Simvastatin effects on portal‐systemic collaterals of portal hypertensive rats

Background and Aim: Portal‐systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals. Methods: Partially portal vein‐ligated rats received oral simvastatin (20 mg/kg/day) or distilled water from ?2 to +7 day of ligation. After hemodynamic measurements on the eighth postoperative day, baseline perfusion pressure (i.e. an index of collateral vascular resistance) and arginine vasopressin (AVP, 0.1 nM–0.1 µM) responsiveness were evaluated with an in situ perfusion model for collateral vascular beds. RT‐PCR of endothelial NO synthase (eNOS), inducible NOS (iNOS), cyclooxygenase‐1 (COX‐1), COX‐2, thromboxane A₂ synthase (TXA₂‐S) and prostacyclin synthase genes was performed in parallel groups for splenorenal shunt (SRS), the most prominent intra‐abdominal collateral vessel. To determine the acute effects of simvastatin, collateral AVP response was assessed with vehicle or simvastatin. SRS RT‐PCR of eNOS, iNOS, COX‐1, COX‐2 and TXA₂‐S, and measurements of perfusate nitrite/nitrate, 6‐keto‐PGF1_α and TXB₂ levels were performed in parallel groups without AVP. Results: Acute simvastatin administration enhanced SRS eNOS expression and elevated perfusate nitrite/nitrate and 6‐keto‐PGF1_α concentrations. Chronic simvastatin treatment reduced baseline collateral vascular resistance and portal pressure and enhanced SRS eNOS, COX‐2 and TXA₂‐S mRNA expression. Neither acute nor chronic simvastatin administration influenced collateral AVP responsiveness. Conclusion: Simvastatin reduces portal‐systemic collateral vascular resistance and portal pressure in portal hypertensive rats. This may be related to the enhanced portal‐systemic collateral vascular NO and prostacyclin activities.     

Chronic inhibition of nitric oxide increases the collateral vascular responsiveness to vasopressin in portal hypertensive rats

BACKGROUND/AIMS: Nitric oxide (NO), a potent vasodilator, plays a significant role in the vascular hyposensitivity to vasoconstrictors related to portal hypertension. Chronic NO inhibition ameliorates portal-systemic collaterals in portal hypertensive rats. This study investigated whether chronic NO inhibition by NG-nitro-L-arginine methyl ester (L-NAME) improves the portal-systemic collateral vascular responsiveness to arginine vasopressin (AVP) in portal hypertensive rats. METHODS: Partially portal vein-ligated (PVL) rats received L-NAME in tap water (approximately 25 mg/kg per day) or tap water only (control) since 2 days prior to until 7 days after PVL. Mean arterial pressure was measured on the 8th day. By in situ perfusion model, different concentrations of AVP (10(-10)-10(-7) M) with a constant flow rate (20 ml/min) were applied to assess the perfusion pressure of collateral vessels. In another series, perfusion with different flow rates (5-30 ml/min) was used to obtain flow-pressure curves: the slopes represent collateral vascular resistances and higher resistances indicate less collaterals. RESULTS: Mean arterial pressure was higher in the L-NAME-treated group than that of the control group (P<0.05). As compared with the controls, L-NAME-treated rats achieved significantly higher perfusion pressures in response to AVP. In addition, chronic L-NAME treatment also induced an increase of collateral vascular resistance, suggesting the attenuation of portal-systemic shunting. CONCLUSIONS: Chronic NO inhibition ameliorates portal-systemic shunting and improves the collateral vascular responsiveness to AVP in portal hypertensive rats.     

Chronic cyclooxygenase blockade enhances the vasopressin responsiveness in collaterals of portal hypertensive rats

OBJECTIVE: Collateral vascular responsiveness to vasoconstrictors may be crucial in the management of acute variceal bleeding. In an in situ perfusion model, arginine vasopressin (AVP) has been shown to cause a direct vasoconstrictive effect on portal-systemic collaterals and this effect is enhanced by preincubation of indomethacin (INDO). The purpose of this study was to investigate the effects of chronic INDO administration on the portal-systemic collateral responsiveness to AVP and the degree of portal-systemic shunting in portal hypertensive rats. MATERIAL AND METHODS: Rats with partial portal vein ligation randomly received daily subcutaneous injections with INDO (5 mg/kg) or distilled water (control group) 2 days prior to until 7 days after ligation. Systemic and portal hemodynamics was evaluated on the 8th day. Using an in situ collateral perfusion model, AVP (10(-10)-10(-7) M) at a constant flow rate (20 ml/min) was applied. In another series, Krebs solution with different flow rates (5-30 ml/min) was used to obtain flow-pressure curves: the slopes represent collateral vascular resistances--the higher resistances indicate fewer collaterals. RESULTS: Mean arterial pressure and portal pressure were not significantly different between the INDO-treated group and the control group (p>0.05). In the first series of experiments, INDO treatment increased the collateral perfusion pressure to AVP at 10(-8) M, 3x10(-8) M, and 10(-7) M (p<0.05). In the second series, INDO did not change collateral vascular resistance, which suggests that the degree of shunting was not altered. CONCLUSIONS: Chronic INDO treatment improves the collateral vascular responsiveness to AVP without ameliorating portal-systemic shunting in portal hypertensive rats.     

Diet Restriction Increases Ubiquinone Contents and Inhibits Progression of Hepatocellular Carcinoma in the Rat

Objective Arginine vasopressin (AVP) exerts a constrictive effect on the portal-systemic collaterals of non-cirrhotic portal hypertensive rats, but its effect on cirrhotic rats is unknown. The aim of this study was to investigate the response of AVP and the modulatory roles of nitric oxide and prostaglandin on collaterals of common bile duct-ligated (BDL) cirrhotic rats. Material and methods The collateral vascular responsiveness to graded concentrations of AVP (10^?10–3×10^?7 M) was tested by an in situ collateral perfusion system pretreated with N^ω-nitro-L-arginine (L-NNA, 100 μM), indomethacin (INDO, 10 μM), or both. The collateral responses to AVP with the pretreatment of a vasopressin V₁ receptor antagonist d(CH₂)₅Tyr(Me) arginine vasopressin or a V₂ receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 10^?10–3×10^?7 M) were also evaluated. Results The perfusion pressure of collaterals was significantly increased by AVP, and this effect was inhibited by the addition of the V₁ receptor antagonist. DDAVP had no effect on the collaterals. Incubation with L-NNA or L-NNA plus INDO, but not INDO alone, significantly potentiated the constrictive effects of AVP. The constrictive effect of AVP in the combination group was similar to that in the L-NNA alone group. Conclusions The results show that AVP produces a direct vasoconstrictive effect on the portal-systemic collaterals of BDL cirrhotic rats. The constrictive effect of AVP is mediated by the vasopressin V₁, instead of V₂, receptors. Nitric oxide may play a more important role than prostaglandin in modulating the collateral vascular response to AVP in BDL cirrhotic rats.     

Endothelin-1 induces vasoconstriction on portal-systemic collaterals of portal hypertensive rats

Portal hypertension is associated with increased hepatic and collateral resistance to an increased portal blood flow. Endothelin-1 (ET-1) can induce intrahepatic vasoconstriction and consequently increase portal pressure. It is unknown if ET-1 also modulates portal pressure by a direct vasoconstrictive effect on collaterals. This study investigated the collateral vascular responses to ET-1, the receptors in mediation, and the regulation of ET-1 action by nitric oxide and prostaglandin. The portal-systemic collaterals of partially portal vein-ligated rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) mol/L) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) mol/L), BQ-788 (ET(B) receptor antagonist, 10(-7) mol/L) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of n(omega)-nitro-L-arginine (NNA; 100 mol/L), indomethacin (INDO; 10 mol/L), or in combination were performed. ET-1 increased the perfusion pressure of collaterals and its effect was significantly suppressed by BQ-123 alone and BQ-123 plus BQ-788, but not BQ-788 alone (P <.05). Incubation with NNA, INDO, or both significantly enhanced the response of collaterals to ET-1 (P < .05). These results show that ET-1 produces a direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. This effect is mediated by ET(A,) but not ET(B), receptors. Both nitric oxide and prostaglandin modulate the collateral vascular response to ET-1 and may therefore participate in the development and maintenance of portal hypertension.     

Role of endothelin-1 in congestive gastropathy in portal hypertensive rats

BACKGROUND: The aim of this study was to determine the role of endothelin (ET)-1 in portal hypertensive gastropathy (PHG) under portal hypertension, in order to investigate whether the ET(A/B) receptor inhibitor improves the permeability of gastric mucosal microvessels in PHG. METHODS AND RESULTS: Portal hypertensive rats (PVL) and sham-operated rats (CTR) were prepared and then the concentration of plasma ET-1 was measured and the vasopressor response to ET-1 was compared between the two groups. The plasma ET-1 levels in PVL increased significantly compared with CTR; however, the vasopressor response to ET-1 in PVL decreased more than in CTR. Next, the portal venous pressure was measured in both CTR and PVL pretreated with or without a nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), before the injection of ET-1. The portal venous pressure of PVL after receiving ET-1 and being pretreated with L-NAME significantly increased in comparison to the pressure of PVL treated with ET-1 alone (without L-NAME). Moreover, Evans-Blue was injected into each rat and the absorbancy of the gastric contents was measured. The absorbancy of Evans-Blue in PVL increased significantly compared with CTR; however, the absorbancy in PVL+ ET(A/B) receptor inhibitor (Ro47-0203) decreased significantly more than in PVL. CONCLUSIONS: This study showed that ET-1 is a potent vasoconstrictive substance that also has a transitory vasodilative response through NO induced by ET-1 in portal hypertension. In addition, it was found that the vascular permeability of the gastric mucosa increased in portal hypertension and that Ro47-0203 inhibited the hyper-permeability. Accordingly, ET-1 may, thus, play an important role in the development of PHG through NO induced by ET-1. Ro47-0203 may, therefore, be a useful substance for improving PHG in portal hypertension.     

Effects of somatostatin and octreotide on portal-systemic collaterals in portal hypertensive rats

BACKGROUND/AIMS: Somatostatin and its long-acting analogue, octreotide, have been used to cease variceal bleeding with uncertain mechanisms. This study investigated whether somatostatin and octreotide have a direct vasoconstrictive effect on the portal-systemic collaterals of portal-hypertensive rats and potentiate the vasoconstriction induced by endothelin-1 in these vascular beds. METHODS: The vascular responses of collateral vessels to graded concentrations of somatostatin (10(-9)-10(-5) mol/l), octreotide (10(-10)-10(-6) mol/l), norepinephrine (10(-9)-10(-5) mol/l) and vehicle (Krebs solution) were evaluated in perfused collateral vascular beds of rats with portal hypertension induced by partial portal vein ligation. In addition, the perfusion pressure changes of collateral vessels to endothelin-1 (10(-8) mol/l) in the presence of vehicle(control), somatostatin (10(-6) mol/l) and octreotide (10(-6) mol/l) were tested. RESULTS: Compared with the vehicle group, norepinephrine significantly increased the perfusion pressure of collateral vessels at concentrations between 10(-7) and 10(-5) mol/l. In contrast, neither somatostatin nor octreotide significantly changed the perfusion pressure. Somatostatin and octreotide significantly enhanced the endothelin-1-induced vasoconstrictive effect on the collaterals. CONCLUSIONS: Somatostatin and octreotide exert no direct vasoconstrictive effect on the collateral vessels of portal hypertensive rats. In the presence of endothelin-1, somatostatin and octreotide exert a local vasoconstrictive effect on these vascular beds.     

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.     

Effects of vasopressin on portal-systemic collaterals of cirrhotic rats

OBJECTIVE: Arginine vasopressin (AVP) exerts a constrictive effect on the portal-systemic collaterals of non-cirrhotic portal hypertensive rats, but its effect on cirrhotic rats is unknown. The aim of this study was to investigate the response of AVP and the modulatory roles of nitric oxide and prostaglandin on collaterals of common bile duct-ligated (BDL) cirrhotic rats. MATERIAL AND METHODS: The collateral vascular responsiveness to graded concentrations of AVP (10(-10) - 3 x 10(-7) M) was tested by an in situ collateral perfusion system pretreated with Nomega-nitro-L-arginine (L-NNA, 100 microM), indomethacin (INDO, 10 microM), or both. The collateral responses to AVP with the pretreatment of a vasopressin V1 receptor antagonist d(CH2)5Tyr(Me) arginine vasopressin or a V2 receptor agonist 1-desamino-8-D-arginine vasopressin (DDAVP, 10(-10) - 3 x 10(-7) M) were also evaluated. RESULTS: The perfusion pressure of collaterals was significantly increased by AVP, and this effect was inhibited by the addition of the V1 receptor antagonist. DDAVP had no effect on the collaterals. Incubation with L-NNA or L-NNA plus INDO, but not INDO alone, significantly potentiated the constrictive effects of AVP. The constrictive effect of AVP in the combination group was similar to that in the L-NNA alone group. CONCLUSIONS: The results show that AVP produces a direct vasoconstrictive effect on the portal-systemic collaterals of BDL cirrhotic rats. The constrictive effect of AVP is mediated by the vasopressin V1, instead of V2, receptors. Nitric oxide may play a more important role than prostaglandin in modulating the collateral vascular response to AVP in BDL cirrhotic rats.     

Pravastatin affects blood pressure and vascular reactivity

Summary To investigate the effect of endogenous cholesterol synthesis on blood pressure and vascular response, a HMG CoA reductase inhibitor, pravastatin (1 or 10mg/kg per day) was administered orally for 2 or 4 weeks to spontaneously hypertensive rats (SHR/lzm) and normotensive Wistar-Kyoto (WKY/lzm) rats. Blood pressure was significantly increased in the pravastatin-treated groups of both strains, occurring in WKY after a longer treatment period than in SHR. The thoracic aortas from SHR and WKY were pretreated with pravastatin (10^–4M). The vascular response to norepinephrine in terms of both contractility and sensitivity, was increased in the pravastatin-treated SHR aorta but not in the WKY aorta. The increased response was not observed in the presence of mevalonate. Acetylcholine-induced vascular relaxation in the aortas from both strains was not affected by pravastatin pretreatment. These results suggest that the vascular response to norepinephrine may be affected by the intracellular cholesterol synthesis pathway.     

Effect of isolated portal hypertension on kupffer cell function

The increased incidence of infection in cirrhotics may in part be attributable to dysfunction of the reticuloendothelial system (RES) in removing pathogens from the circulation. The portosystemic shunting (PSS) that results from portal hypertension in cirrhotics may compromise RES function by allowing enteric pathogens to be shunted away from the Kupffer cells. A well-characterized model of portal hypertension induced by partial portal vein ligation (PVL), in which there is no hepatic parenchymal cell damage, was used. Kupffer cell function is unaltered and the effect of PSS alone on overall RES function can be evaluated. In addition to the usual immunologically inert [^99mTc]sulfur colloid, an actual pathogen was also evaluated. PVL and sham-ligated rats were given either [^99mTc]sulfur colloid orE. coli via the ileocolic vein. The right femurs, lungs, livers and spleens of the animals receiving^99mTc were excised and the radioactivity counted. The lungs, livers, and spleens of the animals receivingE. coli were liquefied and the bacteria were quantified. For both groups the ratios of^99mTc orE. coli in the lung, spleen, and femur to liver were calculated. PVL rats had significantly more^99mTc in the lung, spleen, and femur than the sham rats. There were also significantly moreE. coli in the lungs for PVL rats but no significant difference in the spleen counts. These results imply that even in the absence of Kupffer cell dysfunction, PSS alters reticuloendothelial system function by causing a greater distribution of pathogens to the periphery. This altered distribution may contribute to an increased susceptibility to infection in cirrhotics.     

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.     

Thalidomide inhibits tumor necrosis factor alpha,decreases nitric oxide synthesis,and ameliorates the hyperdynamic circulatory syndrome in portal-hypertensive rats

A hyperdynamic circulatory state frequently is observed in portal hypertension with liver failure or extensive portal-systemic shunting. Tumor necrosis factor alpha (TNF) causes marked hypotension in mammals by inducing nitric oxide synthesis and has been shown to play a role in the development of the hemodynamic changes observed in portal hypertension. Thalidomide selectively inhibits TNF production by enhancing messenger RNA degradation. We investigated the systemic and portal hemodynamic effects of thalidomide in a prehepatic model of portal hypertension and evaluated whether suppressing TNF synthesis decreases NO production. Portal hypertension was induced by partial ligation of the portal vein (PVL). Animals received thalidomide (T) (50 mg/kg/d) + water or water alone (W), orally, daily for 2 days before and 13 days after PVL operation, at which time hemodynamic studies were performed and TNF plasma levels were obtained. Sham-operated animals were studied identically. In an additional group of PVL animals, 24-hour urinary excretion of NO₂^- and NO₃^- was measured during treatment. PVL animals receiving T presented with a significantly higher mean arterial pressure and systemic vascular resistance and significantly lower portal pressure, TNF plasma levels, and 24-hour urinary excretion of NO₂^- and NO₃^-, in comparison with rats receiving W. A significant correlation (r = -0.61) was observed between TNF plasma levels and mean arterial pressure among PVL animals. Thalidomide did not have any significant effects on sham rats. Thalidomide inhibits TNF synthesis and reduces NO production, blunts the development of the hyperdynamic circulation, and decreases portal pressure in PVL-operated rats. (Hepatology 1996 Jun;23(6):1616-21)     

Vascular,hemodynamic and renal effects of low‐dose losartan in rats with secondary biliary cirrhosis

Background: In cirrhosis, splanchnic and systemic vasodilatation induce a hyperdynamic circulatory dysfunction, portal hypertension and renal sodium retention. This vasodilatation is in part because of an impaired vascular response to α1‐adrenoceptor agonists. Recently, the angiotensin II type 1‐receptor antagonist losartan has been shown to attenuate portal hypertension. We hypothesized that losartan decreases portal pressure by counteracting the impaired vascular responsive to α1‐adrenoceptor agonists. Methods: We studied, in rats with secondary biliary cirrhosis and sham‐operated rats, the effect of 0.5 and 10 mg losartan/kg × day on aortic responsiveness to α1‐adrenoceptor stimulation with methoxamine and angiotensin II (myograph), splanchnic and systemic hemodynamics (colored microspheres), plasma noradrenaline levels and kidney function. Results: In cirrhotic rats, 10 mg losartan/kg × day completely inhibited aortic contractility to angiotensin II, decreased vascular resistance and arterial pressure and induced renal failure. In contrast, 0.5 mg losartan/kg × day only partially inhibited aortic contractility to angiotensin II, but improved aortic contractility to methoxamine, increased splanchnic and systemic vascular resistance, decreased portal pressure, decreased plasma norepinephrine levels and induced natriuresis. Conclusions: In cirrhotic rats, losartan at a very low dose increases splanchnic vascular resistance, decreases portal pressure and improves kidney function, possibly by an increased vascular responsiveness to α1‐adrenoceptor agonists.     

Arterial hypoxemia and intrapulmonary vasodilatation in rat models of portal hypertension

Background Rats with chronic bile duct ligation (CBDL) and portal vein ligation (PVL) are used as models of portal hypertension. CBDL rats show hypoxemia with intrapulmonary vasodilatation (IPVD), and are recognized as a model of hepatopulmonary syndrome (HPS), while PVL rats are normoxemic. We investigated the differences in arterial oxygenation between these models, and the key factors leading to HPS.Methods Forty-eight Sprague-Dawley rats were prepared as CBDL or PVL models, or as Sham rats. Arterial oxygenation, hemodynamics (reference sample method), and IPVD were simultaneously evaluated in conscious and unrestrained animals, using ¹⁴¹Ce- or ¹¹³Sn-labeled microspheres (15 µm in diameter), respectively. Endothelin-1 (ET-1) and nitrate/nitrite (end products of nitric oxide; NOx) production by the lung tissue (increment across the lungs) was also determined.Results The extent of IPVD was similar in both models, but hypoxemia was only observed in CBDL rats. The ET-1 level and the increment in NOx were significantly increased in CBDL rats, and the increment was directly correlated with impairment of oxygenation. Blood flow through the bronchial arteries (anatomical shunting) was increased in CBDL rats, reaching more than three times the level in PVL rats or Sham rats.Conclusions These results support the hypothesis that NO derived from the lung tissues contributes to hypoxemia, and IPVD appears to be a prerequisite for impaired oxygenation. The considerable increase of anatomical shunting may potentially contribute to impaired oxygenation in CBDL rats.     

Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats

Background/Aims: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats.Methods: Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate groups, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg · kg⁻¹ · 12 h⁻¹ was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement.Results: Contractile responses to KCl (15–90 mM) and phenylephrine (10⁻⁹−10⁻⁴ M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats.Conclusion: Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.     

Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilation in rat portal hypertension

Background and aims: Portal hypertension is associated with downregulation of mRNA and proteins involved in adrenergic transmission in the superior mesenteric artery (SMA) in portal vein‐ligated (PVL) and cirrhotic rats. We aimed to investigate whether SMA adrenergic dysfunction was accompanied by sympathetic nerve structural changes and whether it was extensive to resistance mesenteric arteries. We also attempted to localize the origin of mRNA of specific adrenergic genes. Methods and results: In situ hybridization showed tyrosine hydroxylase (Th) mRNA expression in neuronal bodies of superior mesenteric ganglia and inside axonal fibres surrounding proximal SMA sections. Comparison of SMA by Th immunohistochemistry, both in PVL and bile duct‐ligated (BDL) rats, demonstrated a significant decrease in the number of nervous structures (69% PVL; 62% BDL), total nervous area (70% PVL; 52% BDL) and Th‐stained nervous area (89% PVL; 64% BDL) compared with sham rats. A strong correlation was detected between the Th‐stained nervous area and the haemodynamic parameters, mainly with SMA resistance (r=0.9, P<0.001 for PVL and r=0.75, P=0.018 for BDL). Western blot analysis of Th, dopamine β‐hydroxylase and synaptosome‐associated protein of 25 kDa indicated a significant inhibition in protein expression (35–58%) in mesenteric resistance arteries from both portal hypertension models compared with sham. By contrast, nervous structure analysis and protein expression in renal arteries showed no differences between sham and PVL rats. Conclusion: Portal hypertension is associated with sympathetic nerve atrophy/regression in the mesenteric arterial vasculature that could contribute to the splanchnic vasodilation associated with portal hypertension.     

Effects of α1 and β-adrenergic antagonists and 5-hydroxytryptamine receptor antagonist on portal-systemic collateral vascular resistance in conscious rats with portal hypertension

In order to study the acute effects of pharmacological agents on the vascular resistance of portal-systemic collaterals, a model of total portal vein occlusion with 100% portal-systemic shunts was developed in the conscious rat. The haemodynamic effects of several vaso-active substances were evaluated in this model and compared with those obtained after saline administration. Prazosin (0.5 mg), an alpha 1-adrenergic antagonist, significantly reduced mean arterial pressure by 29%, portal pressure from 13.8 +/- 1.0(mean +/- s.e.m.) to 10.1 +/- 0.4 mmHg and portal tributary blood flow (radioactive microspheres) from 13.6 +/- 2.1 to 11.7 +/- 1.2 mL/min. It also decreased portal-systemic vascular resistance from 95 +/- 16 to 73 +/- 9 dyn s/cm5 x 10(3). Propranolol (4 mg), a beta-adrenergic antagonist, significantly reduced mean arterial pressure by 12% and portal pressure from 15.5 +/- 1.2 to 13.3 +/- 0.9 mmHg while reducing portal tributary blood flow from 14.6 +/- 1.5 to 11.0 +/- 1.7 mL/min and increasing portal systemic collateral vascular resistance from 88 +/- 7 to 103 +/- 8 dyn s/cm5 x 10(3). Ketanserin (0.25 mg/kg), a 5-hydroxytryptamine receptor antagonist, reduced portal pressure from 15.8 +/- 1.0 to 13.3 +/- 0.7 mmHg at a dose that did not alter mean arterial pressure or portal tributary blood flow. It achieved this by reducing portal-systemic collateral vascular resistance from 90 +/- 14 to 74 +/- 13 dyn s/cm5 x 10(3). Saline had no significant effect on systemic and splanchnic haemodynamics. This study shows that ketanserin decreases vascular resistance of portal-systemic collaterals while propranolol increases it. Thus, it is suggested that collateral vascular resistance is accessible to pharmacological manipulation.     

Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis

Aim: Bacterial translocation (BT) to mesenteric lymph nodes (MLN) in cirrhosis has been linked to impaired host defence. Phagocytosis by polymorphonuclear leucocytes (PMNLs) is the primary event in the killing of bacteria but has not been investigated in relation to the presence of BT. Methods: Mesenteric lymph nodes were harvested sterile and assessed for BT by culture techniques. Study groups included ascitic cirrhotic rats (LC), healthy controls (Con) as well as portal‐vein‐ligated (PVL) rats 2 days (acute PVL with and without norfloxacin) or 3 weeks after surgery (chronic PVL). PMNLs were isolated from systemic blood and the capacity to phagocytose opsonized Escherichia coli was evaluated by FACS analysis. Results: No BT was observed in Con and chronic PVL animals but 11/20 LC (55%) and six out of six acute PVL (100%) presented with BT. In the presence of BT, PMNL from PVL as well as LC rats showed significantly increased phagocytic activity as compared with controls. In contrast, PMNL from animals without BT, whether PVL or LC, exhibited phagocytic activity similar to those from control rats. The number of PMNLs involved in the phagocytic process was significantly increased only in portal‐hypertensive rats with but not without BT as compared with controls. Norfloxacin did prevent BT in acute PVL animals, thereby correcting the increase in phagocytic capacity in PMNL. Conclusions: Cirrhosis per se is not associated with alterations of the phagocytic capacity of PMNL. The occurrence of BT, however, increases the phagocytic capacity of PMNL, being observed likewise in prehepatic portal hypertension, indicating an in vivo‘priming’ of PMNL by BT independent of cirrhosis.     

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.