Renal Tissue Blood Flow Research Articles

The Synthetic Tie2 Agonist Peptide Vasculotide Protects Renal Vascular Barrier Function In Experimental Acute Kidney Injury.

Microvascular barrier dysfunction plays a major role in the pathophysiology of acute kidney injury (AKI). Angiopoietin-1, the natural agonist ligand for the endothelial-specific Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor. Here we evaluate the efficacy of a polyethylene glycol-clustered Tie2 agonist peptide, vasculotide (VT), to protect against endothelial-cell activation with subsequent microvascular dysfunction in a murine model of ischemic AKI. Renal ischemia reperfusion injury (IRI) was induced by clamping of the renal arteries for 35 minutes. Mice were treated with VT or PEGylated cysteine before IRI. Sham-operated animals served as time-matched controls. Treatment with VT significantly reduced transcapillary albumin flux and renal tissue edema after IRI. The protective effects of VT were associated with activation of Tie2 and stabilization of its downstream effector, VE-cadherin in renal vasculature. VT abolished the decline in renal tissue blood flow, attenuated the increase of serum creatinine and blood urea nitrogen after IRI, improved recovery of renal function and markedly reduced mortality compared to PEG [HR 0.14 (95% CI 0.05–0.78) P < 0.05]. VT is inexpensive to produce, chemically stable and unrelated to any Tie2 ligands. Thus, VT may represent a novel therapy to prevent AKI in patients.

Renal Tissue Blood Flow Regulation System in Acute Blood Pressure Modulation is Maintained in Elderly Wistar‐Kyoto Rats

Back ground: Systemic arterial pressure is maintained by sympathetic vasomotor tone regulated by autonomic nerve system. Therefore, attenuation of systemic arterial pressure causes reduction of peripheral tissue blood flow. On the other hand, renal tissue has specific blood flow regulatory system to maintain constant renal blood flow involving autonomic regulatory system. However, the effect of aging in maintenance of renal tissue blood flow regulatory system was not fully established. In this study, we used elderly Wistar-Kyoto (WKY) rats as an aged normotensive animal model, examined relation between systemic arterial pressure modulation and renal tissue blood flow regulation. Method: Aged WKY rats (56w-80w) and control group (16-24w) were anesthetized with chloralose, the arterial pressure, pulse rate and renal tissue blood flow were measured simultaneously. Results: Arterial pressure modulation by intravenous injection of phenylephrine, sodium nitroprusside and the activation of sympathetic vasomotor neurons in rostral ventrolateral medulla were not effected to renal tissue blood flow neither aged group nor control, although baro-reflex was attenuated in aged group. Conclusion These results suggest that renal tissue blood flow regulatory system was maintained in aged normotensive animals, though baro-receptor dependent systemic arterial pressure regulatory system was attenuated. Therefore, although in aged animals, renal tissue autonomic blood flow regulatory system still play important role.

Effect of Cell Permeable Peptide of c-Jun NH2-Terminal Kinase Inhibitor on the Attenuation of Renal Ischemia-Reperfusion Injury in Pigs

The outcomes of organ transplantation have improved due to better immunosuppressive drugs, surgical techniques, and management of complications. However, ischemia-reperfusion injury remains a challenge affecting graft survival. In this study, we employed injection of a protein transduction domain (PTD) to inhibit the c-Jun NH2-terminal kinase (JNK) pathway thereby attenuating ischemia-reperfusion injury in a porcine model. The PTD-JNK inhibitor (JNKI) was administered into the renal artery, allowing it to be taken into various elements including vascular endothelial cells by endocytosis via the PTD. Serum creatinine and blood urea nitrogen concentrations were lower among PTD-JNKI than controls. In addition, renal tissue blood flow was maintained in the PTD-JNKI group, resulting in less tissue injury and fewer apoptotic cells. These results suggested that the PTD technique improved renal transplantation outcomes.

Effect of Milrinone on Ischemia-Reperfusion Injury in the Rat Kidney

Background Milrinone (MIL), a phosphodiesterase (PDE) 3 inhibitor, exhibits cardiotonic and angioectatic effects. Various PDE inhibitors have been shown to suppress inflammatory cytokines. In this study, we evaluated the angioectatic and anti-inflammatory cytokine effects of MIL on renal function after warm ischemia in a rat ischemia-reperfusion (I-R) injury model. Materials and methods MIL or control solution was perfused from the left renal artery to the right kidney, and the left kidney was excised. The right renal artery, vein, and ureter were clamped and then released after 50 minutes to produce warm ischemia. We evaluated control ( n = 7), MIL ( n = 7), and sham operation ( n = 7) groups for serum creatinine, blood urea nitrogen (BUN), blood flow, expression of tumor necrosis factor (TNF)-α mRNA, apoptosis index, and histological evidence of acute tubular necrosis. Results Serum creatinine and BUN concentrations peaked at 24 hours after reperfusion. MIL treatment significantly reduced serum creatinine (control group 1.27 ± 0.45 mg/dL vs MIL group 0.77 ± 0.19 mg/dL, P < .05; sham 0.35 ± 0.2 mg/dL) and BUN (control 67.6 ± 13.6 mg/dL vs MIL 51.0 ± 8.8 mg/dL, P < .05; sham 23.0 ± 4.2 mg/dL) levels at 24 hours. Thereafter, serum creatinine and BUN concentrations in the MIL group remained significantly lower compared with the control group for 120 hours ( P < .05). MIL group exhibited significantly higher tissue blood flow, less acute tubular necrosis, lower expression of TNF-α mRNA in renal tissue, and lower apoptotic index ( P < .05). Conclusions MIL maintained renal tissue blood flow by its vasodilatory effect, suppressed expression of TNF-α mRNA by increasing intracellular cyclic adenosine monophosphate, and ultimately decreased tubular cell apoptosis, thus protecting renal function after warm I-R injury.

Effect of Pneumoperitoneum on Renal Tissue Oxygenation and Blood Flow in a Rat Model

To determine the correlation between the renal blood flow (RBF) and tissue oxygenation (PO(2)) at varying intra-abdominal pressures (IAPs) and to compare the effects on renal blood flow from carbon dioxide-induced pneumoperitoneum. Carbon dioxide pneumoperitoneum was established in Sprague-Dawley rats (n = 6). Licox oxygen/temperature tissue probes were laparoscopically inserted into the renal parenchyma, with the renal PO(2) and RBF recorded every 30 seconds while the IAP was gradually increased. Microprobes measuring the RBF, mean arterial pressures and serum pH were placed into the parenchyma to compare the effects of carbon dioxide pneumoperitoneum (n = 7) with that of open surgery (n = 6) and medical air pneumoperitoneum (n = 6). Renal PO(2) was inversely related to the IAP (P < .001). Despite the reduction in IAP, the renal PO(2) in the recovery phase was lower than at baseline (P = .045). The renal PO(2) and RBF changed in a virtually identical pattern at varying levels of IAP (P > .05). The RBF significantly declined with a pneumoperitoneal pressure of 15 and 20 mm Hg (P = .022), regardless of the gas used to create the pneumoperitoneum. A partial reversal of the RBF occurred with a decrease of the IAP. The RBF in the open surgical arm remained unchanged. Although both the serum pH and the mean arterial pressure were inversely proportional to the IAP (P < .001), the mean arterial pressure was depressed to the greatest extent in the medical air group (P = .02). These results have demonstrated that elevated IAP secondary to pneumoperitoneum causes significant renal hypoxia and decreased RBF. Additionally, this experiment has demonstrated the use of the Licox probes in monitoring the renal PO(2) and established a novel method for evaluating the effects of IAP on the kidney.

Influence on liver, renal tissue blood flow, and metaboric function during hemodilution with hypotension

Influence on liver, renal tissue blood flow, and metaboric function during hemodilution with hypotension

Three-dimensional imaging of living transplanted kidney vasculature by 3D color Doppler ultrasonography

Abstract Background: It is of clinical importance to display the vasculature of transplanted kidney in three-dimensional (3D) and in non-invasive way. 3D color Doppler ultrasonographic imaging (3D-CDUI) is a non-invasive technique to display the 3D vasculature of living organs. Objective: Probe into characteristics of 3D vasculature of living transplanted kidney by 3D-CDUI, and evaluate the clinical value of 3D-CDUI on monitoring complications after operation of renal transplant. Methods: Nine patients who received allogeneic transplantation of kidney were monitored with 3D-CDUI. The instruments used included ACUSON Sequoia 512 and TomTec computer station of 3D-CDUI. Using magnetic positioning free-hand scanning, the 3D reconstruction and display of renal tissue structure and blood flow were performed off-line. Results: All patients underwent 3D-CDUI examinations without any side effect or complication. When acute rejection occurred, the 3D distribution change of renal blood flow signal could be observed clearly. During treatment of acute necrosis of renal tubules, changes of renal blood flow signal in 3D color Doppler images could be detected earlier compared with 2D color Doppler images. The position of embolized vassels could be diagnosed accurately by 3D-CDUI. Conclusion: The 3D-CDUI was helpful to improve diagnosis level of ultrasonography by monitoring complications after renal transplantation.

Activation of Sensory Neurons Reduces Ischemia/Reperfusion-induced Acute Renal Injury in Rats

Prostaglandin I2 (PGI2) produced by endothelial cells improves ischemia/reperfusion-induced acute renal injury by inhibiting leukocyte activation in rats. However, the underlying mechanism(s) of increased PGI2 production is not fully understood. Activation of sensory neurons increases endothelial PGI2 production by releasing calcitonin gene-related peptide (CGRP) in rats with hepatic ischemia or reperfusion. We examined here whether activation of sensory neurons increases PGI2 endothelial production, thereby reducing ischemia/reperfusion-induced acute renal injury. Anesthetized rats were subjected to 45 min of renal ischemia/reperfusion. Rats were pretreated with CGRP, capsazepine (a vanilloid receptor-1 antagonist), CGRP(8-37) (a CGRP receptor antagonist), or indomethacin (a cyclooxygenase inhibitor), or subjected to denervation of primary sensory nerves before ischemia/reperfusion. Renal tissue levels of CGRP and 6-keto-prostaglandin F1alpha, a stable metabolite of PGI2, increased after renal ischemia/reperfusion, peaking at 1 h after reperfusion. Overexpression of CGRP was also noted at 1 h after reperfusion. Increases in renal tissue levels of 6-keto-prostaglandin F1alpha at 1 h after reperfusion were significantly inhibited by pretreatment with capsazepine, CGRP(8-37), and indomethacin. Pretreatment with capsazepine, CGRP(8-37), indomethacin, and denervation of primary sensory nerves significantly increased blood urea nitrogen and serum creatinine levels, renal vascular permeability, renal tissue levels of myeloperoxidase activity, cytokine-induced neutrophil chemoattractant, and tumor necrosis factor-alpha, and decreased renal tissue blood flow. However, pretreatment with CGRP significantly improved these changes. Our results suggest activation of sensory neurons in the pathologic process of ischemia/reperfusion-induced acute renal injury. Such activation reduces acute renal injury by attenuating inflammatory responses through enhanced endothelial PGI2 production.

Quantitative estimation of renal blood flow by power Doppler ultrasonography in renovascular hypertensive dogs

We estimated the value of power Doppler (PD) imaging analysis for the quantitative assessment of renal cortical blood flow (RCBF) in chronic two-kidney, one-clip (2K-1C) hypertensive dogs. To evaluate the correlation between RCBF and PD signals, RCBF and the mean pixel intensity (MPI) of PD signals were simultaneously obtained at same region in renal cortex under progressive constriction of left main renal artery in five mongrel dogs. RCBF was measured by electrolytic hydrogen gas clearance method, and PD images were transferred to computer and analyzed by the image-analysis software Openlab. To assess the value of quantitative PD imaging analysis on RCBF in renovascular hypertension, in six mongrel dogs with chronic 2K-1C hypertension, PD images in both of clipped kidneys (CK) and non-clipped kidneys (NK) were obtained and analyzed before and 60 minutes after the intravenous infusion of captopril or sodium nitroprusside at 10-minute intervals. There was a linear correlation between RCBF and MPI (r= 0.878, P < 0.0001). MPI in both CK and NK significantly increased after the infusion of captopril, while no significant change was observed in both CK and NK after the infusion of sodium nitroprusside, despite similar reduction of mean arterial blood pressure. Our data suggest that the acute inhibition of angiotensin-converting enzyme increased RCBF in both CK and NK of chronic 2K-1C dogs. The quantitative analysis of PD flow signals in kidney is noninvasive and a useful method to evaluate regional changes of renal tissue blood flow in various renal diseases.

OLPRINONE REDUCES ISCHEMIA/REPERFUSION-INDUCED ACUTE RENAL INJURY IN RATS THROUGH ENHANCEMENT OF cAMP

Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats. Forty-five minute renal I/R was induced in uni-nephrectomized rats. Rats were divided into a vehicle group, an olprinone group, and a dibutyril (DB) cAMP group. Olprinone (0.2 microg/kg/minute) infusion began 30 min after reperfusion and continued for 3 h. DBcAMP (5 mg/kg), a stable analog of cAMP, was intraperitoneally administered 5 min after reperfusion to clarify the effect of cAMP in our model. Olprinone reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the outer medulla. Hemodynamic status was not affected by olprinone. I/R-induced a decrease in renal tissue blood flow, an increase in renal vascular permeability, and an enhancement of leukocyte activation, reflected by renal tissue levels of myeloperoxidase activity, and the tissue levels of cytokine-induced neutrophil chemoattractant (an equivalent of human interleukin 8) and tumor necrosis factor-alpha were all significantly decreased by olprinone. Olprinone also increased the renal tissue and plasma levels of cAMP in rats subjected to renal I/R. DBcAMP showed similar effects. Our results indicated that olprinone reduced the I/R-induced acute renal injury, probably by inhibiting leukocyte activation. The effects of olprinone could be explained through its action on cAMP levels.

Effect of synthetic protease inhibitor gabexate mesilate on the attenuation of ischemia/reperfusion injury in canine kidney autotransplantation

Kidneys from non-heart-beating donors are associated with delayed graft function and a high rejection rate due to the long period of warm ischemia. Gabexate mesilate (GM), a synthetic serine protease inhibitor, has been shown to improve organ function by suppressing cytokine activity and neutrophil function after ischemia/reperfusion. In this study, we evaluated the effect of GM on renal function after warm ischemia in a canine kidney autotransplantation model. After 60 minutes of warm ischemia, the left kidney was transplanted into the iliac fossa, and the right kidney was removed. The control group (n = 7) and GM group (n = 7) were evaluated for serum creatinine and blood urea nitrogen (BUN) concentrations, renal tissue blood flow, resistive index, pulsatility index, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha mRNA expression levels in peripheral blood mononuclear cells, apoptotic index, CD10 immunolabeling as an indicator of brush border injury, and standard histopathology. Compared with controls, administration of GM resulted in lower serum creatinine concentrations (11.3 +/- 2.4 vs 5.2 +/- 3.3 mg/dL at 72 hours; P = .04) and BUN concentrations (188 +/- 26 mg/dL vs 98 +/- 41 mg/dL at 72 hours; P = .04), as well as better tissue blood flow, improvement of brush border injury and apoptotic index (each P < .05). The expression of IL-1beta and TNF-alpha mRNA did not change after administration of GM. The present study shows that GM protected renal function after warm ischemia/reperfusion by inhibition of serine proteases, maintenance of tissue blood flow, and amelioration of tubular apoptosis.

Activation of capsaicin-sensitive sensory neurons by carvedilol, a nonselective beta-blocker, in spontaneous hypertensive rats.

We performed a study in spontaneous hypertensive rats (SHR) to determine whether carvedilol, a nonselective beta-adrenoceptor antagonist, activates capsaicin-sensitive sensory neurons (CSSNs), thereby promoting the release of calcitonin gene-related peptide (CGRP), a neuropeptide with an important role in maintenance of cardiovascular homeostasis. Carvedilol given intravenously at a dose of 0.3 mg/kg transiently decreased the mean arterial blood pressure (MABP) and increased renal tissue blood flow with increases in CGRP levels in plasma and kidney. These effects induced by carvedilol were not seen in animals pretreated with capsazepine, an antagonist of capsaicin. Although 1.0 mg/kg cavedilol markedly decreased MABP, it neither increased renal tissue blood flow nor CGRP levels in plasma and kidney. Prazosin, a selective alpha(1)-adrenoceptor antagonist, and bisoprolol, a selective beta(1)-adrenoceptor antagonist, decreased MABP with capsazepine, showing no antagonistic action in either cases, and these agents increased neither renal tissue blood flow nor levels of CGRP in plasma and kidney. Both ICI 118,551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol], a selective beta(2)-adrenoceptor antagonist, at a dose of 0.25 mg/kg and capsaicin mimicked effects induced by 0.3 mg/kg carvedilol. Administration of 1.0 mg/kg ICI 118,551 produced effects similar to those induced by 1.0 mg/kg carvedilol. These observations strongly suggested that the low dose of carvedilol might activate CSSNs in SHR to increase the release of CGRP, thereby decreasing blood pressure with an increase in renal tissue blood flow. The effects induced by carvedilol seemed to be mediated by its beta(2)-adrenoceptor blockade activity.

Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production

AbstractAntithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT is not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)–induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histologic changes, whereas neither dansyl glutamylglycylarginyl chloromethyl ketone–treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF1α, a stable metabolite of prostacyclin (PGI2), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF1α, whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-α, cytokine-induced neutrophil chemoattractant, and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI2, produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI2released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.

Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation

AbstractWe examined whether activated protein C (APC) reduces ischemia/reperfusion (I/R)–induced renal injury by inhibiting leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl glutamylglycylarginyl chloromethyl ketone–treated factor Xa (DEGR-FXa; active-site–blocked factor Xa), heparin or diisopropyl fluorophosphate–treated APC (DIP-APC; inactive derivative of ARC) had no effect. Furthermore, APC significantly inhibited the I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced such effects. Renal I/R-induced increases in plasma levels of fibrin degradation products were significantly inhibited by APC, DEGR-FXa, and heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor-α (TNF-α), rat interleukin-8, and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by APC but not by DEGR-FXa, heparin, or DIP-APC. Leukocytopenia produced effects similar to those of APC. These findings strongly suggest that APC protects against I/R-induced renal injury not by inhibiting coagulation abnormalities but by inhibiting activation of leukocytes that play an important role in I/R-induced renal injury. Inhibition of leukocyte activation by APC could be explained by the inhibitory activity of TNF-α.

Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation

We examined whether activated protein C (APC) reduces ischemia/reperfusion (I/R)–induced renal injury by inhibiting leukocyte activation. In a rat model, intravenous administration of APC markedly reduced I/R-induced renal dysfunction and histological changes, whereas intravenous administration of dansyl glutamylglycylarginyl chloromethyl ketone–treated factor Xa (DEGR-FXa; active-site–blocked factor Xa), heparin or diisopropyl fluorophosphate–treated APC (DIP-APC; inactive derivative of ARC) had no effect. Furthermore, APC significantly inhibited the I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability, whereas neither DEGR-FXa, heparin, nor DIP-APC produced such effects. Renal I/R-induced increases in plasma levels of fibrin degradation products were significantly inhibited by APC, DEGR-FXa, and heparin. These observations suggest that APC reduces I/R-induced renal injury independently of its anticoagulant effects but in a manner dependent on its serine protease activity. Renal levels of tumor necrosis factor- (TNF-), rat interleukin-8, and myeloperoxidase were significantly increased after renal I/R. These increases were significantly inhibited by APC but not by DEGR-FXa, heparin, or DIP-APC. Leukocytopenia produced effects similar to those of APC. These findings strongly suggest that APC protects against I/R-induced renal injury not by inhibiting coagulation abnormalities but by inhibiting activation of leukocytes that play an important role in I/R-induced renal injury. Inhibition of leukocyte activation by APC could be explained by the inhibitory activity of TNF-.

The roles of platelet-activating factor and endothelin-1 in renal damage after total hepatic ischemia and reperfusion.

This study was designed to verify the involvement of platelet-activating factor (PAF) in renal damage associated with hepatic ischemia and reperfusion (HIR) injury through the release of endothelin (ET)-1 and to determine the modulating effect of a specific PAF receptor antagonist on these insults in rats. Male rats pretreated with either normal saline as a vehicle (NS group) or intravenous TCV-309, a PAF receptor antagonist (TCV group), were subjected to 120 min of total hepatic ischemia under an extracorporeal portosystemic shunt. Plasma aspartate transaminase, creatinine, blood urea nitrogen, and ET-1 levels and the relative renal wet weight were determined under nonischemic conditions and at 1, 3, and 6 hr of reperfusion after hepatic ischemia. Changes in mean arterial blood pressure and renal tissue blood flow measurements in the kidney were determined throughout the experiment. Increased plasma aspartate transaminase, creatinine, blood urea nitrogen, and ET-1 levels and the relative renal wet weight after HIR in the NS group were significantly suppressed by TCV-309 pretreatment. Mean arterial blood pressure and renal tissue blood flow after HIR in the TCV group were significantly improved when compared with those in the NS group. These effects resulted in attenuation of structural hepatic and renal damage with the improvement of 7-day survival (62%). The present study demonstrates that renal damage as well as critical liver injury is produced after reperfusion following 120 min of total hepatic ischemia. A PAF receptor antagonist may be therapeutically useful to protect against these types of damage via indirect modulation of plasma ET-1 levels.

Effect of lipo-prostaglandin E1 on crescentic-type anti-glomerular basement membrane nephritis in rats.

The antinephritic effect of lipo-prostaglandin E1, prostaglandin E1 ((1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopent ane heptanoic acid) incorporated in lipid microspheres was investigated using an experimental model of nephritis, crescentic-type anti-glomerular basement membrane nephritis. Lipo-prostaglandin E1 was given i.v. twice a day at 20, 40 and 80 microg/kg and azathioprine, an immunosuppressive agent, at 20 mg/kg was given p.o. once daily from the autologous phase, in which glomerulonephritis was fully developed (the 21 st day after injection of the anti-glomerular basement membrane serum), to the 50th day. Lipo-prostaglandin E1 (40 and 80 microg/kg x 2 per day) significantly inhibited the development of glomerular alterations as well as the elevation of proteinuria and plasma creatinine. Lipo-prostaglandin E1 (20 microg/kg x 2 per day) and azathioprine (20 mg/kg per day) significantly inhibited only the glomerular histopathological changes. Lipo-prostaglandin E1 at three doses significantly decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on the glomerular basement membrane in nephritic rats, but azathioprine apparently inhibited only the deposition of rat immunoglobulin G. A single administration of lipo-prostaglandin E1 inhibited the elevation of platelet aggregation and restored the decrease in renal tissue blood flow in nephritic rats. In addition, a single administration of lipo-prostaglandin E1 inhibited the elevation of glomerular thromboxane B2 and 6-keto prostaglandin F1alpha production in nephritic rats. These results suggest that lipo-prostaglandin E1 may be an effective agent for the treatment of glomerulonephritis. Its antinephritic effect may be due to the inhibition of platelet aggregation, an increase in renal tissue blood flow, a decrease in rabbit and rat immunoglobulin G deposition, and amelioration of the abnormal metabolism of arachidonic acid.

Thromboxane A2 Interferes with a Disposal Process of Aggregated Protein in Glomeruli

Immune complexes in glomeruli are involved in development of diverse glomerulonephritis. The disposal process of glomerular immune complexes has been unclarified. The present studies were undertaken to determine if thromboxane A2 (TXA2) is associated with the disposal of macromolecules in the glomeruli using mice injected with aggregated bovine serum albumin (a-BSA). A-BSA promptly accumulated in the glomeruli, the level reaching a plateau at 6 hr after the injection of a-BSA, and then decreased by 48 hr. The production of glomerular TXA2, prostaglandin E2 (PGE2) and prostaglandin I2 concomitantly increased with the decrease of a-BSA in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists accelerated clearance of glomerular a-BSA without enhancing renal tissue blood flow. They did not affect a-BSA level in the plasma. In contrast, aminophylline, dopamine and mannitol significantly increased renal tissue blood flow, but did not decrease glomerular a-BSA. TXA2 synthase inhibitors decreased TXA2 production in the glomeruli. TXA2 synthase inhibitors and TXA2 receptor antagonists did not influence the generation of PGE2. The TXA2 analogue U-46619 significantly increased the accumulation of a-BSA in the glomeruli. We propose that TXA2 interferes with the disposal process of aggregated protein in the glomeruli. We also postulate that interception of glomerular activity of TXA2 may be an effective intervention for managing immune complex-mediated glomerulonephritis and glomerulosclerosis.

Effect of DP-1904, a thromboxane A 2 synthase inhibitor, on passive Heymann nephritis in rats

The antinephritic effect of DP-1904 [6-(1-imidazolylmethyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride], a thromboxane A 2 synthase inhibitor, was evaluated using an experimental model of membranous nephropathy, viz. accelerated passive Heymann nephritis in which the glomerular injury is mediated by immune complexes. DP-1904 markedly inhibited the development of glomerular alteration as well as the elevation of proteinuria and plasma creatinine. When the treatment was started from the 22nd day, at which time proteinuria is fully developed, DP-1904 showed beneficial effects on proteinuria and glomerular histopathological changes. DP-1904 apparently decreased the deposition of both rabbit immunoglobulin G and rat immunoglobulin G on glomerular basement membrane in nephritic rats. A single administration of DP-1904 restored the decreased renal tissue blood flow, inhibited glomerular thromboxane B 2 production and increased glomerular prostaglandin E 2 and 6-keto prostaglandin F 1α production in nephritic rats. These results suggest that DP-1904 may be an effective agent for the treatment of idiopathic membranous nephropathy and that the beneficial effect of this drug may be due to the elimination of glomerular immune deposits and to an increase in renal tissue blood flow related to amelioration of the abnormal metabolism of arachidonic acid.

A Porcine Model for Renal Hemodynamic Study during Laparoscopy

Laser Doppler flowmetry (LDF) is a sensitive method for the measurement of microvascular blood flow in tissue. The method has been found useful for estimating skin, liver, or gastrointestinal blood flow. Whether it can be applied laparoscopically and whether it is able to measure the intraparenchymal blood flow of an intraabdominal organ is still unknown. In a pilot study, 6 pigs received a laparotomy for placement of a 19-gauge LDF needle probe into the renal parenchyma. Three different locations of the lower pole kidney were chosen for the blood flow measurement. The reliability of using the instrument to measure the renal tissue blood flow was assessed by comparison of the results of renal arterial blood flow obtained from a well-established methodology—ultrasonic Doppler flowmetry. Recordings were taken following (a) intravenous administration of 0.005 mg/kg norepinephrine, (b) manual compression of the suprarenal aorta, and (c) intravenous injection of a lethal dose of phenobarbital (50 mg/kg). Measurements of LDF were possible in all kidney units. The renal tissue perfusion detected by LDF correlated excellently with the renal arterial blood flow under different renal perfusion pressures. The feasibility of using LDF probe to measure the renal tissue perfusion in a laparoscopic model was then assessed in 15 pigs. Under pneumoperitoneum, the right kidneys were approached transperitoneally with the animal in the decubitus position. A total of three trocars were used. The peritoneum and Gerota's fascia were incised and the LDF needle probe was manipulated and inserted by an endoforceps into the renal tissue via a 5-mm trocar. The insertion of the LDF needle probe was technically feasible in all 15 kidney units, and the depth of insertion could be adjusted under direct vision. Baseline values for the renal cortical and renal medullary blood flow were 50.1 ± 17.7 and 8.8 ± 3.3 ml/min/100 g tissue, respectively. Spatial variations of the LDF measurements averaged 6%, and temporal variations over 15 min averaged 5%. Four additional hemodynamic parameters were simultaneously recorded, including left carotid artery blood flow, aortic blood pressure, inferior vena caval pressure, and intraabdominal pressure. It appears that systemic and renal hemodynamic parameters can be monitored reliably and continuously in the porcine model. This method allows further information concerning hemodynamic changes and safety of laparoscopy to be obtained.