The Effect of Inhibition of Renin-Angiotensin System in Experimental Unilateral Ischemia-Reperfusion Renal Injury / 대한신장학회잡지

BACKGROUND: It has been suggested that the activation of proinflammatory cytokines and growth factors play an important role in many renal injury processes including ischemia-reperfusion. The activation of renin-angiotensin system in ischemia-reperfusion renal injury may be also involved in injury process. METHODS: In order to evaluate the renal gene expressions of renin, TGF-beta, TNF-alpha, MCP-1, endothelin-1, iNOS, Fas and the role of renin-angiotrensin system (RAS) in experimental unilateral renal ischemia-reperfusion (I-R) injury, 28 male Sprague-Dawley rats weighing 250-270 g underwent sham operation (n=6), I-R injury (clamping left renal artery for 60 minutes) without any treatment (n=11), I-R injury with angiotensin converting enzyme inhibitor (enalapril 100 mg/L in drinking water for one week, n=11) under thiopental sodium anesthesia (50 mg/kg, body weight, I.P.). Systolic blood pressure was measured with tail cuff method before surgery and 24 hours after surgery. Plasma renin activity (PRA) of all study group was measured at the time of sacrifice, 24 hours after surgery. Competitive RT- PCR was performed for the estimation of renin, TGF-beta, TNF-alpha, MCP-1, endothelin-1, iNOS, and Fas gene expression levels of the kidneys. The magnitude of each gene expression was expressed the ratio to beta-actin gene. RESULTS: The systolic blood pressure of untreated I-R injured group (135+/-6 mmHg, mean+/-SE) was significantly higher than those of sham operated (105+/-3 mmHg) rats and enalapril treated I-R injured rats at 24 hour after surgery (98+/-2 mmHg) (p<0.05, p<0.05). PRA of untreated I-R injury group was 6.6+/-1.1 ng/mL/hr and also significantly higher than that of sham operated rats (2.6+/-0.3 ng/mL/hr) (p<0.05). Renal gene expressions of renin, TGF-beta, MCP-1, TNF-alpha, endothelin-1, iNOS and Fas of untreated I-R injured rats were significantly higher than those of sham operated rats at 24 hours after surgery. The level of TGF-beta, TNF-alpha, MCP-1, endothelin-1, iNOS and Fas gene expressions of ACEI treated I-R injured rats was significantly lower than those of untreated I-R injured rats (all, p<0.05). CONCLUSION: With the above result, we speculate that the early up-regulation of renin, TGF-beta, MCP- 1, TNF-alpha, endothelin-1, iNOS, and Fas genes in the kidney may be related to the renal injury mechanism in this model and at least in part, the early activation of renin-angiotensin system of the kidney may be involved in this mechanism.

Renin-angiotensin System and the Renal Expression of bcl-2 and Fas Genes in Experimental Unilateral Ureteral Obstruction / 대한신장학회잡지

BACKGROUND: The progression of hydronephrosis due to urinary obstruction is one of major causes of end stage renal failure. The activation of renin-angiotensin system (RAS) and renal cell apoptosis may be involved in this mechanisms. METHODS: In order to investigate the role of RAS in renal injury mechanism and renal expression of TGF-beta, bcl-2 and Fas in experimental unilateral ureteral obstruction (UUO) mouse model, 15 CBA strain mice were underwent sham operation (n=5), UUO without treatment (n=5) and UUO with angiotensin converting enzyme inhibitor (ACEI, enalapril, n=5) under ethyl ether anesthesia. Each group was sacrificed at 72 hours after surgery. Competitive RT-PCR was performed for the estimation of renin, angiotensin II AT1 receptor (AT1 R), TGF-beta, bcl-2, Fas and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) gene expression levels in the kidneys. RESULTS: Systolic blood pressure (SBP) and renal gene expressions of renin and AT1 R in untreated control UUO group were significantly increased compared to sham operated group at 72 hours after surgery. The level of TGF-beta and bcl-2 gene expressions of ACEI treated UUO group was significantly lower than that of untreated UUO group. On the other hand, Fas gene expression of ACEI treated UUO group was not significantly different from that of ACEI untreated UUO group. CONCLUSION: We speculate that the upregulation of bcl-2 and Fas gene expressions and the early activation of renin-angiotensin system of kidney are important factors of renal injury mechanism in this model. (Korean J Nephrol 2003;22(2): 174-184)

Effect of Intraoperative Fentanyl and Ketorolac Administration on Postoperative Emergence and Analgesia / 대한마취과학회지

BACKGROUND: One of the goals of anesthesia is a complete, comfortable, and rapid recovery without sequelae from anesthesia. Perioperative intravenous fentanyl treatment, due to its rapid onset and brief duration of action, is the one of the most commonly used narcotics. However, the dosage of fentanyl used varies a great deal depending on the purpose and plan of postoperative pain management. When a large dose of fentanyl is used, delayed emergence may occur. This study is designed to evaluate the effective dose of fentanyl and ketorolac for postoperative analgesia. METHODS: Sixty ASA physical status 1 or 2 patients were divided into three groups: fentanyl group (fentanyl 2micro gram/kg, n = 20), mixed group (fentanyl 1micro gram/kg and ketorolac 0.5 mg/kg, n = 20) or ketorolac group (ketolorac 1 mg/kg, n = 20). Each group received a drug ten minutes before the expected termination of the surgical procedure. At the operating room, durations for return of spontaneous breathing, spontaneous eye opening, and extubation were evaluated. At the recovery room, VAS (Visual Analogue Scale) and K-MMSE (Korean Minimental Status Exam) were measured. RESULTS: When compared to the ketolorac group, return times of the spontaneous breathing, spontaneous eye opening, and extubation were prolonged in the fentanyl group (P < 0.05). In the mixed group, the duration of these parameters was intermediate. Postoperative pain scores were also significantly lower in the fentanyl group and mixed group than in the ketorolac group (P < 0.05). The K-MMSE scores for emergence from anesthesia were not significantly different between the three experimental groups. CONCLUSIONS: Based on these results, we suggest that intravenous administration of reduced doses of fentanyl and ketorolac could effectively reduce the pain score without delay from emergence.

Effect of Intraoperative Fentanyl and Ketorolac Administration on Postoperative Emergence and Analgesia / 대한마취과학회지

BACKGROUND: One of the goals of anesthesia is a complete, comfortable, and rapid recovery without sequelae from anesthesia. Perioperative intravenous fentanyl treatment, due to its rapid onset and brief duration of action, is the one of the most commonly used narcotics. However, the dosage of fentanyl used varies a great deal depending on the purpose and plan of postoperative pain management. When a large dose of fentanyl is used, delayed emergence may occur. This study is designed to evaluate the effective dose of fentanyl and ketorolac for postoperative analgesia. METHODS: Sixty ASA physical status 1 or 2 patients were divided into three groups: fentanyl group (fentanyl 2micro gram/kg, n = 20), mixed group (fentanyl 1micro gram/kg and ketorolac 0.5 mg/kg, n = 20) or ketorolac group (ketolorac 1 mg/kg, n = 20). Each group received a drug ten minutes before the expected termination of the surgical procedure. At the operating room, durations for return of spontaneous breathing, spontaneous eye opening, and extubation were evaluated. At the recovery room, VAS (Visual Analogue Scale) and K-MMSE (Korean Minimental Status Exam) were measured. RESULTS: When compared to the ketolorac group, return times of the spontaneous breathing, spontaneous eye opening, and extubation were prolonged in the fentanyl group (P < 0.05). In the mixed group, the duration of these parameters was intermediate. Postoperative pain scores were also significantly lower in the fentanyl group and mixed group than in the ketorolac group (P < 0.05). The K-MMSE scores for emergence from anesthesia were not significantly different between the three experimental groups. CONCLUSIONS: Based on these results, we suggest that intravenous administration of reduced doses of fentanyl and ketorolac could effectively reduce the pain score without delay from emergence.

The Role of Renin-Angiotensin System in Progressive Renal Injury / 대한신장학회잡지

Angiotensin II(A II) -a main effector molecule of renin-angiotensin system(RAS) has been known to increase blood pressure and glomerular capillary pressure, and filtration fraction which may be involved in the progressive renal injury process. The action of A II takes place mainly through AT1 receptor. RAS can be blocked by angiotensin converting enzyme inhibitor(ACEI) and recently developed A II AT1 receptor antagonist(AT1 RA). ACEI also activate kinin system, simultaneously. However, AT1 RA does not affect kinin system. The renoprotective mechanism of ACEI may be related with activation of kinin system. In order to evaluate the renoprotective mechanism of long-term ACEI(enalapril, 100mg/L in drinking water for 12 weeks) or AT1 RA treatment(losartan 300mg/L in drinking water for 12 weeks), and its effect on the cytokines and growth factor expressions of renal cortical tissue by compatitive RT-PCR, 46 5/6 nephrectomized(5/6 NPX) rats and 8 sham operated rats were included in this study. Five sixth NPX rats showed marked hypertensin, significant proteinuria and glomerulosclerosis(mean 30.5%) in 12 weeks after surgery. However, enelapril or losartan treated rats revealed significantly lower 24 hour urinary protein excretion(UProtV), systolic blood pressure(SBP), and glomerulosclerosis than those of control 5/6 NPX rats. Plasma renin activity and angiotensin II levels of 5/6 NPX untreated control rats were not significantly increased compared to sham operated rats in 12 week after surgery. Renal cortical renin gene expression of untreated 5/6 NPX rats was significantly suppressed compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly increased renin gene expression compared to untreated 5/6 NPX rats. Renal cortical gene expressions of TGF-beta, TNF-alpha, MCP-1, IL-6, osteopontin, and endothelin-1 were significantly increased in 5/6 NPX untreated control rats compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly less level of renal TGF-beta gene expression compared to 5/6 NPX control rats. The magnitude of SBP and UProtV were significantly positively correlated with the degree of glomeruloslerosis(p<0.001, p<0.001). With the above result, we speculate that because ACEI or AT1 RA showed similar renoprotective effect in 5/6 NPX rats, at least in part, local activation of RAS plays an important role in the progressive renal injury process of this model.

The Role of Renin-Angiotensin System in Progressive Renal Injury / 대한신장학회잡지

Angiotensin II(A II) -a main effector molecule of renin-angiotensin system(RAS) has been known to increase blood pressure and glomerular capillary pressure, and filtration fraction which may be involved in the progressive renal injury process. The action of A II takes place mainly through AT1 receptor. RAS can be blocked by angiotensin converting enzyme inhibitor(ACEI) and recently developed A II AT1 receptor antagonist(AT1 RA). ACEI also activate kinin system, simultaneously. However, AT1 RA does not affect kinin system. The renoprotective mechanism of ACEI may be related with activation of kinin system. In order to evaluate the renoprotective mechanism of long-term ACEI(enalapril, 100mg/L in drinking water for 12 weeks) or AT1 RA treatment(losartan 300mg/L in drinking water for 12 weeks), and its effect on the cytokines and growth factor expressions of renal cortical tissue by compatitive RT-PCR, 46 5/6 nephrectomized(5/6 NPX) rats and 8 sham operated rats were included in this study. Five sixth NPX rats showed marked hypertensin, significant proteinuria and glomerulosclerosis(mean 30.5%) in 12 weeks after surgery. However, enelapril or losartan treated rats revealed significantly lower 24 hour urinary protein excretion(UProtV), systolic blood pressure(SBP), and glomerulosclerosis than those of control 5/6 NPX rats. Plasma renin activity and angiotensin II levels of 5/6 NPX untreated control rats were not significantly increased compared to sham operated rats in 12 week after surgery. Renal cortical renin gene expression of untreated 5/6 NPX rats was significantly suppressed compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly increased renin gene expression compared to untreated 5/6 NPX rats. Renal cortical gene expressions of TGF-beta, TNF-alpha, MCP-1, IL-6, osteopontin, and endothelin-1 were significantly increased in 5/6 NPX untreated control rats compared to sham operated rats. Enalapril or losartan treated 5/6 NPX rats showed significantly less level of renal TGF-beta gene expression compared to 5/6 NPX control rats. The magnitude of SBP and UProtV were significantly positively correlated with the degree of glomeruloslerosis(p<0.001, p<0.001). With the above result, we speculate that because ACEI or AT1 RA showed similar renoprotective effect in 5/6 NPX rats, at least in part, local activation of RAS plays an important role in the progressive renal injury process of this model.

The Role of Renin-Angiotensin System in Experimental Unilateral Ureteral Obstruction / 대한신장학회잡지

In order to evaluate the renal expression of renin, TGF-beta, TNF-alpha, IL-6, MCP-1, endothelin-1, osteopontin, and the role of renin-angiotensin system(RAS) in renal injury mechanism of experimental unilateral ureteral obstruction(UUO), 44 male Sprague-Dawley rats weighing 260-280g underwent sham operation(n= 8), UUO without treatment(n=12), UUO with angiotensin converting enzyme inhibitor(ACEI, enalapril 100 mg/kg body weight in drinking water, n=12) and UUO with angiotensin II AT1 receptor antagonist(AT1 RA, losartan 300mg/Kg body weight in drinking water, n= 12) under thiopental sodium anesthesia(50mg/kg, body weight, I.P.). Half number of each group was sacrificed at 3 and 7 days after surgery. With standard point count method, we evaluated the magnitude of tubulointerstitial mononuclear cell infiltration and relative volume of interstitium by light microscopic examination (PAS stain and immunohistochemistry for ED-1). Competitive RT-PCR was performed for the estimation of renin, TGF-beta, TNF-alpha, IL-6, MCP-1, endothelin-1, osteopontin and beta-actin gene expression levels of the kidneys. Renal gene expressions of renin, TGF-beta, MCP-1, TNF-alpha, IL-6, endothelin-1, and osteopontin of untreated control UUO rats were significantly increased compared to sham operated rats at 3 and 7 days after surgery. The level of TGF-beta, TNF-alpha, IL-6 and endothelin-1 gene expressions of ACEI treated UUO rats was significantly lower than those of untreated control UUO rats. AT1 RA treated UUO rats also showed significantly lower level of TGF-beta and osteopontin gene expression than those of control UUO group. Untreated control UUO rats showed significantly increased mononuclear cell infiltration of tubulointerstitium and relative volume of interstitium of the kidney compared to sham operated rats. ACEI or AT1 RA treated UUO rats showed significantly less relative volume of interstitium and mononuclear cell infiltration than those of untreated UUO rats(p<0.05, p<0.05). With the above result, we speculate that the upregulation of renin, TGF-beta, MCP-1, TNF-alpha, IL-6, osteopontin and endothelin-1 genes is closely related to the progressive renal injury process in this model and at least in part, the early activation of renin angiotensin system of the kidney is involved in this mechanism.