Central nervous system manganese induced lesions and clinical consequences in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Around 47-74% of patients with hereditary hemorrhagic telangiectasia (HHT) have hepatic vascular malformations (HVMs); magnetic resonance images (MRI) of the central nervous system (CNS) might show in T1 sequences a hyper-intensity signal in different areas, mainly in the basal ganglia (BG) as consequence of manganese (Mn) deposits as observed in cirrhotic patients. These patients might suffer from different neuropsychiatric disorders (hepatic encephalopathy). In HHT patients, even in the presence of hepatic shunts, hepatocellular function is usually preserved. Additionally, Mn shares iron absorption mechanisms, transferrin and CNS transferrin receptors. In iron deficiency conditions, the Mn may harbor transferrin and access BG. The objectives were to describe frequency of BG Mn deposit-induced lesions (BGMnIL) in HHT patients, its relationship with iron deficiency anemia (IDA) and HVMs. Finally, explore the association between neuropsychological and motor consequences. We performed a cross-sectional study. We determined HHT patients with or without BG-MnIL by the MRI screening of the CNS. We included all patients with lesions and a random sample of those without lesions. All patients underwent standardized and validated neuropsychological assessment to evaluate BG actions. Results were analyzed with multiple logistic regression, adjusting for potential confounders. RESULTS: Among 307 participants from a cohort included in the Institutional HHT Registry, 179 patients had MRI performed and Curaçao Criteria ≥3. The prevalence of BG-MnIL was 34.6% (95%CI 27.69-42.09). While neuropsychological symptoms were present in all patients, BG-MnIL patients performed poorly in three of the neuropsychological tests (serial dotting, line tracing time, number connection test A). HVMs frequency in BG-MnIL was 95.1%, versus 71.4% in those without lesions (p < 0.001). IDA frequency was 90.3% versus 54% (p < 0.001). When IDA is present, estimated risk for BG-MnIL is remarkably high (OR 7.73, 95%CI 2.23-26.73). After adjustment for possible confounders (gender, age, presence of HVMs), IDA was still associated with increased risk of BG-MnIL (adjusted OR 6.32, 95% CI 2.32-17.20; p < 0.001). CONCLUSIONS: Physicians should assess BG-MnIL in HHT patients in CNS-MRI. IDA and HVMs present increased risk of lesions. Patients with BG-MnIL have neuropsychological impairment, and they might benefit from sparing IDA, or undergoing future therapeutic options. TRIAL REGISTRATION: NCT01761981 . Registered January 3rd 2013.

Chronic administration of propylthiouracil ameliorates hyperdynamic circulation in portal hypertensive rats.

OBJECTIVE: To evaluate the effect of a hypothyroid state, induced by chronic propylthiouracil administration, on splanchnic and systemic hemodynamic parameters in rats with portal hypertension due to portal vein ligation. METHODS: Portal hypertension was induced by surgical stenosis of the portal vein. Cardiac index and portal blood flow were measured using radioactive microspheres. Measurements were performed after treatment with propylthiouracil (1 mg/ml in drinking water) for 5 days. RESULTS: Propylthiouracil-treated portal hypertensive rats had a lower portal pressure (12.4 +/- 1.9 versus 16.3 +/- 0.7 mmHg; p < 0.05) and portal blood flow (11.6 +/- 0.7 versus 13.2 +/- 1.3 ml/min/100 g; p < 0.05) than non-treated animals. Splanchnic vasoconstriction in treated animals was associated with a higher peripheral vascular resistance (2.3 +/- 0.4 versus 1.8 +/- 0.3 mmHg/ml/min/100 g; p < 0.05) than controls. CONCLUSION: These results suggest that portal pressure can be lowered by inducing a hypothyroid state by chronic administration of propylthiouracil.

Pentoxifylline reduces nephrotoxicity associated with cyclosporine in the rat by its rheological properties.

BACKGROUND: The goals of this study were to evaluate whether administration of pentoxifylline (POF) reduces the nephrotoxicity associated with cyclosporine (CsA) in the rat, and whether the effect of POF is related to its rheological properties. METHODS: Mean arterial pressure was measured by an intraarterial catheter. Glomerular filtration rate and renal plasma flow were determined by measuring inulin and para-aminohippurate clearances, after double-blind coadministration for 10 days of CsA (25 mg/kg/day) with either vehicle or POF (45 mg/kg every 12 hr). These results were compared with those obtained in control rats. Blood viscosity and erythrocyte deformability were also evaluated after treatment using a cone plate viscometer and a filtration method, respectively. RESULTS: No changes were observed in mean arterial pressure in both groups compared with controls. Glomerular filtration rate was significantly lower in CsA-treated rats (0.3+/-0.1 ml/min/100 g) than in control animals (0.6+/-0.1 ml/min/100 g, P<0.02). The coadministration of CsA with POF normalized the glomerular filtration rate (0.6+/-0.1 ml/min/100 g). A parallel decrease in renal plasma flow was observed in CsA-treated rats compared with controls (CsA+vehicle: 1.5+/-0.2 vs. control: 2.2+/-0.1 ml/min/100 g, P<0.02), this effect completely reversed by cotreatment with POF (3.1+/-0.2 ml/min/100 g). Blood viscosity was significantly higher in CsA-treated rats than in the control group (CsA+vehicle: 5.6+/-0.7 vs. control: 5.0+/-0.4 m x Pa x s, P<0.05). This effect was associated with a lower erythrocyte deformability (CsA+vehicle: 1.2+/-0.2 vs. control: 1.5+/-0.3 ml/min, P<0.05). These rheological abnormalities were normalized by coadministration with POF (blood viscosity: 4.9+/-0.7 m x Pa x s and erythrocyte deformability: 1.9+/-0.4 ml/min, P<0.05). CONCLUSIONS: Our results show that administration of POF prevents the nephrotoxicity associated with CsA. This beneficial effect could be related to its rheological properties.

Influence of VIP on the number of enterochromaffin and mucosal mast cells in the colon of the rat.

The possibility that VIP (Vasoactive intestinal peptide) could influence the enterochromaffin (EC) cell secretion of serotonin (5HT) and the action of VIP on the mast cell population of lamina propria were investigated in Wistar rat colon infused with a short chain fatty acid solution (sodium acetate), during a 1 h period. Under the action of an intravenous injection of synthetic porcine VIP, 14 micrograms/kg/h), the number of EC cells diminished significantly in the cecum and left colon, when compared to non-injected animals, both infused with a sodium acetate solution. At the same time, the number of mucosal mast cells in the crypts and lamina propria decreased significantly in the cecum. The postulate we put forward is that these VIP-induced changes are exerted through the stimulation of 5HT released from EC cells not only under normal physiological conditions but probably also under pathological conditions.

Action of cisapride on rat colonic secretion.

The stimulating effect of cisapride on the motility of the digestive tract is well known. However, there are only a few studies on the influence of this drug on the absorptive or secretory activity of the colonic mucosa. In the present study, the ability of cisapride to alter the mural transport of water and electrolytes in the colon and its effects on mucus secretion and albumin permeation were studied. The effects of cisapride on the rat colon in vivo were studied under different conditions, by means of an instillation of sodium acetate solution at pH 6.9, which induced absorption of water and electrolytes, and in two models of colonic secretion, one employing the instillation of an acetic acid solution at pH 2.9 and the other, an intravenous infusion of 5-hydroxytryptamine (serotonin) 45 micrograms.kg-1.min-1 together with intracolonic instillation of sodium acetate. Cisapride (i.v.), at a dose of 0.32 mg.kg-1, in rats whose colon was instilled with sodium acetate (pH 6.9) induced an increase in sodium absorption and a reduction in water absorption. Cisapride (i.v.), at doses of 0.32, 0.64 and 1.0 mg.kg-1, inhibited the secretion of water, Na+, Cl-, and mucus and the permeation of albumin induced by acetic acid instillation or by serotonin infusion. It is concluded that the effect of cisapride on the colonic mucosa varies in accordance with the functional mucosal conditions and that this action may be of clinical importance.

Pentoxifylline, a drug with rheological effects, decreases portal pressure in an experimental model of cirrhosis.

OBJECTIVE: To evaluate the influences of blood viscosity changes, mediated by a haemorheological agent, on splanchnic and systemic haemodynamic parameters in rats with cirrhosis due to chronic bile duct ligation. METHODS: Blood viscosity was measured using a cone-plate viscometer and whole blood filterability was determined by a filtration method. Cardiac index and portal venous inflow were measured using radioactive microspheres. Measurements were performed 30 min after double-blind administration of placebo or pentoxifylline (25 mg/kg, intravenously). RESULTS: As compared with placebo, pentoxifylline-treated cirrhotic rats had a lower portal pressure (13.8 +/- 1.4 vs. 12.1 +/- 1.6 mmHg, P < 0.05) and blood viscosity at shear rates of 115/s (6.6 +/- 0.8 vs. 5.8 +/- 0.3 mPas, P < 0.05), associated with an improvement of whole blood filterability (45.0 +/- 12.9 vs. 20.0 = 3.9 s/ml, P < 0.01). Similar values of mean arterial pressure, cardiac index and portal venous inflow were observed in both groups. A significant correlation was found between portal pressure and blood viscosity at a shear rate of 115/s (r = 0.71, P < 0.01). CONCLUSION: These results suggest that portal pressure can be modified by pentoxifylline in an experimental model of cirrhosis. These haemodynamic changes are associated with a lower blood viscosity and whole blood filterability. Pentoxifylline may be a new approach in the treatment of portal hypertension.

[Dexamethasone, an inhibitor of the expression of inducible nitric oxide synthase, does not modify the hyperdynamic state in cirrhotic rats]. / La dexametasona, un inhibidor de la expresion de la óxido nítrico sintasa inducible, no modifica el estado hiperdinámico en ratas cirróticas.

Increased nitric oxide formation has been shown to be involved in the hyperdynamic circulation of portal hypertension. It has been proposed that it could be related to stimulation of the inducible nitric oxide synthase by endotoxin. Therefore, the aim of the present study was to evaluate whether dexamethasone treatment, an inhibitor of the expression of the inducible enzyme, ameliorates the hyperdynamic circulation observed in cirrhotic rats due to chronic bile duct ligation. Systemic and splanchnic hemodynamic parameters were measured after administration of dexamethasone (3 mg/kg/day during 3 days, i.p.) or its vehicle. In cirrhotic rats dexamethasone treatment caused a mild but not significantly higher mean arterial pressure in comparison with vehicle while similar values of cardiac output, peripheral vascular resistance, portal blood flow and portal pressure were observed in both group of animals. A significant body weight loss over the three days of treatment was observed in rats receiving dexamethasone. In sham-operated rats, dexamethasone administration caused similar changes as observed in cirrhotic animals. Endotoxemia was observed in five of six cirrhotic rats while it was not detected in the control group. Our results show that dexamethasone administration does not modify systemic and splanchnic hemodynamic parameters in endotoxemic cirrhotic rats. This finding suggests that stimulation of the inducible nitric oxide synthase may not play a role in the increased nitric oxide production in portal hypertension.

[Role of nitric oxide in alterations of the systemic and splanchnic hemodynamics in a experimental model of portal hypertension]. / Papel del óxido nítrico en las alteraciones de la hemodinámica sistémica y esplácnica en un modelo experimental de hipertensión portal.

Recent experimental studies have suggested that an increase in the synthesis of nitric oxide, a powerful vasodilator secreted by endothelial cells, plays a role in the hemodynamic disturbances associated to portal hypertension. The present study was addressed to investigate the effects of L-NNA (a specific inhibitor of nitric oxide) on systemic and splanchnic hemodynamics in portal hypertensive rats, induced by partial portal vein ligation. Intravenous infusion of L-NNA (50 ug/kg/min) significantly increased systemic blood pressure and decreased cardiac output as measured by radiolabeled microspheres. A significant increase in systemic and splanchnic vascular resistance was also observed in L-NNA-treated rats; whereas portal blood flow decreased significantly, L-NNA did not modify portal pressure. Pretreatment with L-arginine (300 mg/Kg, i.v.) prevented the hemodynamic changes induced by L-NNA. Similar values of endotoxin levels were detected in both groups of animals. In the control group, L-NNA caused a mild but significant increase of mean arterial pressure; no significant changes on the other hemodynamic parameters were observed. These results suggest that an increase in endogenous synthesis of nitric oxide may play an important role in hemodynamic disturbances associated with chronic portal hypertension.

Effect of loperamide and bisacodyl on intestinal transit time, fecal weight and short chain fatty acid excretion in the rat.

We analyzed the effect of drugs that modify the colonic motility on rat intestinal transit time (ITT) (measured with radiopaque markers), fecal weight (FW) and fecal concentration of short chain fatty acids (FSCFA) (assayed by gas liquid chromatography), over a four-week period. Bisacodyl was used to accelerate and Loperamide to retard the intestinal transit in rats maintained on a conventional diet. The first and 3rd week were drug-free control periods. The mean values of these periods were: ITT = 28.9h +/- 1.9 FW: 9.2 +/- 1.2 g/24 h and FSCFA = 60.6 +/- 17.9 mmol/g. After loperamide administration, we observed an increase in the mean ITT as compared to the control period (40.4 +/- 8.0h) and decrease in FW (4.8 +/- 3.6 g/24h) and in FSCFA = 32.2 +/- 5.6 mmol/g). After bisacodyl administration, we found a shorter ITT in relation to controls (24.8 +/- 2.5h), and increases in FW (27.5 +/- 3.6g/24h) and in FSCFA (108.2 +/- 39.9 mmol/g). There was a negative correlation between ITT and FW (R = 0.67 p less than 0.01) and a positive correlation between total SCFA concentration and FW (R = 0.71 p less than 0.01). The concentration of acetic, propionic and butyric acids increased with progressive increments in fecal weight, whereas concentrations of isovaleric and caproic acids decreased. The results of this study show that the FW and the FSCFA may be influenced by modifications in the intestinal transit time.

Stimulation of inflammatory mediators secretion by chemotactic peptides in rat colitis model.

Colonic inflammation was produced in rats by chemotactic peptides acting on polymorphonuclear leucocytes. Instillation during one hour of formylated tripeptide: formylmethionyl-leucyl-phenylalanine (FMLP) and a tetrapeptide: alanine-glycine-sefine-glutamine (AGSG) into rat colon caused erosions and exulcerations. Neutrophils increased secondary to instillation, predominantly with FMLP, and mucus depletion was marked in the cecum. Chloride ion secretion and mucosal permeability were significatively greater in the colonic lumen with the chemotactic peptides. Histamine and serotonin concentration were greater in the colonic fluid in animals treated with the peptides. These observations could suggest that the presence of chemotactic peptides at the colonic lumen produce changes at the mucosal wall, that would participate in generation and perpetuation of the colonic inflammation.

Use of liver grafts from anti-hepatitis B core-positive donors: a multicenter study in Argentina.

Liver transplantation success is limited by the availability of donors. To overcome this limitation, anti-core-positive donors are increasingly being accepted, but underutilization of this resource still occurs. We performed the current study to determine the prevalence of anti-core-positive donors in our region and to describe the management of these donors and their recipients. Between January 2005 and July 2011, the national transplant database included 2,262 registered liver donors among whom 106 (4.7%) were anti-core-positive including 59 (56%) discarded and 47 (44%) implanted organs. A median of 14.5 offers (range 4-60) were rejected before harvesting and implanting the accepted grafts. The only difference between the implanted and the discarded grafts was found for the alanine aminotransferase level, which was higher among the discarded ones (50 ± 59 UI/L vs 25 ± 16, P < .05). Among 40 recipients included in the study, 5 (12.5%) did not receive any prophylaxis; 18 (45%) a nucleos(t)ide analog 11 (25.5%), heptitis B immunoglobulin and nucleos(t)ide analogs and 6 (15%) pretransplant hepatitis B vaccination. Over a mean follow-up of 871 ± 585 days, 4 de novo hepatitis B cases were identified at 545, 720, 748, and 1,080 days posttransplantation. None of these patients had received any prophylaxis. In all cases entecavir successfully controlled viral replication. We believe that better utilization of these donors and careful management of their recipients represent safe strategies to expand the liver donor pool in Argentina.

Blood flow measurements by the reference sample method with microsphere injection in to the aorta: an accurate and easy approach.

The validity of hemodynamic measurements by the reference sample method with microspheres injection into the aorta, via a carotid artery catheter, was evaluated in rats and compared with the results obtained after left ventricle injection. In the aorta injection group, a good mix of microspheres was observed in 83% of the animals. Moreover, a symmetrical distribution of microspheres was observed in 10 out of 12 rats (83%). An excellent correlation between right and left kidney-testes blood flows was observed (r = 0.93 and 0.96, respectively; P less than 0.01). Mean arterial pressure was not modified during microspheres injection into the aorta. Cardiac output (104 +/- 26 vs 101 +/- 23 ml/min, NS) and portal blood flow (14.2 +/- 3.3 vs 13.5 +/- 2.2 ml/min, NS) were similar after aorta and left ventricle injections series, respectively. Our results indicate that the injection of microspheres into the aorta is an adequate and easy approach to systemic and splanchnic hemodynamic measurements. This approach could be a good alternative to left ventricle injection of microspheres in experimental studies in rats.

Effects of F-180, a new selective vasoconstrictor peptide, compared with terlipressin and vasopressin on systemic and splanchnic hemodynamics in a rat model of portal hypertension.

The present study is aimed at characterizing the portal, splanchnic, and systemic circulatory effects of F-180, a new long-acting analog of vasopressin (VP) with selective effect on the vascular (V1) receptor, both in normal rats and in portal-hypertensive animals. In preliminary vasopressor tests, F-180 was 18 times more potent than terlipressin (TP) (164 +/- 10 IU x mmol(-1) vs. 9.2 +/- 1.2 IU x mmol(-1)) and four times less potent than arginine VP (614 +/- 25 IU x mmol(-1)). F-180 had negligible antidiuretic potency, resulting in vascular selectivity (V1/V2) of 858 compared with 1.0 for VP and 2.2 for TP. In portal-hypertensive rats with partial portal vein ligation (PPVL), the vasopressor effect of F-180 was 19 times that of TP on a molar basis (ED50 F-180: 0.54 vs. TP: 10.02 nmol x kg(-1)). At low doses (0.405 nmol x kg(-1)), F-180 significantly reduced portal pressure (PP) (-13.8% +/- 6.7%) and superior mesenteric artery blood flow (SMABF) (-25.6% +/- 4.5%), whereas TP at 8.10 nmol x kg(-1) was required to achieve comparable splanchnic effects; however, this dose caused a significantly greater increase in mean arterial pressure (MAP) than F-180 at 0.405 nmol x kg(-1) (28.2% +/- 2.7% vs. 8.9% +/- 2.7% at 20 minutes; P < .05). F-180 at 0.405 nmol x kg(-1) had effects on PP and SMABF similar to a 30-minute intravenous infusion of VP at 10 mU x kg(-1) in PPVL rats, but VP caused a significantly greater elevation in systemic vascular resistance (SVR) and MAP, and more pronounced reduction in cardiac index (P < .05).

Effects of right hemicolectomy on nitrogen balance in the rat.

Rats with right hemicolectomy were divided into two groups. One group was free-fed (RHFF), the other group pair-fed (RHPF) and both were compared with a group of control animals. The nitrogen balance (NB) was studied for 5 days at 2 and 14 weeks after surgery. The two groups of rats with right hemicolectomy excreted significantly more fecal nitrogen than the control group (p less than 0.01) during the two periods of study. At 2 weeks the RHFF group increased N intake so that their NB was similar to that of the control group. In the same period the nitrogen lost in urine and the NB were reduced in the RHPF rats (p less than 0.01). At 14 weeks the results were similar to those for 2 weeks although the increase in food intake for RHFF and the decrease in NB for RHPF were not statistically significant. The rats with right hemicolectomy showed a decreased gain in body weight. This decrease was more pronounced in the RHPF group. The nitrogen content of the carcass and liver was significantly reduced in the RHPF group 4 months after surgery. It is concluded that the rats with right hemicolectomy were characterized by an increment in the nitrogen lost in feces, and when they were only allowed the same intake of food as the control group, the animals showed marked abnormalities in growth and in the nitrogen content of the organism.

Mechanical pumping of portal blood to the liver: hemodynamic effects of a new experimental treatment for portal hypertension.

BACKGROUND/AIMS: It has been suggested that mechanical pumping of portal blood to the liver may correct portal hypertension while increasing portal flow to the liver, which may enhance liver function in cirrhosis. However, the hemodynamic effects of this procedure are unknown. The present study investigated these issues in rats with portal hypertension due to portal vein stenosis. METHODS: Mechanical pumping of portal blood to the liver was established by an extracorporeal shunt bypassing the portal vein stenosis, connected to a continuous withdrawal/infusion pump. Portal pressure, portal-systemic shunting (mesenteric injection of Cr-51 microspheres, n = 10), mesenteric artery blood flow (perivascular Transonic flowmeter, n = 7) and systemic hemodynamics and regional blood flows (left ventricle injection of Ce-141 microspheres, n = 15), were measured at pumping rates of 0, 3 and 6 ml.min-1. RESULTS: Mechanical pumping of portal blood to the liver caused a marked decrease in portal pressure (from 17 +/- 1 to 12.6 +/- 1 and 9.4 +/- .9 mmHg at pumping rates of 0, 3 and 6 ml.min-1) and portal-systemic shunting (from 97 +/- 4 to 70 +/- 4 and 51 +/- 6% respectively) (p < 0.001). However, there were no significant changes in mesenteric artery flow (5.5 +/- 3 vs 5.6 +/- 3 ml.min-1.100 g-1), suggesting that all blood pumped to the liver was withdrawn from that circulating through the collaterals. Moreover, there were no changes in mean arterial pressure, cardiac index, peripheral resistance and splanchnic arteriolar resistance. CONCLUSIONS: The short-term mechanical pumping of portal blood to the liver effectively decreases portal pressure and portal-systemic shunting and has no significant effects on systemic and splanchnic hemodynamics in portal hypertensive rats.

Circulatory effects of graded diversion of portal blood flow to the systemic circulation in rats: role of nitric oxide.

Total portal-systemic shunting in normal animals is associated with splanchnic and systemic vasodilation, suggesting that vasodilation in cirrhosis may be facilitated by spontaneous shunts promoted by portal hypertension. However, the mechanism of this vasodilation is unknown. The aim is to study the acute effects of the graded diversion of portal blood flow to the systemic circulation in normal and portal hypertensive rats. Portal and systemic hemodynamics were measured in normal and portal hypertensive rats before and during graded portacaval diversion of portal blood flow, in basal conditions, and after nitric oxide inhibition. In portal hypertensive rats, graded portal flow diversion caused a rate-related decrease in portal pressure (from 15.3 +/- 0.6 to 11.2 +/- 0.7 mm hg at 6 mL x min(-1), P < .001) and a redistribution of portal-collateral blood flow from the spontaneous portal-systemic collaterals to the portacaval circuit, without changing total portal-systemic shunting. Graded portal diversion caused an immediate systemic vasodilation, with reduced peripheral resistance. This vasodilatory response was more pronounced in normal than in portal hypertensive rats (increase in cardiac index 23.6% +/- 2.8% vs. 8.5% +/- 4.9%, P < .02, fall in peripheral resistance -24.5% +/- 3.4% vs. -16.5% +/- 2.6%, P = .08), and was totally prevented by nitric oxide inhibition. The graded diversion of portal blood flow caused a flow-rate-related reduction in portal pressure and blood flow through spontaneous portal-systemic collaterals in portal hypertensive rats, and caused a nitric-oxide dependent systemic vasodilatory response, which was greater in normal than in portal hypertensive rats. These results suggest that portal-systemic shunting per se may contribute to the vasodilatation in portal hypertension.

Prolonged bleeding time in experimental cirrhosis: role of nitric oxide.

BACKGROUND/AIMS: Nitric oxide is a powerful in vitro inhibitor of platelet adhesion and aggregation. Our aim was to investigate whether the in vivo inhibition of nitric oxide release shortens bleeding time, in rats with cirrhosis induced by chronic bile duct ligation. METHODS: Mean arterial pressure and bleeding time were measured under basal conditions and 5, 15 and 30 min after administration of vehicle (0.9% saline) or an inhibitor of nitric oxide synthesis, Nw-nitro-L-arginine (5 mg/kg, iv). Mean arterial pressure was measured with an intra-arterial catheter and bleeding time with a standardized Simplate device. RESULTS: Cirrhotic rats showed a lower mean arterial pressure (116+/-4 mmHg) and a prolonged bleeding time (177+/-40 s) compared to control animals (133+/-6 mmHg and 95+/-12 s, respectively, p<0.01). In cirrhotic rats, Nw-nitro-L-arginine significantly increased mean arterial pressure (from 116+/-5 to 141+/-11 mmHg, p<0.05) and completely normalized bleeding time (from 170+/-39 to 103+/-21 s, p<0.05) 15 min after administration. Pretreatment with L-arginine (300 mg/kg, iv) prevented the hemodynamic and hemostatic changes induced by Nw-nitro-L-arginine. A trend to normalize platelet adhesion was observed in cirrhotic rats after the inhibition of nitric oxide production. In control animals, Nw-nitro-L-arginine increased mean arterial pressure, while no effect on bleeding time was observed. CONCLUSIONS: These findings support the concept that nitric oxide may be a mediator in the bleeding time abnormalities associated with experimental cirrhosis.

Time profile of the haemodynamic effects of terlipressin in portal hypertension.

BACKGROUND/AIMS: Terlipressin is a long-acting vasopressin analogue that has been proved useful in the treatment of variceal haemorrhage. This study investigates the time profile of the haemodynamic effects of terlipressin on portal hypertension as well as the efficacy in decreasing portal-pressure and collateral blood flow of reduced doses, suitable for longer therapy to prevent early rebleeding. METHODS: Splanchnic and systemic haemodynamics were measured in 23 patients with cirrhosis and portal hypertension in baseline conditions and at 30 min, 1, 2, 3 and/or 4 h after the double-blind administration of a single intravenous injection of 1 mg (n=8) or 2 mg (n=8) of terlipressin, or placebo (n=7). RESULTS: Placebo caused no significant effects. At 30 min of terlipressin administration, the hepatic venous pressure gradient (1 mg: -16+/-9%, 2 mg: -21+/-11%; p<0.01) and azygos blood flow (1 mg: -19+/-13%, 2 mg: -25+/-17%; p<0.05) were significantly reduced. These effects were still significant at 4 h (2 mg) or 3 h (1 mg). Both doses moderately increased arterial pressure at 1 h. At 4 h, neither arterial pressure nor peripheral vascular resistance was significantly modified by either dose of terlipressin. Terlipressin caused no significant changes in hepatic blood flow. CONCLUSIONS: In patients with cirrhosis, a single injection of 2 mg of terlipressin significantly and markedly reduces portal pressure and azygos blood flow for up to 4 h. The effects of a reduced dose (1 mg) were almost as pronounced and prolonged, suggesting that after the initial control of variceal bleeding, terlipressin therapy could be maintained for several days at low dosage to reduce the risk of early rebleeding.

Postprandial vascular response in patients with cirrhosis. Short-term effects of propranolol administration.

Systemic and portal hemodynamic parameters were evaluated in eight cirrhotic patients in basal conditions and after food intake and placebo. Following seven days of oral propranolol administration, hemodynamic parameters were reevaluated in the fasting and postprandial states under similar conditions. Cardiac output and portal blood flow were measured by Doppler technique. Intraobserver variability of repeated measurements was less than 10%. Food intake caused a significant increase of portal blood flow (+28%, P < 0.05). No significant changes were observed in the other hemodynamic parameters studied. Propranolol at doses achieving effective beta blockade (84 +/- 14 mg/day) (mean +/- SD) reduced portal blood flow (-24%, P < 0.05). Food intake caused a significant increase in portal blood flow (+35%, P < 0.05) in propranolol treated patients. However, in absolute values, postprandial portal blood flow during propranolol treatment was significantly lower (986 +/- 402 ml/min) than that obtained after the initial food intake (1214 +/- 537 ml/min, P < 0.05). Placebo administration had no significant hemodynamic effects in either group. This study demonstrates that chronic propranolol administration could protect from portal hemodynamic changes following food intake. Doppler technique is a reliable technique to evaluate changes on portal and systemic hemodynamic parameters during a short period of time in patients with cirrhosis.