Hemodynamic effects of hypothyroidism induced by methimazole in normal and portal hypertensive rats

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1±0.2 vs 4.8±0.3 ml/min/100 g body wt (P<0.01) and 13.4±0.9 vs 10.9±0.8 mm Hg; (P<0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.     

肝前型门静脉高压症大鼠血浆PGI2水平变化及其机理的实验研究

检测肝前型门静脉高压症（ＰＶＬ）大鼠不同时期血流动力学变化、血浆前列环素（ＰＧＩ２）水平和计算内脏ＰＧＩ２合成量，结果ＰＶＬ第五天以后全身和内脏出现高动力循环状态；ＰＶＬ术后内脏ＰＧＩ２合成量和门静脉ＰＧＩ２水平持续升高，后者与门静脉压力呈显著相关（ｒ＝０．８０，Ｐ＜０．００１），第五天以后，由于大量门体分流形成，主动脉ＰＧＩ２也明显升高，且与门静脉ＰＧＩ２水平呈显著相关（ｒ＝０．９７，ｐ＜０．００１；ｒ＝０．９０，Ｐ＜０．００１）。表明ＰＶＬ大鼠血浆ＰＧＩ２水平升高可能是内脏过多合成的ＰＧＩ２逃避了肝脏的灭活作用所致，且对高动力循环状态形成起介导作用。     

Endotoxin and the hyperdynamic circulation of portal vein-ligated rats

Humoral factors may be responsible for the hyperdynamic circulation seen in portal hypertension. Endotoxin, a peripheral arteriolar vasodilator, has been proposed to mediate this hemodynamic picture. We examined the pathogenic role of endotoxin in portal vein-ligated rats, a prehepatic portal hypertensive model with a well-developed hyperdynamic circulation. To this end, we (a) administered oral neomycin, a poorly absorbable antibiotic, at doses of 50 and 100 mg/day for 7 days and found no evident splanchnic hemodynamic effects of a 2-log-fold reduction of cecal aerobic bacterial flora as assessed by the radioactive microsphere technique in portal vein-ligated rats studied in the postanesthesia awake state; (b) assayed endotoxin in arterial samples using a quantitative limulus assay and found no evidence of endotoxinemia in PVL rats; (c) induced a state of endotoxin tolerance by repeated daily intraperitoneal injections of low-dose endotoxin and found no amelioration of the hyperdynamic state in portal vein-ligated rats. Our results do not support the hypothesis that endotoxin plays a major pathogenic role in the hyperdynamic circulation of this experimental model.     

Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats

AIM: To examine the participation of HSP90 in portal hypertensive rat mesentery in vitro. METHODS: Immunohistochemistry and Western-blot were used to examine the expression of HSP90 in mesenteric vasculature. HSP90 mRNA was detected by RT-PCR, and the role of HSP90 in hyperdynamic circulation was examined by in vitro mesenteric perfusion studies. RESULTS: HSP90 was overexpressed in endothelium of mesentery vasculature in animals with experimental portal hypertension induced by partial portal vein ligation (PVL) compared with normal animals. Geldanamycin (GA), a special inhibitor of HSP90 signaling, attenuated ACh-dependent vasodilation but did not affect vasodilation in response to sodium nitroprusside in normal rats. In PVL animals, the perfused mesentery was hyporesponsive to vasoconstrictor methoxamine. GA significantly potentiated methoxamine-induced vasoconstrictor after PVL. CONCLUSION: HSP90 plays a key role in NO-dependent hyperdynamic circulation in portal hypertension and provides a novel method for future treatment of portal hypertension.     

Overproduction of nitric oxide inhibits vascular reactivity in portal hypertensive rats

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

Chronic Inhibition of Nitric Oxide Ameliorates Splanchnic Hyposensitivity to Glypressin in a Hemorrhage-transfused Rat Model of Portal Hypertension

Background: Vasopressin given during hemorrhage is less effective than when given during a stable state in experimental portal hypertension or patients with cirrhosis (the so-called hyposensitivity phenomenon). This study investigated whether chronic inhibition of nitric oxide (NO) synthesis by N^G-nitro-L-arginine methyl ester (L-NAME), a non-selective NO synthase inhibitor, could potentiate the portal-hypotensive effect of glypressin (a long-acting vasopressin analogue) in portal-hypertensive rats during acute bleeding status. Methods: Portal hypertension was induced by partial portal vein ligation (PVL). Rats were divided to receive either L-NAME (~25 mg/kg/day in tap water) or placebo (tap water) treatment orally from 2 days prior to until 14 days after the operation. At the end of treatment, L-NAME-and placebo-treated PVL rats were subdivided into without-bleeding and with-bleeding groups to assess the effects of glypressin (0.07 mg/kg) on systemic and portal hemodynamics. In rats with a hypotensive hemorrhage, 4.5 ml of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin. Results: As compared with placebo-treated rats, chronic treatment with L-NAME in PVL rats significantly increased mean arterial pressure (P &lt; 0.001) without modulating portal pressure (P &gt; 0.05). In placebo-treated PVL rats, glypressin resulted in a less decrease in portal pressure in rats with bleeding than in those without bleeding (P &lt; 0.05). For PVL rats with bleeding, the portal-hypotensive effect of glypressin was significantly potentiated after chronic L-NAME treatment (P &lt; 0.05). Conclusions: Chronic inhibition of NO alleviates the splanchnic hyposensitivity to glypressin observed in bleeding PVL rats, suggesting the pathophysiological role of nitric oxide in mediating this splanchnic hyposensitivity.     

Asymmetric dimethylarginine and hemodynamic regulation in middle-aged men

The goal of this study was to evaluate the role of asymmetric dimethylarginine (ADMA) in the regulation of hemodynamic functions in hypertensive men. It has been suggested that ADMA, as an endogenous nitric oxide synthase inhibitor, is linked to hypertension and vascular reactivity. Sixty-seven men aged 51.1 years (range, 45-55 years) were studied. Plasma ADMA and symmetric dimethylarginine were determined by high-performance liquid chromatography-tandem mass spectrometry. Blood pressure (BP) was measured by 24-hour ambulatory recordings and casual measurements. Hemodynamic regulation was assessed by noninvasive methods. The nitric oxide production was estimated based on plasma nitrate (NO₃⁻) determination. Results showed that plasma arginine derivatives or l-arginine/ADMA ratio was not associated with BP values observed during 24-hour monitoring or in casual measurements. Systemic vascular resistance, pulse wave velocity, or cardiac output was not associated with plasma ADMA or plasma NO₃⁻ levels. No association was found between plasma ADMA and NO₃⁻ either. Interestingly, subjects on antihypertensive treatment had lower plasma ADMA concentrations than nontreated subjects (0.30 ± 0.08 and 0.36 ± 0.11 μmol/L, respectively, P = .04) despite higher BP values. In conclusion, these results suggest that plasma ADMA does not have a determinative role in the regulation of hemodynamic functions in Finnish middle-aged men.     

Effects of prostacyclin inhibition on splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension

BACKGROUND: Hyposensitivity to vasopressin is a well-documented phenomenon in animals with portal hypertension and patients with cirrhosis and hemorrhage. Similar findings exist with infusion of glypressin (a long-acting vasopressin analogue), and this phenomenon could be ameliorated by inhibition of nitric oxide (NO) synthase. Besides NO, excessive formation of prostacyclin (PGI2) has been shown to play an important role in the development of hyperdynamic circulation and the mediation of hyporeactivity to vasoconstrictors in portal-hypertensive states. This study was designed to investigate whether the blockade of PGI2 activity by indomethacin infusion could enhance the portal-hypotensive effect of glypressin in portal-hypertensive rats with bleeding. METHODS: Portal hypertension was induced by partial portal vein ligation (PVL). Fourteen days after operation systemic and portal hemodynamics were measured in stable or bleeding PVL rats receiving intravenous glypressin (0.07 mg/kg) or indomethacin (5 mg/kg) followed by glypressin infusion. In rats with a hypotensive hemorrhage 4.5 ml of blood was withdrawn, and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin. RESULTS: Splanchnic hyposensitivity to glypressin was shown in hemorrhage-transfused PVL rats. Indomethacin infusion did not cause significant systemic and portal-hemodynamic changes in bleeding PVL rats (P > 0.05). The addition of indomethacin significantly enhanced the portal-hypotensive effects of glypressin and potentiated the increases in mean arterial pressure induced by glypressin infusion in bleeding PVL rats. CONCLUSIONS: The improvement of splanchnic hyposensitivity to glypressin in a hemorrhage-transfused rat model of portal hypertension by the administration of indomethacin suggests that PGI2 has in the development of this hyposensitivity.     

Effect of 1-week losartan administration on bile duct-ligated cirrhotic rats with portal hypertension

BACKGROUND/AIMS: Nitric oxide and angiotensin play important roles in the pathogenesis of the hemodynamic derangement in cirrhosis and portal hypertension. The hemodynamic effects of losartan, an angiotensin II type 1 receptor antagonist, in cirrhotic patients with portal hypertension are conflicting. This study was undertaken to explore the possible mechanism of action of losartan on portal hypertension in cirrhotic rats produced by bile duct ligation (CBL). METHODS: Three weeks after surgery, CBL and sham-operated rats randomly received vehicle or losartan (3 mg/kg per 12 h by gavage) for 1 week. Hemodynamic values, hormone levels, and aortic eNOS protein expression were measured after drug administration. RESULTS: In CBL rats, 1-week losartan treatment decreased portal pressure and ameliorated hyperdynamic circulation associated with a blunted vascular response to N(omega)-nitro-L-arginine methyl ester infusion. The hematocrit increased and the plasma volume, aldosterone, plasma renin activity, norepinephrine, and nitrate and nitrite levels decreased. The eNOS protein expression was reduced in CBL rats receiving losartan compared with those receiving vehicle. CONCLUSIONS: One-week losartan treatment in CBL rats decreased portal pressure and ameliorated hyperdynamic circulation. In addition to the suppression of renin-angiotensin axis, the reduced aortic eNOS protein expression may play a partial role for the mechanism of action of losartan in CBL rats.     

Effects of long-term administration of octreotide in portal vein-stenosed rats

The hemodynamic effects of long-term administration of octreotide in portal hypertension has not been established. In addition, whether long-term octreotide treatment prevents the development of portosystemic shunts has not yet been evaluated. Hence, the current study was undertaken to evaluate the effects of long-term administration of octreotide in rats with portal vein stenosis. Immediately after portal vein stenosis or sham operation, rats were given either a long-term octreotide administration of 100 micrograms/kg or a placebo every 12 hours by subcutaneous injection for 14 consecutive days. Systemic hemodynamics and regional blood flows, degree of mesenteric-systemic shunts, and plasma glucagon concentrations were measured after the final dose of octreotide or placebo. A fifth group of portal vein-stenosed rats received hemodynamic and plasma glucagon measurements after 1-day octreotide treatment given at 14 days after surgery. Long-term octreotide treatment modified the hyperdynamic circulation without affecting the degree of mesenteric-systemic shunts, and 1-day octreotide treatment decreased portal tributary blood flow without affecting the portal pressure, systemic hemodynamics, and degree of mesenteric-systemic shunts. Plasma glucagon levels were decreased in portal vein-stenosed rats receiving either long-term or 1-day octreodtide compared with rats receiving placebo. In contrast, chronic octreotide treatment did not affect any of the hemodynamic values or plasma glucagon levels in sham-operated rats. In conclusion, long-term administration of octreotide modified in part the development of portal hypertension and hyperdynamic circulation in portal vein-stenosed rats without affecting the degree of mesenteric-systemic shunts. (Hepatology 1996 Mar;23(3):537-43)     

Role of nitric oxide and endothelin-1 in a portal hypertensive rat model

BACKGROUND: Portal hypertension is often accompanied by a hyperdynamic circulation state. Some reports have suggested that nitric oxide (NO) plays an important role in this hyperdynamic state. On the other hand, although endothelin (ET)-1, a powerful vasoconstrictor, was recently identified, little is known about its role in portal hypertension or about the interaction between NO and ET-1. The aim of this study was therefore to investigate whether or not the inhibitor of NO synthase (NOS) might improve portal hypertension, and also to clarify the relationship between NO and ET-1. METHODS: Portal hypertensive (PHT) rats, in which hypertension was induced by a two-step ligation of the portal vein (PVL), were used. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), and serum levels of NO and ET-1 were determined in PVL rats treated with two NOS inhibitors with different functions: N(G)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). Control (CTR) rats. treated by a sham operation (SO), were also studied. RESULTS: Two-step PVL treatment induced a significant increase in the serum level of NO3-and ET-1 in the portal vein. L-NAME and AG administration significantly decreased PP at doses of 50 mg/kg in PHT rats after 60 min administration, while no inhibitor effected any modification in the CTBR rats. Both NOS inhibitors increased MAP and decreased PP and BFV in the portal vein, gastric mucosa, and spleen, in addition to decreasing the serum levels of NO3- and ET-1 in the PHT rats, while neither blockade modified any parameters in the CTR rats. In PHT rats, L-arginine, a NO substance, reversed the effect of L-NAME, while it did not induce any recovery from the AG effect. CONCLUSIONS: In PHT rats, NO seems to contribute to portal hypertension. PVL increases not only the serum level of NO3-, but also that of ET-1 in the portal vein. Both L-NAME and AG reduce PP and BFV of the portal vein, spleen, gastric mucosa. and liver. In addition, the inhibition of NOS diminishes the serum level not only of NO, but also of ET-1. Use of an appropriate NOS inhibitor may therefore positively affect the hyperdynamic state in portal hypertension.     

Role of Nitric Oxide and Endothelin-1 in a Portal Hypertensive Rat Model

Background: Portal hypertension is often accompanied by a hyperdynamic circulation state. Some reports have suggested that nitric oxide (NO) plays an important role in this hyperdynamic state. On the other hand, although endothelin (ET)-1, a powerful vasoconstrictor, was recently identified, little is known about its role in portal hypertension or about the interaction between NO and ET-1. The aim of this study was therefore to investigate whether or not the inhibitor of NO synthase (NOS) might improve portal hypertension, and also to clarify the relationship between NO and ET-1. Methods: Portal hypertensive (PHT) rats, in which hypertension was induced by a two-step ligation of the portal vein (PVL), were used. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), and serum levels of NO and ET-1 were determined in PVL rats treated with two NOS inhibitors with different functions: NG-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). Control (CTR) rats, treated by a sham operation (SO), were also studied. Results: Two-step PVL treatment induced a significant increase in the serum level of NO3- and ET-1 in the portal vein. L-NAME and AG administration significantly decreased PP at doses of 50 mg/kg in PHT rats after 60 min administration, while no inhibitor effected any modification in the CTR rats. Both NOS inhibitors increased MAP and decreased PP and BFV in the portal vein, gastric mucosa, and spleen, in addition to decreasing the serum levels of NO3- and ET-1 in the PHT rats, while neither blockade modified any parameters in the CTR rats. In PHT rats, L-arginine, a NO substance, reversed the effect of L-NAME, while it did not induce any recovery from the AG effect. Conclusions: In PHT rats, NO seems to contribute to portal hypertension. PVL increases not only the serum level of NO3-, but also that of ET-1 in the portal vein. Both L-NAME and AG reduce PP and BFV of the portal vein, spleen, gastric mucosa, and liver. In addition, the inhibition of NOS diminishes the serum level not only of NO, but also of ET-1. Use of an appropriate NOS inhibitor may therefore positively affect the hyperdynamic state in portal hypertension.     

Therapeutic Effect of Captopril, Pentoxifylline, and Cordyceps Sinensis in Pre-Hepatic Portal Hypertensive Rats

Background/Aim:

Portal hypertension is an important and potentially fatal complication of liver disease whereby cellular and fibrotic alterations manifest to increase portal venous pressure. The aim of this study is to investigate the effect of captopril, pentoxifylline (PTX), and cordyceps sinensis in pre-hepatic portal hypertensive rats.

Settings and Design:

Wister male rats were divided at random into 3 main groups: the first group: control rats. The second group: sham-operated rats and the third group: prehepatic portal hypertensive rats (PHPHT) induced by regulated pre-hepatic portal vein ligation. After 14 days, Group 3 was subdivided into 5 subgroups. Subgroup (1): portal vein-ligated (PVL) was killed at once; Subgroup (2): received distilled water for 30 days (untreated PVL group); subgroups 3-5 were treated with captopril (60 mg/kg, orally); PTX (100 mg/kg, orally); and C. sinensis (200 mg/kg, orally), respectively, as a single daily dose for 30 days.

Patients and Methods:

Portal pressure, nitric oxide (NO), antioxidant enzymes, Liver enzymes, and creatinine levels were measured to evaluate the status of the liver state.

Results:

Portal vein ligation produced significant increments in liver enzymes, NO, creatinine and portal pressure concomitant with significant decrements in glutathione content and superoxide dismutase activity. Treatment with captopril, PTX, and C. sinensis resulted in a significant reduction in liver enzymes, NO, creatinine and portal pressure and observable increase in antioxidant enzymes.

Conclusions:

captopril, PTX, and C. sinensis have promising effect in controlling PHPHT and reducing hyperdynamic circulatory state through reduction of portal pressure and NO level.     

Effects of somatostatin analog on splanchnic hemodynamics and plasma glucagon level in portal hypertensive rats

ＥｆｅｃｔｓｏｆｓｏｍａｔｏｓｔａｔｉｎａｎａｌｏｇｏｎｓｐｌａｎｃｈｎｉｃｈｅｍｏｄｙｎａｍｉｃｓａｎｄｐｌａｓｍａｇｌｕｃａｇｏｎｌｅｖｅｌｉｎｐｏｒｔａｌｈｙｐｅｒｔｅｎｓｉｖｅｒａｔｓＷＵＺｈｉＹｏｎｇ,ＺＨＡＮＧＸｉａｏＪｉｅ,ＪＩ...     

Effects of tumor necrosis factor, endothelin and nitric oxide on hyperdynamic circulation of rats with acute and chronic portal hypertension

AIM:To evaluate the effect of tumor necrosis factor (TNF),endothelin (ET) and nitric oxide (NO) on hyperdynamic circulation (HC) of rats with acute and chronic portal hypertension (PHT).METHODS: Chronic portal hypertension was induced in Wistar rats by injection of carbon tetrachloride. After two weeks of cirrhosis formation, L-NMMA (25mg/kg) was injected into one group of cirrhotic rats via femoral vein and the experiment was begun immediately. Another group of cirrhotic rats was injected with anti-rat TNFα (300mg/kg) via abdominal cavity twice within 48h and the experiment was performed 24h after the second injection. The blood concentrations of TNFα, ET-1 and NO in portal vein and the nitric oxide synthase (NOS) activity in hepatic tissue were determined pre-and post-injection of anti-rat TNFα or LNMMA. Stroke volume (SV), cardiac output (CO), portal pressure (PP), superior mesenteric artery blood flow (SMA flow) and lilac artery blood flow (IAflow) were measured simultaneously. Acute portal hypertension was established in Wistar rats by partial portal-vein ligation (PVL). The parameters mentioned above were determined at 0.5h,24h, 48h, 72h and 120h after PVL. After the formation of stable PHT, the PVL rats were injected with anti-rat TNFα or L-NMMA according to different groups, the parameters mentioned above were also determined.RESULTS:In cirrhotic rats, the blood levels of TNFα, NO in portal vein and the liver NOS activity were significantly increased (P&lt;0.05) while the blood level of ET-1 was not statistically different (P&gt;0.05) from the control animals(477.67&#177;83.81pg/mL vs 48.87&#177;32.79pg/mL, 278.41&#177;20.11μmol/L vs 113.28&#177;14.51μmol/L, 1.81&#177;0.06μ/mg.prot vs 0.87&#177;0.03μ/mg.prot and 14.33&#177;4.42pg/mL vs8.72&#177;0.79pg/mL, respectively). After injection of anti-rat TNFα,the blood level of TNFα was lower than that in controls (15.17&#177;18.79pg/mL vs 48.87&#177;32.79pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP,SV,CO, SMAflow and IAflow were ameliorated. After injection of L-NMMA, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP and CO were also recovered to those of the controls. SV, SMAflow and IAflow were ameliorated. In PVL rats, the blood levels of TNFα NO in portal vein and the liver NOS activity were gradually increased and reached the highest levels at 48h after PVL. The blood level of ET-1 among different staged animals was not significantly different from the control animals. PP among different staged animals (2.4&#177;0.18kPa at 0.5h, 1.56&#177;0.08kPa at 24h, 1.74&#177;0.1kPa at 48h,2.38&#177;0.05 kPa at 72h, 2.39&#177;0.16 kPa at 120h) was significantly higher than that in controls (0.9&#177;0.16kPa). After injection of anti-rat TNFα in 72h PVL rats, the blood level of TNFα was lower than that in controls (14&#177;14pg/mL vs 48.87&#177;32.79pg/mL). The blood level of NO and the liver NOS activity were significantly decreased, but still higher than those of the controls. The blood level of ET-1 was not significantly changed. PP was decreased from 2.38&#177;0.05kPa to 1.68&#177;0.12kPa, but significantly higher than that in controls. SV, CO, SMAflow and IAflow were ameliorated.After injection of L-NMMA in 72h PVL rats, the blood level of NO and the liver NOS activity were recovered to those of the controls. PP, SV, CO, SMAflow and IAflow were also recovered to those of the controls.CONCLUSION:NO plays a critical role in the development and maintenance of HC in acute PHT and is a key factor for maintenance of HC in chronic PHT. TNFα may not participate in the hemodynamic changes of HC directly, while play an indirect role by inducing the production of NO through activating NOS. No evidence that circulating ET-1 plays a role in both models of portal hypertension has been found.     

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.     

Persistence of a hyperdynamic circulation in cirrhotic rats following removal of the sympathetic nervous system.

The sympathetic nervous system is thought to play a role in the pathogenesis of the hyperdynamic circulation associated with portal hypertension. However, the extent of this role is unknown. After elimination of all neurological control by pithing, systemic and regional hemodynamics were studied in rats with portal hypertension caused by either portal vein stenosis or biliary cirrhosis. In normal rats, pithing induced a two-thirds decrease in mean arterial pressure and cardiac index. Compared with pithed normal rats, pithed portal vein-stenosed rats showed similar values for mean arterial pressure, cardiac index, and portal tributary blood flow. In contrast, pithed cirrhotic rats still showed hyperdynamic circulation with increased cardiac index and portal tributary blood flow. Although pithing dramatically reduced portal pressure in all groups, portal pressure remained significantly higher in portal hypertensive rats than in normal rats. These results indicate that in rats with portal vein stenosis, the sympathetic nervous system plays a major role in hemodynamic alterations, whereas in rats with cirrhosis, nonneurogenic factors participate in the pathogenesis of the hyperdynamic circulation.     

Reduced liver function is the trigger for renal sodium retention following portal vein ligation in the rat

Sodium retention along with peripheral vasodilation are features of prehepatic portal hypertension. In several models of experimental liver damage, sodium retention occurs only when hepatic function, measured by the aminopyrine breath test (ABT-k), falls below a critical threshold. The relationship between renal sodium handling, ABT-k and systemic and renal haemodynamics in partial portal vein ligated (PVL) rats was examined to test the hypothesis that peripheral vasodilation was responsible for initiating sodium retention. Haemodynamic measurements were conducted early after surgery in portal hypertensive rats with and without sodium retention and in sham-operated controls. Compared with control, both PVL groups of rats had elevated portal pressure and lower peripheral vascular resistance (P<0.05). Sodium retaining-PVL rats had both lower ABT-k (0.95 ± 0.05 vs 1.38 ± 0.06 times 10^-2/min; P<0.05) and higher sodium balance (1.38 ± 0.09 vs 0.43 ± 0.09 mmol/day; P< 0.05) than non-sodium retaining PVL rats. No differences in plasma renin activity or noradrenaline concentrations were observed. In a separate group of rats, hydralazine-induced peripheral vasodilation did not induce sodium retention. These results suggest that the presence of peripheral vasodilation alone is not sufficient to trigger a sodium-retaining status. A factor, probably liver function-dependent, acting directly on renal tubules may be necessary for changes in renal sodium handling in this model.     

Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension

BACKGROUND/AIMS: Splanchnic vasodilation initiates the hyperdynamic syndrome in portal hypertension. We aimed to explore molecular mechanisms involved in the development of mesenteric vasodilation in portal hypertension. METHODS: Superior mesenteric artery (SMA) samples from portal vein ligated (PVL) and sham rats were compared in a time course experiment using DNA microarrays. Selected genes were quantified by qRT-PCR in PVL and cirrhotic rats. Inmunohistochemistry of tyrosine hydroxylase (Th) and norepinephrine was assessed in SMA sections of PVL and sham rats. Western blot analysis of Th, dopamine beta-hydroxylase (Dbh) and synaptosome-associated protein (Snap-25) was performed in SMA and jejunum samples from the animal models. RESULTS: Fifty differentially expressed genes implicated in neurotransmission, especially adrenergic, were detected in SMA samples from PVL rats. Sequential analysis showed a profound down-regulation at 14 days in PVL rats. These down-regulated genes were confirmed by RT-PCR in SMA from PVL and cirrhotic rats. Th and NE detection by immunohistochemistry was reduced in PVL compared to sham. Th, Dbh and Snap-25 expression was lower in SMA from 14-day PVL and cirrhotic rats compared to sham and control rats, respectively. CONCLUSIONS: Genetic down-regulation of genes related to the adrenergic system might have a role in splanchnic vasodilation of portal hypertension.