received a TXA₂ synthetase inhibitor. A temporary active portacaval shunt was used to eliminate the effects of splanchnic venous stasis during clamping of the hepatic pedicle. Postoperative changes in liver function, assessed by the transaminase enzyme levels, and in prostaglandins were recorded and the histologic liver findings of both groups 1 week after ischemia were compared. The levels of 6-K-PGF₁ increased after reperfusion in both groups, while those of TXB₂ increased in the control group but maintained low levels in the OKY-046 group. Liver function was better and histologic changes less marked in the OKY-046 group than in the control group, suggesting the important role of TXA₂ in ischemic liver injury and the usefulness of a TXA₂ synthetase inhibitor for protecting the liver against ischemic injury.     

6-keto-prostaglandin E1-stimulated bone resorption in organ culture

Summary Previous investigations have shown that prostaglandin E₂ (PGE₂), 13,14-dihydro-PGE₂, and prostacyclin (PGI₂) are among the most potent prostaglandin stimulators of bone resorption. 6-Ketoprostaglandin F_1α (6-keto-F_1α; also called 6-oxo-prostaglandin F_1α), a metabolite of PGI₂ formed by spontaneous hydrolysis, has little bone resorptive or other biological activity. The present study demonstrated that another metabolite of PGI₂, 6-keto-prostaglandin E₁ (6-keto-PGE₁; also called 6-oxo-prostaglandin E₁), was active in stimulating bone resorption in fetal rat long bone organ culture. 6-Keto-PGE₁ stimulated significant release of previously incorporated⁴⁵Ca over the concentration range of 10⁻⁹ to 10⁻⁵ M. The potency of 6-keto-PGE₁ was one-twelfth that of PGE₂. If 6-keto-PGE₁ is formed by bone or adjacent tissues, or reaches bone through the circulation, it could significantly affect bone mineral metabolism.     

Single dose of anti-transforming growth factor-beta1 monoclonal antibody enhances liver regeneration after partial hepatectomy in biliary-obstructed rats

BACKGROUND: Transforming growth factor (TGF) beta is a potent inhibitor of hepatocyte DNA synthesis and liver regeneration. TGF-beta(1) expression progressively increases in obstructive jaundice. We investigated the effect of TGF-beta(1) blockage on liver regeneration in rats induced with obstructive jaundice. MATERIALS AND METHODS: Male Wistar-albino rats were divided into three groups: sham, control, and study groups. In the study and control groups, the common bile duct was ligated and divided, and 7 days later a partial hepatectomy was performed. In the study group, anti-TGF-beta(1) monoclonal antibody (10-microg single dose) was administered immediately after the 70% hepatectomy. In the control group, those rats in which obstructive jaundice was induced received normal saline after the 70% hepatectomy, and nonjaundiced rats received anti-TGF-beta(1) monoclonal antibody after the 70% hepatectomy. Rats were sacrificed after 48 or 72 h. Relative liver weight, AST, ALT, total and conjugated bilirubin, and TGF-beta(1) levels were measured. The mitotic index and proliferating cell nuclear antigen (PCNA) labeling index were evaluated as histopathologic parameters. RESULTS: At 72 h, the TGF-beta(1) level in the study group was similar to that in the sham group, whereas TGF-beta(1) in the study group was significantly lower than that of the jaundiced control group at 48 or 72 h (P < 0.001). The relative liver weight, mitotic index, and PCNA labeling index were significantly higher in the study group than in the jaundiced control group at 48 and 72 h (P < 0.001). The AST, ALT, and TGF-beta(1) levels were significantly higher in the jaundiced control group compared to the study group after 48 and 72 h, whereas these values were significantly lower in the nonjaundiced control group (P < 0.001). CONCLUSIONS: In obstructive jaundiced rats, TGF-beta(1) blockage with anti-TGF-beta(1) monoclonal antibody after liver resection improved liver regeneration both morphologically and functionally.     

The effect of antagonism of adenosine A1 receptor against ischemia and reperfusion injury of the liver

BACKGROUND: Adenosine is known to exert protective roles in hepatic ischemia and reperfusion injury, while all adenosine receptors do not play the cytoprotective roles. We have tested our hypothesis that blockage of adenosine binding to A(1) receptor by its antagonist, KW3902 [8-(noradamantan-3-yl)-1,3-dipropylxanthine] attenuates hepatic ischemia-reperfusion injury. METHODS: Adult female beagle dogs underwent a 2 h total hepatic vascular exclusion (THVE) with a venovenous bypass. Nontreated animals that underwent THVE with a venovenous bypass alone were used as the control (Group CT, n=6). KW3902 was given to the animals by continuous intraportal infusion for 60 min before ischemia at a dose of 1 microg/kg/min (Group KW, n=6). Two wk survival, hemodynamics, hepatic tissue blood flow (HTBF), liver function, energy metabolism, cAMP concentration, and histopathological findings were studied. RESULTS: Two wk animal survival was significantly improved in group KW compared with that in group CT (group CT: 16.7% versus group KW: 83.3%). HTBF, liver function, and hepatic adenine nucleotide concentration were remarkably better in group KW than group CT. In addition, cAMP concentration in group KW was maintained significantly higher than group CT. Histopathological examination revealed preservation of hepatic architecture and suppression of neutrophil infiltration into hepatic tissue in group KW. CONCLUSION: Administration of adenosine A(1) receptor antagonist before ischemia attenuates hepatic ischemia-reperfusion injury. To elicit the beneficial effect of adenosine against ischemia and reperfusion injury of the liver, it is important to oppose adenosine A1 receptor activation.     

Prostaglandin E1 reduces blood loss during and after resection of lumbar herniated disc

Controlled hypotension was employed during resection of lumbar herniated disc on 10 patients. Prostaglandin E₁ (PG) was used as a hypotensive agent. The systolic blood pressure was lowered less than 100mmHg in the hypotensive group. The average blood loss during surgery was 95 ± 41ml for the hypotensive group compared with 154 ± 81ml for the normotensive group (P 0.05). The blood loss after surgery was also significantly less in the hypotensive group than in the normotensive group (P 0.05). We conclude that PG is an effective hypotensive agent on blood loss during and after surgery.(Kashimoto S, Nakamura T, Yamaguchi T: Prostaglandin E₁ reduces blood loss during and after resection of lumbar herniated disc. J Anesth 6: 294–296, 1992)     

Enhancing effect of thoraco-laparotomy on liver metastasis and the role played by active oxygens in its mechanism

The enhancing effect on liver metastasis produced by the excessive surgical stress of thoraco-laparotomy (TL), and its regulation with a radical scavenger, were studied in 10-week-old Donryu rats. The rats were divided into three groups: those given thoraco-laparotomy for 1h (the TL group); those given laparotomy alone for 1 h (the L group); those given a short laparotomy (the C group). The effects of treatment with 5 mg/kg of EPC-K₁ was assessed in the TL group. A rat hepatocellular carcinoma cell line AH 60C (5× 10⁵ cells) was administered into the portal vein under general anesthesia. The number of metastatic liver nodules was counted 3 weeks later, and the lipid peroxide (LPO) levels of the liver and serum were measured by the TBA method on postoperative days (PODs) 1,2, and 3. The number of metastatic liver nodules was 40.6±29.7, 15.0±15.8, and 13.7±9.4 in the TL, L, and C groups, respectively. When EPC-K₁ was administered to the TL group, the LPO level on POD 1 decreased from 49.8±25.8 to 18.9±7.9nM/g, and the number of metastatic liver nodules decreased from 27.2±30.0 to 8.9±12.7 in parallel. The findings of this study suggested that the excessive surgical stress produced by thoraco-laparotomy enhanced liver metastasis in parallel with an increase in LPO levels; however, the radical scavenger EPC-K₁ could aid in reversing this effect.     

Metabolism of prostaglandins in porcine liver transplantation with a graft harvested after 30- and 60-minute warm ischemia

The influence of warm ischemia on the metabolism of prostaglandins was investigated using a pig liver transplantation model employing the temporary portal arterialization technique. Eighteen pigs were divided into three groups according to warm ischemia time: 0 min (group I,n=6), 30 min (group II,n=6), and 60 min (group III,n=6). During portal arterialization, the hepatic venous prostaglandin E₂ (PGE₂) level in group III (3356.0±1011.8pg/ml) was significantly higher than that in group I (831.7±182.1pg/ml;P=0.0285). The hepatic venous PGE₂ levels were significantly higher than the arterial counterparts in all groups both at the beginning and during portal arterialization. At 60 min after portal revascularization, the arterial PGE₂ level in group III (886.7±268.0pg/ml) was significantly higher than that in groups I (99.0±18.6 pg/ml;P=0.0116) and II (204.2±65.4pg/ml;P=0.0282). Neither thromboxane B₂ (TXB₂) nor 6-keto PGF_1α showed any significant differences. In conclusion, the intra-operative changes of PGE₂ thus reflected the degree of warm ischemic damage, and PGE₂ could also be released from the graft. On the other hand, the increased levels of TXB₂ and 6-keto PGF_1α were throught to have an extrahepatic origin.     

Pharmacologic preconditioning effects: Prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.     

A pharmacological analysis of prostaglandin E1 on portal blood flow after partial hepatectomy in rats

Portal venous flow (PVF) and portal venous pressure (PVP) were examined after the jugular or portal injection of Prostaglandin E₁ (PGE) in rats partially hepatectomized by either 40% or 66%. In the 66% hepatectomized animals, the jugular injection of PGE at 5.0 g/kg/min produced an increase in PVF concomitant with a fall in systemic arterial pressure (SAP), while PVP remained unchanged. The portal injection of PGE at 0.5 g/kg/min increased PVF to a level equivalent to that evoked by the jugular injection of 5.0 g/kg/min PGE, without any change in SAP. PVP was reduced synchronistically with an increase in PVF. The PVF response to a portal injection of PGE at 0.5 g/kg/min was not reproduced in liver intact rats. These results suggest that PGE is potent in increasing PVF in the partially resected condition of the liver and that the portal vascular bed is involved in this response.     

Prostaglandin E1 increased cardiac contractility in cardiac arrest during open-heart surgery

Key words  Prostaglandin E₁  - Cardiac Arrest - Open-Heart surgery     

Treatment of postherpetic neuralgia with prostaglandin E1 ointment a preliminary study

Journal of Anesthesia -