IM To evaluate the relationship between nitric oxide (NO) and hyperdynamic circulatory status in portal hypertension.METHODS Twenty male SpragueDawley rats (weighing 200g±20g) randomized into two groups, portal...IM To evaluate the relationship between nitric oxide (NO) and hyperdynamic circulatory status in portal hypertension.METHODS Twenty male SpragueDawley rats (weighing 200g±20g) randomized into two groups, portal hypertension group (n=12) and the controls (n=8). Portal hypertensive models were established by means of graded constriction of the portal vein. The concentrations of nitrite (NO2) in portal vein and peripheral blood were measured to reflect NO levels with flourimetric analysis. The reactivitiy of isolated abdominal aortic rings from partial portal veinconstricted and shamoperated rats was observed by potassium chloride (KCl) (10mmol/L-80mmol/L) and phenylephrine (10-9mol/L10-4mol/L) with or without NO synthase inhibitor NωnitroLarginine (LNNA).RESULTS Serum concentrations of NO2 in portal vein (0766μmol/L±0097μmol/L) and peripheral blood (0687μmol/L±0092μmol/L) were elevated in portal hypertensive rats as compared with those in controls (0613μmol/L±0084μmol/L, 0591μmol/L±0045μmol/L, P<001, respectively). The rates of NO2 in portal vein blood were markedly higher than those in peripheral blood (P<005) of portal hypertensive rats. Abdominal aortic rings from portal veinconstricted rats exhibited significantly impaired contractility to phenylephrine and potassium chloride as compared with the controls. The EC50 values of KCl were markedly higher in portal hypertensive rings (265mmol/L±09mmol/L) than those of the control rings (223mmol/L±17mmol/L, P<001), and so were the EC50 values of phenylephrine (372nmol/L±04nmol/L) vs (281nmol/L±02nmol/L, P<001). After preincubation of rings with LNNA, the difference in EC50 values no longer statistically significant between portal hypertensive and control rings in both KCl (2018mmol/L±08mmol/L, and 194mmol/L±12mmol/L, P>005) and phenylephrine (224nmol/L±18nmol/L, 218nmol/L±14nmol/L, P>005). However, the maximal KCl and phenylephrineinduced contractions were still lower in portal hypertensive rings (KCl: 108g±01g, phenylephrine: 143g±014g) than those of the control rings (KCl: 121g±011g, phenylephrine: 172g±011g, P<005, respectively). This showed that addition of the NO synthase inhibitor LNNA could partially restore contractile responses to KCl and phenylephrine in portal hypertensive rings.CONCLUSION NO overproduction inhibits the vascular reactivity to vasocontrictors, and it might be one of the main causes which results in vasodilatation and hyperdynamic circulatory status in portal hypertension.展开更多
Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndro...Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.展开更多
AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley r...AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCI4, prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nω-nitro-L-arginine (L-NNA)group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1mL of saline, L-NNA (3.3 mg/kg-d) and INDO (5 mg/kg·d) respectively through gastric tubes for one week/then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite(NO2-/NO3-) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1α, a stable hydrolytic product of PGI2, was determined by radioimmunoassay. RESULTS: The concentrations of plasma 6-keto-PGFla (pg/mL) and serum NO2-/NO3- (μmol/L) in IHPH rats (1123.85±153.64, 73.34±4.31) and PHPH rats (891.88±83.11, 75.21±6.89) were significantly higher than those in SO rats (725.53±105.54, 58.79±8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and spanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGFla and serum NO2/7NO3-in IHPH and PHPH rats (P<0.05) .Meanwhile, CI, FPP and PVI lowered but MAP, TPR and SVR increased(P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI2 level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI2, NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto- concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO2-/NO3- in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05). CONCLUSION: It is NO rather than PGI2 that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.展开更多
AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min w...AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective i NOS inhibitor 1400W(10 mg/kg) was administered before reperfusion(n = 6) vs control group(n = 7). Creatinine(1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400 W had a higher level of creatinine clearance(CrC l) [area under the curve(AUC) CrC l: 2.37 ± 0.97 mL /min per 100 g vs 0.96 ± 0.32 mL /min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium(AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400 W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400 W group after 1 h of reperfusion(1h Pr/Cr: 1400 W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400 W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400 W 139 ± 47 pg/L/mmol/L, P = 0.041].CONCLUSION: This study demonstrated that 1400 W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.展开更多
文摘IM To evaluate the relationship between nitric oxide (NO) and hyperdynamic circulatory status in portal hypertension.METHODS Twenty male SpragueDawley rats (weighing 200g±20g) randomized into two groups, portal hypertension group (n=12) and the controls (n=8). Portal hypertensive models were established by means of graded constriction of the portal vein. The concentrations of nitrite (NO2) in portal vein and peripheral blood were measured to reflect NO levels with flourimetric analysis. The reactivitiy of isolated abdominal aortic rings from partial portal veinconstricted and shamoperated rats was observed by potassium chloride (KCl) (10mmol/L-80mmol/L) and phenylephrine (10-9mol/L10-4mol/L) with or without NO synthase inhibitor NωnitroLarginine (LNNA).RESULTS Serum concentrations of NO2 in portal vein (0766μmol/L±0097μmol/L) and peripheral blood (0687μmol/L±0092μmol/L) were elevated in portal hypertensive rats as compared with those in controls (0613μmol/L±0084μmol/L, 0591μmol/L±0045μmol/L, P<001, respectively). The rates of NO2 in portal vein blood were markedly higher than those in peripheral blood (P<005) of portal hypertensive rats. Abdominal aortic rings from portal veinconstricted rats exhibited significantly impaired contractility to phenylephrine and potassium chloride as compared with the controls. The EC50 values of KCl were markedly higher in portal hypertensive rings (265mmol/L±09mmol/L) than those of the control rings (223mmol/L±17mmol/L, P<001), and so were the EC50 values of phenylephrine (372nmol/L±04nmol/L) vs (281nmol/L±02nmol/L, P<001). After preincubation of rings with LNNA, the difference in EC50 values no longer statistically significant between portal hypertensive and control rings in both KCl (2018mmol/L±08mmol/L, and 194mmol/L±12mmol/L, P>005) and phenylephrine (224nmol/L±18nmol/L, 218nmol/L±14nmol/L, P>005). However, the maximal KCl and phenylephrineinduced contractions were still lower in portal hypertensive rings (KCl: 108g±01g, phenylephrine: 143g±014g) than those of the control rings (KCl: 121g±011g, phenylephrine: 172g±011g, P<005, respectively). This showed that addition of the NO synthase inhibitor LNNA could partially restore contractile responses to KCl and phenylephrine in portal hypertensive rings.CONCLUSION NO overproduction inhibits the vascular reactivity to vasocontrictors, and it might be one of the main causes which results in vasodilatation and hyperdynamic circulatory status in portal hypertension.
文摘Portal hypertension is a clinical syndrome which leads to several clinical complications, such as the formation and rupture of esophageal and/or gastric varices, ascites, hepatic encephalopathy and hepato-renal syndrome. In cirrhosis, the primary cause of the increase in portal pressure is the enhanced resistance to portal outflow. However, also an increase in splanchnic blood flow worsens and maintains portal hypertension. The vasodilatation of arterial splanchnic vessels and the opening of collateral circulation are the determinants of the increased splanchnic blood flow. Several vasoactive systems/substances, such as nitric oxide, cyclooxygenase-derivatives, carbon monoxide and endogenous cannabinoids are activated in portal hypertension and are responsible for the marked splanchnic vasodilatation. Moreover, an impaired reactivity to vasoconstrictor systems, such as the sympathetic nervous system, vasopressin, angiotensin II and endothelin-1, plays a role in this process. The opening of collateral circulation occurs through the reperfusion and dilatation of preexisting vessels, but also through the generation of new vessels. Splanchnic vasodilatation leads to the onset of the hyperdynamic circulatory syndrome, a syndrome which occurs in patients with portal hypertension and is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure. Understanding the pathophysiology of splanchnic vasodilatation and hyperdynamic circulatory syndrome is mandatory for the prevention and treatment of portal hypertension and its severe complications.
文摘AIM: To investigate the role of prostacyclin (PGI2) and nitric oxide (NO) in the development and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats. METHODS: Ninety male Sprague-Dawley rats were divided into three groups: intrahepatic portal hypertension (IHPH) group by injection of CCI4, prehepatic portal hypertension (PHPH) group by partial stenosis of the portal vein and sham-operation control (SO) group. One week after the models were made, animals in each group were subdivided into 4 groups: saline controlled group (n = 23), Nω-nitro-L-arginine (L-NNA)group (n = 21) group, indomethacin (INDO) group (n = 22) and high-dose heparin group (n = 24). The rats were administrated 1mL of saline, L-NNA (3.3 mg/kg-d) and INDO (5 mg/kg·d) respectively through gastric tubes for one week/then heparin (200 IU/Kg/min) was given to rats by intravenous injection for an hour. Splanchnic and systemic hemodynamics were measured using radioactive microsphere techniques. The serum nitrate/nitrite(NO2-/NO3-) levels as a marker of production of NO were assessed by a colorimetric method, and concentration of 6-keto-PGF1α, a stable hydrolytic product of PGI2, was determined by radioimmunoassay. RESULTS: The concentrations of plasma 6-keto-PGFla (pg/mL) and serum NO2-/NO3- (μmol/L) in IHPH rats (1123.85±153.64, 73.34±4.31) and PHPH rats (891.88±83.11, 75.21±6.89) were significantly higher than those in SO rats (725.53±105.54, 58.79±8.47) (P<0.05). Compared with SO rats, total peripheral vascular resistance (TPR) and spanchnic vascular resistance (SVR) decreased but cardiac index (CI) and portal venous inflow (PVI) increased obviously in IHPH and PHPH rats (P<0.05). L-NNA and indomethacin could decrease the concentrations of plasma 6-keto-PGFla and serum NO2/7NO3-in IHPH and PHPH rats (P<0.05) .Meanwhile, CI, FPP and PVI lowered but MAP, TPR and SVR increased(P<0.05). After deduction of the action of NO, there was no significant correlation between plasma PGI2 level and hemodynamic parameters such as CI, TPR, PVI and SVR. However, after deduction of the action of PGI2, NO still correlated highly with the hemodynamic parameters, indicating that there was a close correlation between NO and the hemodynamic parameters. After administration of high-dose heparin, plasma 6-keto- concentrations in IHPH, PHPH and SO rats were significantly higher than those in rats administrated vehicle (P<0.05). On the contrary, levels of serum NO2-/NO3- in IHPH, PHPH and SO rats were significantly lower than those in rats administrated Vehicle (P<0.05). Compared with those rats administrated vehicle, the hemodynamic parameters of portal hypertensive rats, such as CI and PVI, declined significantly after administration of high-dose heparin (P<0.05), while TPR and SVR increased significantly (P<0.05). CONCLUSION: It is NO rather than PGI2 that is a mediator in the formation and maintenance of hyperdynamic circulatory state of chronic portal hypertensive rats.
文摘AIM: To investigate the effects of 1400W-a selective inducible nitric oxide synthase(iN OS) inhibitor in a model of donation after circulatory death(DCD) kidneys. METHODS: Porcine kidneys were retrieved after 25 min warm ischemia. They were then stored on ice for 18 h before being reperfused ex vivo with oxygenated autologous blood on an isolated organ perfusion system. The selective i NOS inhibitor 1400W(10 mg/kg) was administered before reperfusion(n = 6) vs control group(n = 7). Creatinine(1000 μmol/L) was added to the system, renal and tubular cell function and the level of ischemia reperfusion injury were assessed over 3 h of reperfusion using plasma, urine and tissue samples. RESULTS: Kidneys treated with 1400 W had a higher level of creatinine clearance(CrC l) [area under the curve(AUC) CrC l: 2.37 ± 0.97 mL /min per 100 g vs 0.96 ± 0.32 mL /min per 100 g, P = 0.004] and urine output [Total: 320 ± 96 mL vs 156 ± 82 mL, P = 0.008]. There was no significant difference in levels of fractional excretion of sodium(AUC, Fr ex Na+: Control, 186.3% ± 81.7%.h vs 1400 W, 153.4% ± 12.1%.h, P = 0.429). Levels of total protein creatinine ratio were significantly lower in the 1400 W group after 1 h of reperfusion(1h Pr/Cr: 1400 W 9068 ± 6910 mg/L/mmol/L vs Control 21586 ± 5464 mg/L/mmol/L, P = 0.026). Levels of 8-isoprostane were significantly lower in the 1400 W group [8-iso/creatinine ratio: Control 239 ± 136 pg/L/mmol/L vs 1400 W 139 ± 47 pg/L/mmol/L, P = 0.041].CONCLUSION: This study demonstrated that 1400 W reduced ischaemia reperfusion injury in this porcine kidney model of DCD donor. Kidneys had improved renal function and reduced oxidative stress.
