Lisinopril inhibits endothelin-1 in the early period of hepatic reperfusion injury in a partial hepatectomy model.

BACKGROUND: Ischemia-reperfusion (I/R) injury is a major problem during liver surgery. We investigated the effects of lisinopril, an angiotensin-converting enzyme inhibitor, in the early postoperative period of reperfusion injury after Pringle's maneuver during an 80% partial hepatectomy (PH) in rats. METHODS: Four groups of male Sprague-Dawley rats were studied: Group 1 (n = 10), sham laparotomy; group 2 (n = 10), PH without portal occlusion; group 3 (n = 10), PH with portal pedicle clamping; group 4 (n = 15), same as group 3 with additional intravenous lisinopril preconditioning (1 mg/kg(-1)). We analyzed superoxide radical (O(2)(-)), nitric oxide (NO), peroxynitrite (ONOO(-)) levels in the liver tissue and blood levels of alanine aminotransferase (ALT) and endothelin-1 (ET-1). RESULTS: ALT and ET-1 levels were progressively increased in group 2 (P > .05) versus group 3 (P < .001 and P < .05), showing hepatocellular damage due to I/R injury in the remnant liver, although histopathologic changes were unremarkable at this early stage. The levels of ALT and ET-1 decreased with lisinopril precontioning in group 4 compared with group 2 (P > .05 and P < .01) or group 3 (P < .05 and P < .001). O(2)(-) levels were increased significantly in groups 2 and 3 (P < .01 for both). O(2)(-) level in Group 4 was remarkably decreased albeit not significant compared with the other groups. NO and ONOO(-) levels were also significantly greater in groups 2 (P < .01 and P < .05) and 3 (P < .001 and P < .01). These levels were decreased significantly among group 4 compared with group 3 (P < .05), a decline almost to the level of group 1 (P > .05). CONCLUSION: In the early postoperative period of an extended hepatectomy model, Pringle's maneuver causes I/R increasing the insult to the remnant liver. Lisinopril preconditioning alleviated I/R injury by decreasing the O(2)(-), NO, ONOO(-), ET-1, and ALT levels, thereby exerting a protective role on the remaining liver.

The effects of thromboxane synthase inhibition on reperfusion injury and endothelin-1,2 levels in allograft kidney transplantation in rats.

Thromboxane A2 is a proaggregative vasoconstrictor that is synthesized and released in reperfusion injury. We aimed to investigate the effects of thromboxane synthase inhibitor, UK 38485, on endothelin-1,2 (ET) response of the renal endothelium and lipid peroxidation and protein oxidation in the early period of kidney transplantation. Four groups (n=8 in group IV and n=10 in the others) [corrected] of Sprague-Dawley rats were designed as Group I (sham nephrectomy), Group II (autotransplantation), Group III (allotransplantation) and Group IV (allotransplantation group in which the allografts were perfused with UK 38485. All subjects underwent right nephrectomy after transplantation. The grafts were flushed with 4 ml of ice-cold Ringer's lactate and in Group IV 10 microg of UK 38485 was added into the solution for each kidney. In allotransplantation groups, the kidneys were harvested from allogeneic white Wistar albino rats. The kidney grafts were allowed 120 min of reperfusion after 40 min of cold ischemic period. ET-1,2 plasma concentrations in the renal vein blood and diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels as the products of lipid peroxidation, protein carbonyls and protein sulfhydryls as the indicators of protein oxidation were analyzed in kidney tissue. Plasma ET-1,2 concentrations increased significantly in Group II and Group III (P<0.01) when compared to Group I but decreased in Group IV in comparison with Group III (P<0.05). DC, HAA, HAE and MDA levels increased in Groups II and III (P<0.001). Significant protein oxidation occurred only in Group III (P<0.01). Perfusion of the allografts with UK 38485 prevented lipid peroxidation and protein oxidation in Group IV. Histopathological changes were mild in the last group. We concluded that, in kidney transplantation, local administration of UK 38485 has cytopreservative effects on the allografts and this effect can be related to ET-1,2 concentrations.

BQ-123, a specific endothelin (ETA) receptor antagonist, prevents ischemia-reperfusion injury in kidney transplantation.

We studied the effects of the specific endothelin (ETA) receptor antagonist, BQ-123, on reperfusion injury in a rat model of kidney transplantation. First, Sprague-Dawley rats were divided into three groups: a sham nephrectomy (SNEPH), an autotransplantation (AUTO-Tx), and an allotransplantation (ALLO-Tx) group. In a fourth group, ALLO-Tx + BQ, allografts were flushed with 20 micrograms BQ-123 containing cold Ringer's lactate before transplantation. For the allograft groups, kidneys from white Wistar albino rats were transplanted into allogeneic Sprague Dawley recipients. Grafts were allowed 120 min of reperfusion after 40 min of cold ischemia. ET-1,2 plasma concentrations in the renal venous blood, and kidney tissue prostaglandin (PG) E2 and leukotriene (LT) B4 levels were studied. Diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels, as the products of lipid peroxidation, and protein carbonyls (PC) and protein sulphydryls (PS), as the parameters of protein oxidation, were also analyzed in the kidney tissue. Plasma ET concentrations increased significantly in the AUTO-Tx and ALLO-Tx groups (P < 0.05 and P < 0.01, respectively) but this increase was reversed in the ALLO-Tx + BQ group. None of the lipid peroxidation products except DCs (P < 0.05) increased in the AUTO-Tx group, whereas they all increased in the ALLO-Tx group (P < 0.01). Protein oxidation parameters also changed significantly (P < 0.01) in the ALLO-Tx group but did not in the AUTO-Tx group (P < 0.05). The differences in PGE2 and LTB4 levels were not significant. Histopathologic examination revealed prominent glomerular and tubular injury in the AUTO-Tx and ALLO-Tx groups but less in the ALLO-Tx + BQ group. In the last group, all parameters of lipid peroxidation (P < 0.001 for all) and PCs decreased, and PSs were preserved (P < 0.001 for both) when compared with the AUTO-Tx and ALLO-Tx groups. We conclude that BQ-123, in addition to inhibiting the binding of ET-1,2 to the ETA receptor, may also inhibit the release and/or synthesis of ET-1,2 and prevent reperfusion injury in kidney transplantation.

How minimally invasive is laparoscopic cholecystectomy?

To determine the extent of surgical stress induced by open (n = 20) and laparoscopic (n = 20) cholecystectomy, postoperative serum cortisol, growth hormone, and insulin responses were determined for each group. The groups were similar regarding age, sex distribution, and duration of the surgical procedures. The open cholecystectomy group had significant elevations of serum cortisol, growth hormone, and insulin levels 8 h after surgery (p < 0.05). The increased cortisol and growth hormone levels returned to preoperative control values 48 h after surgery. In the laparoscopically operated group, although all hormones increased after surgery, only the increase in growth hormone was statistically significant (p < 0.05). Serum cortisol and growth hormone levels gradually returned to control values 48 h after surgery, but the increased serum insulin levels remained significantly high in both groups 24 and 48 h after surgery (p < 0.05). It is concluded that acute surgical stress induced by open cholecystectomy is more severe than that induced by laparoscopic surgery as reflected by serum hormone determinations. However, the hormonal convalescence rate was similar for both groups. It appears that laparoscopic cholecystectomy is "minimally invasive" concerning the hormonal responses.

Captopril increases endothelin serum concentrations and preserves intestinal mucosa after mesenteric ischemia-reperfusion injury.

Endothelial cells modulate the tone of the underlying smooth muscle by generating endothelium-derived relaxing and constricting factors. Captopril (CPT), unlike other angiotensin-converting enzyme (ACE) inhibitors, contains a sulfhydryl (-SH) group and can act as a free radical scavenger. Iloprost (ILO) is a synthetic analogue of prostacyclin and mimics the effects of this compound. This study was designed to investigate the effect of ILO and CPT on the mechanism of endothelin (ET) release after mesenteric ischemia-reperfusion (I/R) injury in the rat. Sprague-Dawley rats were divided into five groups: sham-operated, control, ILO (25 micrograms/kg), CPT (10 micrograms/kg), and ILO + CPT. The superior mesenteric artery was occluded for 30 min and then allowed 90 min of reperfusion, except in the sham-operated group, and the corresponding agents were given to the treated groups prior to I/R injury. After I/R injury, portal venous blood was obtained for ET assay, and ileal tissue samples were also obtained for the determination of malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) and for histopathological examination. MDA levels were significantly lower in the CPT, ILO and, ILO + CPT groups than in the control group, indicating the inhibition of lipid peroxidation in all groups. ET levels increased in the control group, and this increase was reversed with ILO. In the CPT group, ET levels were significantly increased, and the addition of ILO did not affect this increase. Significant cytopreservative effect was achieved with ILO and CPT, the latter being more prominent histopathologically. CPT exerts a significant protective effect on the intestinal mucosa after I/R injury. This protection is accomplished by increased ET levels and seems to be unrelated to its inhibitory effect on lipid peroxidation and also unrelated to the arachidonic acid cascade.

Does PGE2 act as a mediator for endothelin release?

To investigate the effect of iloprost (ZK 36374) and thromboxane synthetase inhibitor UK 38485 on endothelin release by the intestinal vascular endothelium after ischemia/reperfusion (IR) injury, five experimental groups were formed. The groups consisted of sham, control, iloprost treated (ILO), UK 38485 treated (TSI), and iloprost + UK 38485 treated (ILO + TSI) groups. The last three groups received the corresponding agents and then the superior mesenteric artery was clamped for 30 min followed by 90 min reperfusion. Endothelin levels in the portal blood and malondialdehyde (MDA), prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) levels in the intestinal tissue were determined. The MDA levels increased significantly in the control group and this increase was reversed in ILO, TSI, and ILO + TSI groups, the two drugs together showing a synergistic effect in preventing lipid peroxidation. The changes in the LTC4 levels were not significant among the groups. The increased endothelin levels in the control group were reversed in ILO and TSI groups but these two agents did not have a synergistic effect. Increased PGE2 levels were reversed with iloprost but neither UK 38485 nor the combination of the two agents was effective in decreasing PGE2 levels. It is concluded that endothelin release after mesenteric IR injury is relatively unrelated to lipid peroxidation and the lipoxygenase pathway. The cylooxygenase pathway has a direct effect on endothelin release and PGE2 may act as a mediator.

Effect of verapamil and iloprost (ZK 36374) on endothelin release after mesenteric ischemia-reperfusion injury.

In this experimental study we studied the effect of verapamil and iloprost on endothelin release in ischemia/reperfusion (IR) injury of the rat intestine. Endothelin levels in the portal blood and malondialdehyde (MDA), PGE2, and LTC4 levels in the intestinal tissue were determined. The MDA levels increased in the control group and this increase was reversed with iloprost, verapamil and both. The change in the LTC4 levels was insignificant between the groups. Iloprost reduced PGE2 and endothelin release, but verapamil was not as effective and no synergistic effect was encountered. The increased PGE2/LTC4 ratio was also reversed in the experimental groups, verapamil being less effective. Endothelin release seems to be related to both PGE2 levels and the PGE2/LTC4 ratio after mesenteric IR injury.