Overproduction of nitric oxide inhibits vascular reactivity in portal hypertensive rats

ＯｖｅｒｐｒｏｄｕｃｔｉｏｎｏｆｎｉｔｒｉｃｏｘｉｄｅｉｎｈｉｂｉｔｓｖａｓｃｕｌａｒｒｅａｃｔｉｖｉｔｙｉｎｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｒａｔｓＬＩＸｉＲｕ,ＷＵＪｉｎＳｈｅｎｇ,ＨＥＺｅＳｈｅｎｇ,ＭＡＱｉｎｇＪｉｕａｎｄＧＡＯ...     

Gender differences in vascular reactivity of mesenteric arterioles in portal hypertensive and non-portal hypertensive rats

BACKGROUND Portal hypertension(PHT) is primarily caused by an increase in resistance to portal outflow and secondarily by an increase in splanchnic blood flow. Vascular hyporeactivity both in systemic circulation and in the mesenteric artery plays a role in the hyperdynamic circulatory syndrome.AIM To explore gender differences and the role of endogenous sex hormones in PHT and vascular reactivity of mesenteric arterioles in rats.METHODS Cirrhosis and PHT were established by subcutaneous injection of carbon tetrachloride(CCl_4) in both male and female integral and castrated rats(ovariectomized [OVX] in female rats, orchiectomy [ORX] in male rats). The third-order branch of the mensenteric artery was divided and used to measure vascular reactivity to vasoconstrictors.RESULTS No significant difference in portal pressure was observed between integral and castrated male PHT rats(15.2 ± 2.1 mm Hg vs 16.7 ± 2.7 mm Hg, P 0.05). The portal pressure in integral female PHT rats was lower than that in OVX female PHT rats(12.7 ± 2.7 mm Hg vs 16.5 ± 2.4 mm Hg, P 0.05). In PHT rats, the concentration response curves of the mesenteric arterioles to norepinephrine were shifted to the right, and the maximal responses(E_(max)) values were decreased and effective concentrations causing half maximum responses(EC_(50)) values were increased, compared to those of non-PHT rats, both in male and female rats.Compared to non-PHT integral male rats, the sensitivity of the mesenteric arterioles of non-PHT ORX male rats to norepinephrine was decreased(P 0.05).However, there was no difference between integral and ORX male rats with PHT.In integral female PHT rats, the concentration response curves were shifted to the left(P 0.05), and the E_(max) values were increased and EC_(50) values were decreased compared to OVX female PHT rats.CONCLUSION Clear gender differences were observed in mesenteric vascular reactivity in CCl_4-induced cirrhotic and PHT rats. Conservation of estrogen can retain the sensitivity of the mesenteric arterioles to vasoconstrictors and has a protective effect on splanchnic vascular function in PHT.     

The role of nitric oxide in the inhibition of gastric epithelial proliferation in portal hypertensive rats

BACKGROUND/AIM: Portal hypertension is associated with inhibition of gastric epithelial proliferation and increased gastric nitric oxide synthase activity. Whether the nitric oxide inhibits gastric epithelial proliferation is unclear. METHODS: Portal vein ligation was performed to induce portal hypertension in rats. The rats were treated for 7 days with either vehicle or N(G)-nitro-L-arginine methyl ester (L-NAME) at 5 mg/kg or 25 mg/kg doses (gastric gavage, twice a day). Sham-operated rats treated with vehicle served as controls. Hemodynamic parameters were measured using radiolabeled microspheres in anesthetized animals. Gastric epithelial proliferation was assessed by evaluating the proliferative cell nuclear antigen labeling index. RESULTS: The cardiac index and gastric fundic blood flow were higher, and the gastric fundic proliferative cell nuclear antigen labeling index was lower in the portal hypertensive rats than in the controls. In portal hypertensive rats, the 5 mg/kg dose of L-NAME decreased the cardiac index and increased the gastric fundic proliferative cell nuclear antigen labeling index to levels similar to those found in the controls, but did not affect gastric fundic blood flow significantly. The 25 mg/kg dose of L-NAME further decreased both the cardiac index and the gastric fundic blood flow, but did not affect the gastric proliferative cell nuclear antigen labeling index significantly. CONCLUSIONS: In portal hypertensive rats, the correction of systemic hyperdynamic circulation by NO inhibition is associated with normalization of gastric epithelial proliferation. Excessive nitric oxide may inhibit gastric epithelial proliferation in portal hypertension.     

肝前性门静脉高压大鼠NO、CO与高动力循环的关系

目的 观察肝前性门静脉高压大鼠血中一氧化氮（NO）、碳氧血红蛋白（COHb)与血液循环动力指标的关系。方法 制作门静脉高压大鼠模型和假手术组模型。分别检测血中NO、COHb浓度，测定门静脉压力。血流和平均动脉压。结果 门静脉高压组大鼠血中NO、COHb浓度均较假手术组高，门静脉高压组大鼠门静脉压增高，门静脉血流减少及平均动脉压降低，血中NO、CO-Hb水平分别与门静脉压力呈正相关，与门静脉血流和平均动脉压呈负相关。结论 NO、一氧化碳（CO）的过度形成和释放对门静脉高压的形成和维持起重要作用。     

Increased heme oxygenase activity in splanchnic organs from portal hypertensive rats: role in modulating mesenteric vascular reactivity

BACKGROUND/AIMS: We have recently demonstrated that heme oxygenase-1 is upregulated in splanchnic organs of portal hypertensive rats. In the present study, we assessed whether heme oxygenase enzymatic activity is increased in splanchnic organs of portal hypertensive rats, and the relative contribution of heme oxygenase and nitric oxide synthase to the vascular hyporeactivity in portal hypertension. METHODS: Heme oxygenase activity was measured in splanchnic organs of portal hypertensive and sham-operated rats. The effects of heme oxygenase and nitric oxide synthase inhibition on pressure responses to potassium chloride and methoxamine were assessed in perfused mesenteric vascular beds of portal hypertensive and sham-operated rats. RESULTS: Heme oxygenase activity was increased in the mesentery, intestine, liver, and spleen of portal hypertensive rats. The hyporeactivity to potassium chloride in portal hypertensive rats was overcome after simultaneous inhibition of both heme oxygenase and nitric oxide synthase, but only partially attenuated after nitric oxide synthase inhibition alone. The hyporeactivity to methoxamine was completely reversed after nitric oxide synthase blockade. CONCLUSIONS: These results demonstrate that heme oxygenase activity is increased in splanchnic organs of portal hypertensive rats. They also suggest that heme oxygenase contributes to the hyporeactivity to potassium chloride, but not to methoxamine, in portal hypertensive rats.     

Expression of TNF-α and VEGF in the esophagus of portal hypertensive rats

AIM: To investigate the expression of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) in the development of esophageal varices in portal hypertensive rats. METHODS: Thirty male Sprague-Dawley (SD) rats in the model group in which a two-stage ligation of portal vein plus ligation of the left adrenal vein was performed, were divided into three subgroups (M7, M14, and M21) in which the rats were kiued on the seventh day, the 14^th d and the 21 d after the complete portal ligation. Thirty male SD rats, which underwent the sham operation in the control group, were also separated into three subgroups (C7, C14 and C21) corresponding to the models. The expression of TNF-α and VEGF in the esophagus of all the six subgroups of rats were measured with immunohistochemical SP technique. RESULTS: The portal pressure in the three model subgroups was significantly higher than that in the corresponding control subgroups (23.82±1.83 vs 11.61±0.86 cmH2O, 20.90±3.27 vs 11.43±1.55 cmH2O and 20.68±2.27 vs 11.87±0.79 cmH2O respectively, P<0.01), as well as the number (9.3±1.6 vs 5.1±0.8, 11.1±0.8 vs 5.4±1.3 and 11.7±1.5 vs 5.2±1.1 respectively, P<0.01) and the total vascular area (78 972.6±3 527.8 vs 12 993.5±4 994.8 um^2, 107 207.5±4 6461.4 vs 11 862.6±5 423.2 um^2 and 110 241.4±49 262.2 vs 11 973.7±3 968.5 um^2 respectively, P<0.01) of submucosal veins in esophagus. Compared to the corresponding controls, the expression of TNF-α and VEGF in M21 was significantly higher (2.23±0.30 vs 1.13±0.28 and 1.65±0.38 vs 0.56±0.30 for TNF-α and VEGF respectively, P <0.01), whereas there was no difference in M7 (1.14±0.38 vs 1.06±0.27 and 0.67±0.35 vs 0.50±0.24 for TNF-α and VEGF respectively, P>0.05) and M14 (1.20±0.25 vs 1.04±0.26 and 0.65±0.18 vs 0.53±0.25 for TNF-α and VEGF respectively, P>0.05). And the expression of TNF-α and VEGF in M21 was significantly higher than that in M7 (2.23±0.30 vs 1.14±0.38 and 1.65±0.38 vs 0.67±0.35 for TNF-α and VEGF respectively, P<0.01) and M14 (2.23±0.30 vs 1.20±0.25 and 1.65±0.38 vs 0.65±0.18 for TNF-α and VEGF respectively, P<0.01), but there was no difference between M7 and M14 (1.14±0.38 vs 1.20±0.25 and 0.67±0.35 vs 0.65±0.18 for TNF-α and VEGF respectively, P >0.05). CONCLUSION: In the development of esophageal varices in portal hypertensive rats, increased TNF-α and VEGF may be not an early event, and probably play a role in weakening the esophageal wall and the rupture of esophageal varices.     

Effect of verapamil on nitric oxide synthase in a portal veinligated rat model： Role of prostaglandin

AIM: To investigate the effects of verapamil on nitric oxide (NO) synthesis in a portal vein-ligated rat model. METHODS: Systemic and splanchnic hemodynamics were measured by radiolabeled microspheres in portal hypertensive rats after acute administration of verapamil (2 mg/kg) on chronic treatment with Nw-nitro-L-arginine (NNA)(80 mg/kg) and/or indomethacin (2 mg/kg) . RESULTS: Verapamil (2 mg/kg) caused a marked fall in both arterial pressure and cardiac output accompanied by an insignificant change in the portal pressure and no change in portal venous inflow. This result suggested that verapamil did not cause a reduction in portal vascular resistance of portal hypertensive rats, which was similar between NW- nitro-L-arginine-treated and indomethacin-treated groups. CONCLUSION: In portal hypertensive rats pretreated with NNA and/or indomethacin, acute verapamil administration can not reduce the portal pressure, suggesting that NO and prostaglandin play an important role in the pathogenesis of splanchnic arterial vasodilation in portal hypertension.     

Expression of TNF-α and VEGF in the esophagus of portal hypertensive rats

AIM: To investigate the expression of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor (VEGF) in the development of esophageal varices in portal hypertensive rats.METHODS: Thirty male Sprague-Dawley (SD) rats in the model group in which a two-stage ligation of portal vein plus ligation of the left adrenal vein was performed, were divided into three subgroups (M7, M14, and M21) in which the rats were kiued on the seventh day, the 14th d and the 21 d after the complete portal ligation. Thirty male SD rats, which underwent the sham operation in the control group, were also separated into three subgroups (C7, C14and C21) corresponding to the models. The expression of TNF-α and VEGF in the esophagus of all the six subgroups of rats were measured with immunohistochemical SP technique.RESULTS: The portal pressure in the three model subgroups was significantly higher than that in the corresponding control subgroups (23.82±1.83 vs 11.61±0.86 cmH2O,20.90±3.27 vs 11.43±1.55 cmH2O and 20.68±2.27 vs 11.87±0.79 cmH2O respectively, P＜0.01), as well as the number (9.3±1.6 vs 5.1±0.8, 11.1±0.8 vs 5.4±1.3 and 11.7±1.5 vs 5.2±1.1 respectively, P＜0.01) and the total vascular area (78 972.6±3 527.8 vs 12 993.5±4 994.8μm2, 107 207.5±4 6461.4 vs 11 862.6±5 423.2 μm2 and 110 241.4±49 262.2 vs 11 973.7±3 968.5 μm2 respectively,P＜0.01) of submucosal veins in esophagus. Compared to the corresponding controls, the expression of TNF-α and VEGF in M21 was significantly higher (2.23±0.30 vs 1.13±0.28and 1.65±0.38 vs 0.56±0.30 for TNF-α and VEGF respectively, P ＜0.01), whereas there was no difference in M7 (1.14±0.38 vs 1.06±0.27 and 0.67±0.35 vs 0.50±0.24for TNF-α and VEGF respectively, P＞0.05) and M14 (1.20±0.25vs 1.04±0.26 and 0.65±0.18 vs0.53±0.25 for TNF-α and VEGF respectively, P＞0.05). And the expression of TNF-α and VEGF in M21 was significantly higher than that in M7(2.23±0.30 vs 1.14±0.38 and 1.65±0.38 vs 0.67±0.35 for TNF-α and VEGF respectively, P＜0.01) and M14 (2.23±0.30vs 1.20±0.25 and 1.65±0.38 vs 0.65±0.18 for TNF-α and VEGF respectively, P＜0.01), but there was no difference between M7 and M14 (1.14±0.38 vs 1.20±0.25 and 0.67±0.35vs 0.65±0.18 for TNF-α and VEGF respectively, P ＞0.05).CONCLUSION: In the development of esophageal varices in portal hypertensive rats, increased TNF-α and VEGF may be not an early event, and probably play a role in weakening the esophageal wall and the rupture of esophageal varices.     

Endothelial,but not the inducible,nitric oxide synthase is detectable in normal and portal hypertensive rats

Abstract: Background: Chronic portal hypertension is accompanied by a nitric oxide (NO) dependent vasodilation. Three isoforms of NO producing synthases (NOS) are characterized: neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS). Sources of increased NO levels in chronic hypertension is disputed. Methods: To determine eNOS and iNOS expression in different organs of portal hypertensive and control rats, we divided Sprague-Dawley rats in 6 groups: (1) Partial portal vein ligated rats, (2) Bile duct ligated rats, (3) Carbon tetrachloride treated rats, (4) Sham operated rats, (5) Untreated control rats, and (6) LPS treated rats. Immunohistochemistry (IHC) and immunoblotting (IB) using antibodies against eNOS or iNOS were carried out on samples from thymus, aorta, heart, lung, oesophagus, liver, spleen, kidney, pancreas, small and large intestine. Results: IHC revealed an even eNOS expression in all groups. Expression of iNOS was restricted to macrophages in organs of LPS treated and the thymus of rats. IB mirrored these results. Conclusion: In chronic portal hypertension, the main source for NO production depends on eNOS activity.     

一氧化氮和前列腺素在门静脉高压性胃病大鼠胃粘膜灌注中的作用

目的 探讨一氧化氮（NO）和前列腺素在门静脉高压性胃病（PHG）大鼠胃粘膜灌注中的作用。方法 部分结扎大鼠门静脉主干2周后,采用中性红清除率法测定大鼠胃粘膜血流量（GMBF）,同时观察门静脉压力（PVP）的变化。结果 PHG组大鼠GMBF和PVP显著高于假手术组（t=3.431、3．312,P＜0．01）。低剂量的NO合成酶抑制剂L－硝基－精氨酸甲酯（L－NAME）呈剂量依赖性降低PHG大鼠GMBF,而对假手术组GMBF无明显影响;高剂量的L－NAME（12mg/kg)能非常显著降低PHG和假手术组大鼠GMBF。前列腺素环氧合酶抑制剂消炎痛能明显降低PHG组大鼠GMBF,而对假手术组GMBF无明显影响;预先给消炎痛处理后在假手术组大鼠中,静脉注射低剂量L－NAME（4mg/kg)前后GMBF无明显变化,高剂量L－NAME（12mg/kg)降低大鼠的GMBF与未用消炎痛处理组比无明显变化;预先给消炎痛处理后在PHG组大鼠中,L－NAME剂量（4mg/kg、12mg/kg)依赖性降低大鼠的GMBF与未用消炎痛处理组比无明显改变。结论 NO、前列腺素在调节PHG大鼠的GMBF起重要作用,但两者无协同作用。     

In vivo angiogenesis in normal and portal hypertensive rats: role of basic fibroblast growth factor and nitric oxide.

BACKGROUND: Angiogenesis plays a pivotal role in many processes. Here, we studied whether angiogenesis to basic fibroblast growth factor (bFGF) in normal and portal hypertensive rats requires nitric oxide (NO). METHODS: To measure angiogenesis in vivo, two Teflon rings filled with collagen I (Vitrogen 100) were fixed in the mesenteric cavity at day 0, with one supplemented with bFGF (100 ng). Portal hypertension was induced by partial portal vein ligation (PVL). Sham-operated rats served as controls (CON). The role of NO was tested by adding the NO formation antagonist N(omega)-nitro-L-arginine (NNA; 3.3 mg/kg per day) to the drinking water. After 16 days, rings were explanted and embedded, and vessels were morphometrically counted. RESULTS: bFGF significantly stimulated vessel formation per implant in CON rats (from 624 +/- 97 without stimulation to 1123 +/- 171, n = 11, P < 0.01), but not in PVL rats (from 1106 +/- 174 without stimulation to 1046 +/- 202, n = 9). Without stimulation, numbers of ingrown vessels were significantly (P < 0.05) higher in PVL compared to CON rats. NNA substantially inhibited angiogenesis in both groups (P < 0.01). Vessel numbers were 202 +/- 124 for PVL (n = 5) and 197 +/- 14 for CON (n = 5) animals. bFGF did not reverse angiogenesis prevented by NNA (373 +/- 98 for PVL, 265 +/- 26 for CON, n = 5 per group, NS). CONCLUSIONS: NO formation inhibition diminishes both unstimulated and bFGF-stimulated angiogenesis in CON rats. Moreover, bFGF cannot rescue NNA-inhibited angiogenesis in PVL rats.     

Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats

BACKGROUND & AIMS: Vasoconstriction of the superior mesenteric artery (SMA) is the earliest hemodynamic event occurring after partial portal vein ligation (PVL). We tested the hypothesis that this early vasoconstriction of the SMA may initiate eNOS up-regulation in PVL. METHODS: Portal hypertension with or without mesenteric vasoconstriction was induced by differentially calibrated stenosis of the portal vein (PVL-20G and PVL-18G, respectively). In a separate group of rats, mesenteric vasoconstriction was achieved by renal artery ligation. Sham-operated rats were used as controls. Effects of vasoconstriction of the SMA in PVL and RAL rats were evaluated by measuring perfusion pressure changes in isolated SMA beds in response to methoxamine, nitric oxide synthase activity, and eNOS protein expression. Mean arterial pressure, portal pressure, and SMA blood flow were measured by catheterization and Doppler flowmetry. SMA vascular resistance was calculated from arterial pressure, portal pressure, and SMA flow. RESULTS: There was a significant increase in SMA vascular resistance in PVL-20G (2.33 +/- 0.13 vs. 1.22 +/- 0.03 mm Hg/% flow; P < 0.05) and RAL (2.32 +/- 0.18 vs. 1.18 +/- 0.02 mm Hg/% flow; P < 0.05) but not in PVL-18G, showing mesenteric vasoconstriction in both PVL-20G and RAL groups. The mesenteric vasculature of PVL-20G and RAL animals showed hyporeactivity to methoxamine (P < 0.01). Whereas both PVL groups were portal hypertensive (P < 0.01), RAL rats were not. The SMA hyporeactivity of PVL-20G and RAL rats was corrected by N(G)()-monomethyl-L-arginine, and nitric oxide synthase enzyme activity was significantly higher in PVL-20G and RAL rats (P < 0.05). CONCLUSIONS: Mesenteric arterial vasoconstriction plays a triggering role in up-regulation of eNOS catalytic activity in the SMA of portal hypertensive rats.     

Effects of vasopressin on portal-systemic collaterals in portal hypertensive rats: role of nitric oxide and prostaglandin.

This study investigated the effect of vasopressin on portal-systemic collaterals in portal hypertensive rats and the influence of nitric oxide (NO) and prostaglandin on the responsiveness of collateral vessels to vasopressin. The vascular responsiveness to graded concentrations of vasopressin was tested with or without the incubation of n(omega)-nitro-L-arginine (NNA) (100 micromol/L) and/or indomethacin (10 micromol/L) in perfused collateral vascular beds of rats with portal hypertension induced by partial portal vein ligation. In addition, concentration-response curves to vasopressin with incubation of a vasopressin V(1) receptor antagonist d(CH(2))(5)Tyr(Me) arginine vasopressin and concentration-response curves to a V(2) receptor agonist 1-desamino-8-D-arginine vasopressin were performed. Vasopressin significantly increased the perfusion pressure of collaterals, and this effect was suppressed by the addition of the V(1) receptor antagonist. Perfusion with the V(2) receptor agonist had no effect on the collaterals. Incubation with NNA, indomethacin, or both significantly potentiated the response of collaterals to vasopressin. In addition, the pressor response to vasopressin in the combination group was significantly higher than that in the NNA-alone group. The results show that vasopressin produces a direct vasoconstrictive effect on the portal-systemic collaterals of portal hypertensive rats. This effect is mediated by the vasopressin V(1,) but not V(2), receptors. The attenuation of the response to vasopressin by NO and prostaglandin suggest a function role of both mediators in the regulation of the portal-systemic collateral circulation in portal hypertensive rats.     

Expression of nitric oxide synthase protein and gene in the splanchnic organsof liver cirrhosis and portal hypertensive rats

AIM To investigate the expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS)protein and eNOS mRNA gene in the splanchnic organs of liver cirrhosis and portal hypertensive rats.METHODS In control and CCl4-induced liver cirrhotic rats, the expression of eNOS and iNOS proteins wasdetected by immunohistochemical method, and eNOS mRNA was detected by in situ hybridization.RESULTS The expression of eNOS protein and eNOS mRNA increased in most organs of the cirrhotic rats,including bronchial and alveolar epithelial cells, renal tubular epithelial cells and mesenchyma, endothelialand adventitial cells of aorta and superior mesenteric artery, whereas no significant increase of iNOS proteinwas found. In the hepatic tissue, NOS protein and eNOS mRNA were present in mesenchymal cells and vesseladventitial cells, no difference was observed in the expression between control and cirrhotic rats.CONCLUSION The expression of NOS varied in region. In splanchnic organs and vasculars there was anincreased expression of eNOS which induced aplanchnic vasodilation and increased the inflow of portal vein,while in the liver tissue and blood vessel showed no increased expression, which may be associated withincreased intrahepatic vascular resistance.     

Effect of terlipressin on in vitro vascular hyporeactivity of portal hypertensive rats

Backgrounds/Aims: Isolated vessels of portal hypertensive rats exhibit decreased responsiveness to vasoconstrictors. The vasopressin analogue terlipressin analogue terlipressin is used in the treatment of portal hypertension since it is known to reduce portal pressure, an effect that is thought to arise from splanchnic vasoconstriction via stimulation of vasoconstrictor V₁ receptors. This study assessed the effect of terlipressin on the in vitro vascular reactivity of portal hypertensive rats to the α-adrenoceptor agonist methoxamine.Methods: Portal hypertension was produced by portal vein ligation. Sham-operated rats served as controls. In isolated perfused mesentric arteries of portal vien ligated and sham-operated rats pressor responses to methoxamine (3 nmol-3 μmol) were determined in the absence and presence of the nitric oxide synthase inhibitor N^g-nitro-L-arginine methyl ester (L-NAME; 100 μM), terlipressin or the selective V₂ receptor agonist desmopressin (each 0.5 μM). In addition, the direct pressor properties of terlipressin (3 pmol-100 nmol) were compared to arginine vasopressin (3 pmol-1 nmol) in vessels of normal rats.Results: Mesenteric vessels of portal vein ligated rats were markedly hyporeactive to methoxamine, even in the presence of L-NAME. Terlipressin alone reduced and in combination with L-NAME abolished the difference in reactivity to methoxamine between the portal vein ligated and sham-operated groups, while desmopressin was ineffective. Arginine vasopressin potently contracted vessels of normal rats with a threshold dose of 10 pmol and was maximally effective at 300 pmol. In contrast, terlipressin failed to produce pressor responses up to 100 nmol.Conclusions: Hyporeactivity of mesenteric vessels of portal vein ligated rats to methoxamine is predominantly independent of nitric oxide. Terlipressin alone ameliorates and in combination with L-NAME abolishes the hyporesponsiveness to methoxamine presumably by inhibiting the nitric oxide-independent mechanism that underlies the reduced responsiveness to methoxamine in portal hypertension. This effect of terlipressin appears to be independent of stimulation of V₂ as well as vasoconstrictor V₁ receptors.     

Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension

Background

Idiopathic portal hypertension is a rare cause of portal hypertension, frequently misdiagnosed as cryptogenic cirrhosis. This study evaluates specific findings at hepatic vein catheterisation or liver stiffness in idiopathic portal hypertension.

Methods

39 cases of idiopathic portal hypertension patients were retrospectively reviewed. Hepatic vein catheterisation and liver stiffness measurements were compared to matched patients with cirrhosis and portal hypertension, and non-cirrhotic portal vein thrombosis, included as controls.

Results

Hepatic vein-to-vein communications were found in 49% idiopathic portal hypertension patients precluding adequate hepatic venous pressure gradient measurements in 12. In the remaining 27 patients, mean hepatic venous pressure gradient (HVPG) was 7.1 ± 3.1 mmHg. Only 5 patients had HVPG ≥ 10 mmHg. HVPG was markedly lower than in cirrhosis (17 ± 3 mmHg, p < 0.001). Mean liver stiffness in idiopathic portal hypertension was 8.4 ± 3.3 kPa; significantly higher than in non-cirrhotic portal vein thrombosis (6.4 ± 2.2 kPa, p = 0.009), but lower than in cirrhosis (40.9 ± 20.5 kPa, p = 0.005). Only 2 idiopathic portal hypertension patients had liver stiffness >13.6 kPa.

Conclusions

Patients with idiopathic portal hypertension frequently have hepatic vein-to-vein communications and, despite unequivocal signs of portal hypertension, HVPG and liver stiffness values much lower than the cut-off for clinical significant portal hypertension in cirrhosis. These findings oblige to formally rule-out idiopathic portal hypertension in the presence of signs of portal hypertension.     

No additive effect between Helicobacter pylori infection and portal hypertensive gastropathy on inducible nitric oxide synthase expression in gastric mucosa of cirrhotic patients

Increased expression of inducible nitric oxide synthase (iNOS) has been reported in gastric mucosa of patients with Helicobacter pylori infection or portal hypertensive gastropathy (PHG) but whether there is an additive or synergistic impact between H. pylori and PHG on iNOS expression was unknown. Sixty cirrhotic patients and 21 age-matched control subjects without liver disease were included. Biopsies from the gastric antrum and body were obtained for quantitative histological assessment and immunohistochemical staining for iNOS. iNOS staining was detected in endothelial cells and macrophages. In the absence of PHG, H. pylori significantly induced iNOS expression in cirrhotic patients. PHG also significantly induced iNOS expression in H. pylori-negative patients. However, there was no synergistic or additive effect between H. pylori and PHG on this expression. Furthermore, expression of iNOS was significantly higher in patients with severe PHG than in those with mild PHG and without PHG.     

Glycerophosphate acyltransferase activity in perfused liver of normal and hyperlipemic rats: Glucagon effect

Summary Mitochondrial glycerophosphate-acyltransferase activity (GPAT) was determined in the isolated and perfused liver of diet-induced hyperlipemic rats, and was found to be significantly increased compared to normal rats. A positive correlation existed between hepatic triglyceride output and GPAT. Perfusion of 10^–5 M glucagon induced a significant reduction in GPAT levels. It is suggested that the lipid-lowering action of glucagon may be mediated also through an inhibition of GPAT activity.     

Influence of hyperbaric oxygen on tumor necrosis factor-alpha and nitric oxide production in endotoxin-induced acute lung injury in rats

We previously demonstrated that hyperbaric oxygen (HBO) treatment alleviated lipopolysaccharide (LPS)-induced acute lung injury in rats. However, the mechanisms responsible for the protective effect are still not fully understood. To obtain further information on the protective effect of HBO, in this study we investigated the role of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in intratracheal spraying LPS-induced acute lung injury in rats after HBO or hyperoxia treatment. The results showed that HBO but not hyperoxia attenuated the TNF-alpha level in plasma and bronchoalveolar lavage (BAL) fluid, NO concentration in BAL and plasma, and inducible NO synthase protein expression in lung tissue based on the Western blotting and immunohistochemical staining.     

Combined inhalation of nitric oxide and oxygen in patients with moderate to severe COPD: effect on blood gases

Inhaled nitric oxide (NO) has been reported to improve oxygenation in patients with COPD if administered in combination with oxygen (O2). Little, however, is known about the variability of these effects and the potential influence of body position. Twenty-six spontaneously breathing patients with moderate to severe COPD inhaled clean air, O2(FiO2, 0.29), 5 ppm NO, 5 ppm NO+O2, 10 ppm NO+O2, 10 ppm NO, and again clean air in an upright position. Blood gas analysis from arterialized capillary blood was performed after each inhalation. Tests were repeated on different days to assess the variability of the response. Furthermore, eight patients were studied in both upright and supine position while inhaling 5 ppm NO in the presence or absence supplemental O2. As compared to clean air, NO led to a mean decrease in PaO2 of -0.9 mmHg at 5 ppm and of -2.8 mmHg at 10 ppm NO. Similarly, NO+O2 led to a dose-dependent fall in PaO2 of -1.8 and -3.6 mmHg, respectively, as compared to O2. Average within-subject variation (SD) of the effects elicited by 5 and 10 ppm NO was 2.4 and 2.3 mmHg without additional O2, and 4.7and 5.3 mmHg with O2. The effects of 5 ppm NO+O2 differed significantly between upright and supine position; as compared to O2 alone, mean (SD) changes were -3.7 +/- 5-8 vs. +1.1 +/- 4.9 mmHg, respectively. Our findings suggest thatthe addition of NO to inhaled oxygen, when given in an upright position, does not lead to an improvement of PaO2 in patients with moderate to severe COPD. Furthermore, it turned out that it was not possible to define responders and non-responders to inhaled NO on an individual basis, since the variability ofthe responses was similar to the mean