Decrease In Portal Pressure Research Articles

Effect of narcotic agents and of bleeding on systemic and renal haemodynamics in healthy and CCl4-treated cirrhotic rats.

1. The haemodynamic effects of different narcotic agents have been tested in healthy rats and in rats with cirrhosis. 2. Pentobarbital suppresses the sympathetic nervous system. Susceptibility to ketamine is unpredictable, leading to both insufficient pain relief and narcosis related mortality. The combination diazepam-fluanisone induces profound hypotension. After insertion of catheters, awake, freely moving rats are stable and not distressed. This allows repeated measurements after manipulation. Moreover, procedure-related mortality is low and rats have a better stress response. 3. In the awake animal, arterial pressure is 126 +/- 10 for healthy animals, and 111 +/- 16 and 102 +/- 10 mmHg for cirrhotic animals without and with ascites, respectively (P = 0.018). The respective values for portal pressure are 6.9 +/- 1.4, 11.6 +/- 2.5 and 16.2 +/- 2.9 mmHg (P = 0.0001). After a bleeding, arterial pressure is better preserved than portal pressure in the three groups (P < 0.0001). Plasma volume in cirrhotic rats exceeds that of healthy rats. Plasma renin activity, aldosterone and catecholamines do not differ between the groups studied. In cirrhotic rats with and without ascites, glomerular filtration rate tends to be higher (P = 0.12), renal plasma flow is elevated (P = 0.001) and filtration fraction is lower (P = 0.002) than in healthy rats. 4. In conclusion, haemodynamic experiments in the cirrhotic rat should be performed in the awake rat. Arterial hypotension, impaired filtration fraction, enlarged plasma volume and portal hypertension are present in cirrhosis before the development of ascites. This can as well be explained by splanchnic pooling of blood, as by peripheral vasodilatation. The decrease in portal pressure with preserved arterial pressure after a bleeding protects cirrhotic rats from ongoing variceal bleeding.

Randomised trial of octreotide for long term management of cirrhosis after variceal haemorrhage

Objective: To assess the efficacy of long term octreotide as adjuvant treatment to programmed endoscopic sclerotherapy after acute variceal haemorrhage in cirrhotic portal hypertension.Design: Randomised clinical trial.Setting: University hospital.Subjects: 32...

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.

Double-blind randomized controlled trial comparing terlipressin and somatostatin for acute variceal hemorrhage. Variceal Bleeding Study Group

BACKGROUND & AIMS: Terlipressin and somatostatin decrease portal pressure and have been used to treat variceal hemorrhage, but they have not been adequately compared. The aim of this study was to compare the efficacy and safety of these drugs in the treatment of variceal bleeding in cirrhotic patients. METHODS: Of 161 patients with variceal bleeding. 80 were randomized to receive (double-blind) intravenous terlipressin (2 mg/4 h) and 81 to receive somatostatin (continuous infusion of 250 micrograms/h after an intravenous injection of 250 micrograms). Success of therapy was defined as a 24-hour bleeding-free period within 48 hours from randomization. RESULTS: Success of therapy was similar with terlipressin (80%) and somatostatin (84%). In patients with Child's class A and B disease, terlipressin was effective in 52 of 60 (87%) and somatostatin in 48 of 55 (87%). Success rates in class C were 60% and 77% (P = 0.33). No differences were observed in rebleeding rates (30% vs. 28.4%) and 6-week mortality rates (13 vs. 13 patients). Incidence of side effects was significantly higher in the terlipressin group (38.8% vs. 23.5%; P = 0.042). Severe side effects requiring intervention occurred in 5 of 80 and 4 of 81 patients, respectively. CONCLUSIONS: Terlipressin and somatostatin are highly effective as first-line treatment of variceal hemorrhage in cirrhotic patients. The low incidence of severe side effects suggests that drug therapy may be maintained for longer periods to prevent early rebleeding. (Gastroenterology 1996 Nov;111(5):1291-9)

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.

Acute haemodynamic responses and inhibition of tumour necrosis factor-alpha by pentoxifylline in rats with cirrhosis.

1. Although pentoxifylline has been shown to reduce portal hypertension, the mechanism for this is unclear. Since pentoxifylline decreases tumour necrosis factor-alpha production and since this cytokine may induce vasodilatation per se, a pentoxifylline-induced decrease in tumour necrosis factor-alpha production may limit arterial vasodilatation and decrease portal pressure. The aim of the present study was to examine the effects of pentoxifylline administration on plasma tumour necrosis factor-alpha concentration and haemodynamics in normal and cirrhotic rats. 2. In both groups, systemic and splanchnic haemodynamics and plasma tumour necrosis factor-alpha concentrations were measured before and 120 min after the administration of saline or pentoxifylline (20 mg/kg intravenous bolus). 3. In cirrhotic rats, pentoxifylline significantly decreased portal pressure (24 +/- 13%) and tributary blood flow (33 +/- 30%). On the other hand, pentoxifylline significantly increased vascular resistance in portal and hepatic arterial territories. Systemic haemodynamics were not altered. In normal rats, pentoxifylline significantly decreased portal pressure but induced no other significant changes in splanchnic or systemic haemodynamics. In cirrhotic rats, plasma tumour necrosis factor-alpha concentrations were significantly reduced after pentoxifylline administration but not after saline administration. No significant correlations were found between pentoxifylline-induced changes in tumour necrosis factor-alpha levels and changes in splanchnic haemodynamics. In normal rats, plasma tumour necrosis factor-alpha concentrations significantly decreased after pentoxifylline or saline administration. 4. This study shows that in rats with cirrhosis, pentoxifylline induces a decrease in both portal pressure and plasma tumour necrosis factor-alpha concentrations. These reductions were not correlated however.

Effect of verapamil on renal haemodynamics in a portal hypertensive rat model

In order to investigate the effects of verapamil on renal haemodynamics in rats with portal hypertension, verapamil was given at either a low (0.2 mg/kg) or high (2 mg/kg) dose to rats after portal vein ligation. An approximate 12% decrease in mean arterial pressure followed administration of low dose verapamil, with a significant decrease in cardiac output and renal blood flow, as well as reduced portal pressure, observed; these signs were all indicative of a rise in renal vascular resistance. In contrast, the marked fall in both mean arterial pressure and cardiac output with high dose verapamil, accompanied by a significant decrease in portal pressure and no change in renal blood flow, suggests a reduction in renal vascular resistance. This study shows that the acute effects of verapamil on renal haemodynamics may vary with the dose used. Also, acute verapamil administration tends to decrease renal blood flow to alter the autoregulation of the kidney; thus, caution should be taken in the clinical use of verapamil in the treatment of cirrhosis with portal hypertension.

The impact of endoscopic variceal ligation on the pressure of the portal venous system

Background/Aims: Endoscopic variceal ligation is a viable substitute for injection sclerotherapy. It is still not known how endoscopic variceal ligation may influence the portal venous system. To clarify this issue we investigated the impact of endoscopic variceal ligation on the pressure of the portal venous system. Methods: Twenty-nine patients with a history of esophageal variceal bleeding but without ascites were enrolled. All had cirrhosis; 63% of them were post-hepatitic. Ligation was performed at intervals of 2–3 weeks until all the varices were obliterated. Portal venograms were performed before institution of ligation and after variceal obliteration to assess venographic findings and pressure changes. The pressures of the main portal vein, splenic vein and superior mesenteric vein were recorded. Results: Twenty-five patients completed the study. A mean of 4.4 sessions (range: 2–7) of ligation over a period of 2 months was needed. Seventeen (68%) patients experienced elevated pressure and eight (32%) patients reduced pressure after ligation. Mean (median) pressure changes were as follows: portal venous pressure, 26.5±4.7 (25.0) mmHg vs. 28.2±7.2 (28.0) mmHg ( p > 0.05); splenic venous pressure, 28.2±4.9 (26.0) mmHg vs. 29.0±6.8 (29.0) mmHg ( p > 0.05); superior mesenteric venous pressure, 28.4±6.0 (27.0) mmHg vs. 29.5±7.0 (29.0) mmHg ( p > 0.05). Five patients (20%) experienced rebleeding before variceal obliteration; all of them presented elevated portal pressures after variceal obliteration. Among the eight patients with decreased portal pressure, seven (87%) had other major collaterals apart from esophageal varices, compared to three out of the 17 (18%) patients with elevated portal pressure who had other major collaterals ( p<0.01). Conclusions: Among patients receiving endoscopic variceal ligation, 68% experienced elevated portal pressure, while 32% had decreased portal pressure. Elevation of portal pressure after variceal ligation may be an important factor in variceal rebleeding. The presence of other major collaterals apart from esophageal varices may be responsible for the decrease in portal pressure after obliteration of esophagel varices.

The relationship between portal venous and hepatic arterial blood flow. I. Experimental liver transplantation.

The relationship between the changes in portal venous and hepatic arterial blood flows, in the liver is a much disputed question, it has tremendous significance in the practice of transplantation, and an explanation has been available since 1981, when Lautt published the so-caled “adenosine washout theory”. According to our earlier observations the decrease of portal pressure or flow consistently led to an increase in hepatic artery flow. At the same time changes in hepatic artery flow or pressure seemed to produce only inconsistent effects on the portal circulation. In the present experiments liver transplantation (OLTX) was carried out on mongrel dogs by Starzl's method. Electromagnetic flow probes were placed on the hepatic artery and the portal vein before removal of recipient’s liver, and after completion of all vascular anastomoses to the newly inserted liver, during the recirculatory phase of OLTX. The flow probes were connected to a Hellige electromagnetic flowmeter, portal venous and systemic arterial pressures were also recorded. The control HAF was 241±23 ml/min, the average PVF was 517±47 ml/min before removal of the recipients's liver. In the recirculatory phase the HAF increased, by 71±12% (p < 0.001). The PVF decreased in most animals after OLTX. The decrease was in average –40.2±3.5% (p < 0.001). The THBF calculated by adding the HAF and PVF showed a small, but not significant decrease during recirculation. The systemic arterial pressure decreased slightly and portal vein pressure rose in most animals after OLTX. There was a substantial increase in portal inflow resistance and prehepatic arteriolar resistance and a decrease in hepatic artery resistance. The decrease of PVF after OLTX can be explained by progressive fluid accumulation in the liver parenchyma and increased sinusoidal and portal inflow resistance. The prolonged and continuous increase in hepatic artery flow during the recirculatory phase of OLTX may be due to the decrease of portal flow. The exact mechanism, by which a change in portal flow leads to arteriolar dilatation, can be most probably explained by the “adenosine washout theory” of Lautt.

Continuous prazosin administration in cirrhotic patients: Effects on portal hemodynamics and on liver and renal function

Background & Aims : Hepatic vascular resistance is influenced by α-adrenergic tone. The aim of this study was to investigate the effects of continuous blockade of α-adrenoceptors with prazosin on hemodynamics, liver function, and renal function and whether the association of propranolol or furosemide enhances the portal pressure lowering effect of prazosin. Methods : Cirrhotic patients with portal hypertension were studied at baseline and after a 3-month course of prazosin (n = 18) or placebo (n = 10). Results : No changes were observed in the placebo group. Prazosin decreased the hepatic venous pressure gradient (HVPG) while increasing hepatic blood flow. Liver function improved as shown by an increase in hepatic and intrinsic hepatic clearances of indocyanine green and galactose elimination capacity. A significant reduction in mean arterial pressure and systemic vascular resistance was associated with increases in plasma renin activity and aldosterone concentration and a decrease in glomerular filtration rate. The plasma volume increased significantly, and 6 patients developed edema. The association of propranolol (n = 8) but not furosemide (n = 7) to prazosin increased the reduction in HVPG and attenuated the increase in plasma renin activity. Conclusions : In cirrhotic patients, continuous prazosin administration reduces portal pressure and improves liver perfusion and function but favors sodium and water retention. The association of propranolol enhances the decrease in portal pressure, suggesting a potential benefit from this combined therapy.

Effects of transjugular intrahepatic portasystemic shunt (TIPS) on splanchnic and systemic hemodynamics, and hepatic function in patients with portal hypertension

The purpose of this study was to evaluate the short-term splanchnic and systemic hemodynamics and hepatic function after TIPS creation. Fifteen cirrhotics with portal hypertension underwent TIPS placement for treatment of variceal hemorrhage, and extensive hemodynamic studies including right heart catheterization, portal pressure measurement, hepatic blood flow, and indocyanine green (ICG) clearance were performed before and 1 month after the procedure. Self-expandable metal stents (Strecker 11 mm diameter) were placed in all cases. Portasystemic gradient significantly diminished (18.3 +/- 4.2 vs 8 +/- 2.8; 54% +/- 18 mm Hg) after the technique, mainly due to a decrease in portal pressure, and remained stable in the final study. Cardiac output and mean arterial pressure increased (6.2 +/- 1.4 vs 8.2 +/- 1.8 liters/min, 80.1 +/- 10.1 vs 91 +/- 11.2 mm Hg, respectively), and a decrease in systemic vascular resistance was registered (1018 +/- 211 vs 872 +/- 168 dyne/sec/cm5); the hepatic blood flow and ICG clearance also decreased significantly (1.5 +/- 0.7 vs 0.68 +/- 0.2 liters/min, 0.4 +/- 0.2 vs 0.24 +/- 0.06 liters/min, respectively). There was an increase in the preload at the final study, as evidenced by a marked increase in right atrial (3.1 +/- 1.6 vs 4.35 +/- 2.2 mmHg, +15%, P < 0.05), pulmonary arterial (12.2 +/- 2.4 vs 15.9 +/- 3.2 mm Hg, +31.8%, P < 0.001), and wedge pulmonary arterial pressures (6.9 +/- 2.4 vs 9.8 +/- 3.1 mm Hg, +53%, P < 0.001). These results suggest that TIPS worsens the hyperdynamic syndrome associated to portal hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor α: A major contributor to the hyperdynamic circulation in prehepatic portal-hypertensive rats

Background/Aims : Portal hypertension is often accompanied by a hyperdynamic circulatory syndrome. Tumor necrosis factor (TNF) α causes vasodilatation and a hyperdynamic state in mammals by activating nitric oxide synthesis. The aim of this study was to investigate whether TNF-α plays a role in developing the hyperdynamic syndrome in portal hypertension. Methods : Portal-hypertensive rats, induced by partial ligation of the portal vein (PVL), were used. In experiment 1, rats that underwent PVL were treated with polyclonal anti-mouse TNF-α or placebo intravenously the same day of the PVL operation and 24 hours before hemodynamic studies. Hemodynamic studies were performed 5 days after PVL. In experiment 2, rats that underwent PVL received anti-TNF-α or placebo intravenously 3 days and 24 hours before hemodynamics as in experiment 1. Hemodynamics were performed 14 days after the PVL operation. TNF-α blood levels were measured using a bioassay. Results : Anti-TNF-α treatment induced a significant increase in mean arterial pressure, heart rate, and systemic vascular resistance and a significant decrease in cardiac index, portal pressure, and TNF-α levels in comparison with placebo animals. No significant effects were observed in sham rats. Conclusions : Anti-TNF-α treatment in rats that underwent PVL significantly blunts the development of the hyperdynamic circulation and reduces portal pressure. TNF-α may play a role in the hemodynamic abnormalities of portal hypertension.

Plasma levels of substance P in liver cirrhosis: relationship to the activation of vasopressor systems and urinary sodium excretion.

The mediators of the hyperdynamic circulation of liver cirrhosis are not well characterized. Substance P is a potent vasodilatory peptide produced by the enteric nervous system and partly cleared by the liver. In this work we have investigated the plasma levels of substance P and their relationship to the hemodynamic, neurohormonal, and renal function changes occurring in patients with cirrhosis. Seven healthy subjects (control group), 7 cirrhotic patients without ascites (group I), and 24 cirrhotic patients with ascites (group II) were studied. Cardiac output (CO), femoral blood flow (FBF), blood volume (BV), femoral arteriovenous difference of oxygen content (Ca-v O2), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma norepinephrine (NE) were determined. Five patients underwent trans-jugular intrahepatic porto-systemic stent shunt (TIPSS) because of refractory ascites. Immunoreactive substance P (irSP) was measured by radioimmunoassay after plasma extraction. irSP was higher in ascitic patients than in healthy controls (P < .01) and directly correlated with PRA, PAC, plasma NE, and Pugh's score and was inversely correlated with urinary sodium excretion, glomerular filtration rate, and Ca-v O2. No differences were observed between portal and peripheral vein irSP concentration. TIPSS placement induced a decrease in portal pressure and an increase in CO but circulating irSP remained unchanged. Our data show that circulating irSP is increased in decompensated cirrhotic patients and may be involved in the pathogenesis of the hemodynamic changes of cirrhosis. Alleviation of portal hypertension did not result in decreased plasma levels of this vasodilatory substance.

Plasma levels of substance p in liver cirrhosis: Relationship to the activation of vasopressor systems and urinary sodium excretion

The mediators of the hyperdynamic circulation of liver cirrhosis are not well characterized. Substance P is a potent vasodilatory peptide produced by the enteric nervous system and partly cleared by the liver. In this work we have investigated the plasma levels of substance P and their relationship to the hemodynamic, neurohormonal, and renal function changes occurring in patients with cirrhosis. Seven healthy subjects (control group), 7 cirrhotic patients without ascites (group I), and 24 cirrhotic patients with ascites (group II) were studied. Cardiac output (CO), femoral blood flow (FBF), blood volume (BV), femoral arteriovenous difference of oxygen content (Ca-v O 2), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and plasma norepinephrine (NE) were determined. Five patients underwent trans-jugular intrahepatic porto-systemic stent shunt (TIPSS) because of refractory ascites. Immunoreactive substance P (irSP) was measured by radioimmunoassay after plasma extraction. irSP was higher in ascitic patients than in healthy controls ( P < .01) and directly correlated with PRA, PAC, plasma NE, and Pugh's score and was inversely correlated with urinary sodium excretion, glomerular filtration rate, and Ca-v O 2. No differences were observed between portal and peripheral vein irSP concentration. TIPSS placement induced a decrease in portal pressure and an increase in CO but circulating irSP remained unchanged. Our data show that circulating irSP is increased in decompensated cirrhotic patients and may be involved in the pathogenesis of the hemodynamic changes of cirrhosis. Alleviation of portal hypertension did not result in decreased plasma levels of this vasodilatory substance.

Transjugular intrahepatic portosystemic shunts with Spiral Z stents: first clinical experience in 20 patients

We report our preliminary experience with Spiral Z stents for transjugular intrahepatic portosystemic shunts (TIPS). The Spiral Z stent is a modification of the Gianturco-Rosch stent. TIPS was performed in 20 patients with symptomatic portal hypertension and was effective in 19 of them. One patient re-bled and died shortly after the procedure, despite of transjugular embolisation of gastro-oesophageal varices. The portal pressure decrease (5–16 mm Hg) was related to stent diameter (8–12 mm). Mean follow-up was 6 months. Our preliminary results confirm that the 12-mm Spiral Z stent is a suitable device for creation of effective TIPS.

Hemodynamic effects of combined treatment with somatostatin analogue (SMS 201-995) and low-dose isosorbide dinitrate on portal hypertension in conscious cirrhotic rats.

The authors investigated whether combined treatment with the somatostatin analogue, SMS 201-995, and low-dose isosorbide dinitrate enhanced the hemodynamic effects of the individual agents on rats with thioacetamide-induced cirrhosis. Four groups of cirrhotic rats received SMS 201-995 (0.1 microgram.min-1.kg-1), isosorbide dinitrate (10 micrograms.min-1.kg-1), both agents, or placebo, respectively. Hemodynamics were measured serially in conscious rats, using a radioactive microsphere method. SMS 201-995 reduced portal venous inflow 21 +/- 4% and portal pressure 17 +/- 3%. Isosorbide dinitrate decreased portal venous inflow 20 +/- 4%, by inducing splanchnic vasoconstriction mediated by low pressure baroreflexes, and this agent also decreased portal pressure, by 14 +/- 2%. Portal venous resistance rose 7.6 +/- 3% with isosorbide dinitrate alone, but decreased 18 +/- 4% with combination therapy. This effect may have been induced by the pronounced vasodilatory effect of isosorbide dinitrate on the venous vasculature, since the reflex splanchnic vasoconstriction that occurs with low-dose isosorbide dinitrate disappears when this agent is combined with SMS 201-995. The decrease in portal pressure was more marked (22 +/- 4%) and changes in systemic hemodynamics were milder with the combined treatment. It was concluded that combination therapy with SMS 201-995 and low-dose isosorbide dinitrate may be beneficial for portal hypertension in liver cirrhosis.

Effect of a somatostatin analogue (SMS 201-995) on hemodynamics and glucagon secretion in cirrhotic rats.

The effects of somatostatin analogue, SMS 201-995, on systemic and splanchnic hemodynamics and glucagon secretion were investigated in control and cirrhotic rats induced by thioacetamide administration. Hemodynamics were measured using the radioactive microsphere method. Immunoreactive glucagon (IRG) was determined in the portal vein and femoral artery and the splanchnic output (OP) of IRG was calculated. In control rats, SMS 201-995 induced a decrease of 5.6% in portal venous inflow and a 25.8% decrease in OP of IRG. In cirrhotic rats, SMS 201-995 produced a 14% decrease in portal pressure, a 13.6% decrease in portal venous inflow, and a 57.8% decrease in OP of IRG. In systemic hemodynamics no significant changes were noted following SMS 201-995 administration in the control or cirrhotic rats. The ratio of cirrhotic rats to the controls in the rate of decrease in portal venous inflow was similar to that in the percentage of decrease in OP of IRG. We conclude that SMS 201-995 is useful for the treatment of portal hypertension because of its effect of reducing portal pressure with mild changes in systemic hemodynamics. We suspect that the decrease in portal venous inflow by SMS 201-995 is mainly due to a reduction in the release of glucagon, a vasodilatory gastrointestinal hormone.

Effects of terlipressin on hemodynamics and oxygen content in conscious portal vein stenosed and cirrhotic rats receiving propranolol

Terlipressin is used in patients with variceal bleeding but its effects in patients receiving beta-adrenergic antagonists are unknown. In this study, the hemodynamic effects of terlipressin were evaluated in conscious portal hypertensive rats which had previously received a single dose of propranolol. Moreover, oxygen content and acid-base status were studied. In portal vein stenosed and cirrhotic rats, the addition of terlipressin (0.05 mg/kg) to propranolol (0.4 mg/kg) produced a decrease in portal pressure of 34% and 17%, respectively, and in portal tributary blood flow of 46% and 42%, respectively. In cirrhotic rats, however, the decrease in portal pressure was not significantly different when propranolol was combined with terlipressin than when propranolol was administered alone. Cardiac index also further decreased after terlipressin administration. In both groups of rats, these values were similar to those observed after terlipressin alone. In portal vein stenosed rats but not in cirrhotic rats, arterial pH was significantly lower following the combination of propranolol plus terlipressin than following saline, propranolol or terlipressin alone. In conclusion, terlipressin further reduces both portal pressure and cardiac index in rats with portal hypertension receiving beta-blockers. In portal vein stenosed rats but not in cirrhotic rats, the addition of terlipressin to propranolol induces acidemia. This study suggests that terlipressin might further reduce portal pressure in patients with portal hypertension treated with beta-blockers.

New approaches in the pharmacologic treatment of portal hypertension

To alleviate the risk of variceal bleeding, the portal pressure gradient--usually evaluated as the hepatic venous pressure gradient (HVPG)--must be reduced to < or = 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to < or = 12 mmHg in only 12% of patients, while only 24% of patients have a > or = 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Portal Decompression after Transjugular Intrahepatic Portosystemic Shunt Creation with Use of a Spiral Z Stent

An experimental swine model of acute presinusoidal portal hypertension was used to investigate the feasibility of a spiral Z stent for transjugular intrahepatic portosystemic shunt (TIPS) placement and the correlation between the shunt (stent) size and degree of portal pressure decrease. Twelve young swine were used. Acute portal hypertension was induced by means of selective injections of absolute alcohol, ethiodized oil, and polyvinyl alcohol sponge particles into intrahepatic portal branches. TIPS was successfully created in all swine by using spiral Z stents that were 6, 8, and 10 mm in diameter; each size stent was deployed in four animals. Being sufficiently flexible, spiral Z stents accommodated for curved shunt tracts. An average of 48% portal pressure decrease was achieved with 6-mm-diameter stents, 61% with 8-mm-diameter stents, and 87% with 10-mm-diameter stents. These results are in agreement with our clinical experience with use of Gianturco-Rösch Z stents for TIPS formation.