Effects of molsidomine, a long acting venous dilator, on portal hypertension. A hemodynamic study in patients with cirrhosis.

The present study investigated the effects of molsidomine, a predominant venous dilator which, contrary to organic nitrates, does not produce pharmacological tolerance on splanchnic and systemic hemodynamics in patients with cirrhosis. Twenty-seven cirrhotic portal hypertensive patients were studied prior to and up to 2 h after the oral administration of 2 mg of molsidomine (n = 11), 4 mg of molsidomine (n = 8) or placebo (n = 8). Molsidomine caused a significant reduction in the hepatic venous pressure gradient. The mean decrease at 60 min was -6.8 +/- 9% after 2 mg (p less than 0.05) and -15.4 +/- 12% after 4 mg (p less than 0.01). The decrease in the hepatic venous pressure gradient was maintained at 120 min: -11% after 2 mg (p less than 0.05) and -19% with 4 mg (p less than 0.01). This was associated with mild changes in azygos blood flow and with a significant decrease in hepatic blood flow (-17%, p less than 0.05). There was a moderate reduction in mean arterial pressure (-12.6% after 2 mg and -13.2% after 4 mg, p less than 0.01), which was due to a reduction in cardiac output, without any significant fall in systemic vascular resistance. Placebo administration did not change systemic or hepatic hemodynamics. This study shows that molsidomine causes a significant and sustained reduction in portal pressure in patients with cirrhosis, suggesting the potential role of this agent in the treatment of portal hypertension.     

Long-term clinical and hemodynamic results of the treatment of refractory cardiac failure with molsidomine

Molsidomine, one of the sydnonimine group of drugs; the object of this study was to evaluate its efforts in refractory cardiac failure. In the first part of the study, the haemodynamic effects of a single oral dose of 2 or 4 mg of molsidomine were compared with placebo controls in 23 patients. This showed molsidomine to be an active venous vasodilator reducing pulmonary artery and right atrial pressures without changing cardiac index or systemic pressures. The peak effect was observed after 1 to 1,5 hours. In the second phase, molsidomine was used in 9 patients aged 32 to 71 years (mean 47 +/- 12 years) over an average period of 19 months (3,5 to 42 months). The maintenance dose varied from 8 to 24 mg/24 hours. These patients had refractory cardiac failure secondary to primary cardiomyopathy with dilatation (6 cases) or ischemic heart disease (3 cases). The 9 patients were in functional classes IV (5 cases) or III (4 cases). Four patients were theoretically good indications for transplantation. Haemodynamic control was performed 1,8 +/- 5 months after a washout period of 8 hours, and after initial right heart catheterisation, the measurements were repeated 1 hour after oral administration of a 4 mg dose of molsidomine. Two patients did not respond initially to molsidomine; one died, the other remained in functional Class III. Another patient who responded initially was improved for over two years but died in cardiac failure after 42 months' treatment. The other six patients have been significantly improved and were in functional Class II at their last control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.     

Acute administration of carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of portal pressure in patients with viral cirrhosis

OBJECTIVE: Propranolol is known to decrease portal pressure in cirrhotic patients with portal hypertension; however, a substantial number of patients do not respond to propranolol administration. The addition of isosorbide-5-mononitrate may enhance portal pressure reduction in patients receiving propranolol. Carvedilol is a nonselective beta-blocker with alpha(1)-adrenergic blocking activity. It has been shown to decrease portal pressure in cirrhotic patients. Additionally, carvedilol has a greater portal hypotensive effect than propranolol alone in patients with cirrhosis. The current study is aimed at comparing the acute hemodynamic effects of carvedilol with the effects of propranolol plus isosorbide-5-mononitrate in patients with viral cirrhosis. METHODS: Patients with viral cirrhosis were randomly assigned to receive an oral administration of carvedilol of 25 mg (n = 11) or an oral administration of propranolol 40 mg plus isosorbide-5-mononitrate 20 mg (n = 11). Hemodynamic values were measured at basal and 90 min after drugs administration. RESULTS: Both carvedilol and propranolol plus isosorbide-5-mononitrate significantly decreased cardiac index, heart rate, and HVPG. The magnitude of changes in HVPG observed between the basal and after drugs administration was greater in patients receiving carvedilol than in those receiving propranolol plus isosorbide-5-mononitrate (-18.6 +/- 3.6%vs-10.1 +/- 3.6%, p < 0.05). Hepatic blood flow increased following carvedilol administration but remained unchanged in patients receiving propranolol plus isosorbide-5-mononitrate. The magnitude of decrease in mean arterial pressure (MAP) did not differ between the two groups of patients. CONCLUSION: In our patients with viral cirrhosis, carvedilol is more effective than propranolol plus isosorbide-5-mononitrate in the reduction of HVPG. Carvedilol administration causes an increase in hepatic blood flow, but its systemic effects were similar to those of propranolol plus isosorbide-5-mononitrate.     

Simvastatin enhances hepatic nitric oxide production and decreases the hepatic vascular tone in patients with cirrhosis

BACKGROUND & AIMS: In cirrhosis, an insufficient release of nitric oxide contributes to increased hepatic resistance and portal pressure and enhances the postprandial increase in portal pressure. We hypothesized that simvastatin, which enhances Akt-dependent endothelial nitric oxide synthase phosphorylation, may increase hepatic nitric oxide release and decrease hepatic resistance in patients with cirrhosis and portal hypertension. METHODS: In protocol 1, 13 patients had measurements of the hepatic venous pressure gradient, hepatic blood flow, mean arterial pressure, cardiac output, and nitric oxide products before and 30 and 60 minutes after 40 mg of simvastatin. In protocol 2, 17 patients were randomized to receive placebo or simvastatin (40 mg) 12 hours and 1 hour before the study. After baseline measurements of the hepatic venous pressure gradient, hepatic blood flow, and nitric oxide products, a standard liquid meal was given, and measurements were repeated at 15, 30, and 45 minutes. RESULTS: In protocol 1, acute simvastatin did not modify the hepatic venous pressure gradient but increased the hepatic blood flow (21% +/- 13% at 30 minutes; P = 0.01) and decreased hepatic sinusoidal resistance by 14% +/- 11% (P = 0.04). Nitric oxide product levels significantly increased in hepatic venous blood (from 31.4 +/- 12.3 nmol. mL(-1) to 35.8 +/- 10.7 nmol. mL(-1); P = 0.04), but not in peripheral blood. Systemic hemodynamics were not modified. In protocol 2, simvastatin pretreatment significantly attenuated the postprandial increase in hepatic venous pressure gradient (mean peak increase, 10% +/- 9% vs. 21% +/- 6% in placebo; P = 0.01). Hepatic blood flow increased similarly in the 2 groups. Hepatic nitric oxide products increased in the simvastatin group but not in the placebo group. CONCLUSIONS: Simvastatin administration increases the hepatosplanchnic output of nitric oxide products and decreases hepatic resistance in patients with cirrhosis.     

Systemic and splanchnic hemodynamic effects of molsidomine in rats with carbon tetrachloride-induced cirrhosis

Molsidomine, a long-acting vasodilator mainly used as an antianginal agent, was reported to decrease the portohepatic venous pressure gradient in patients with alcoholic cirrhosis. This study investigated the effects of linsidomine, the active metabolite of molsidomine, on systemic and splanchnic hemodynamics in rats with CCl4-induced cirrhosis using the microsphere technique. Compared with placebo-treated rats, linsidomine-treated animals were found to have a significant decrease in portal venous pressure (-18%, p less than 0.01) and in mean arterial pressure (-16%, p less than 0.01), smaller peripheral resistances (p less than 0.01), greater portal venous inflow (p less than 0.05), smaller splanchnic arteriolar resistances (p less than 0.01) and smaller protocol-lateral resistances (p less than 0.05). Cardiac output, hepatic arterial blood flow, portal blood flow and estimated hepatic blood flow were not significantly different between the two groups of animals. Linsidomine-treated rats exhibited a trend toward greater collateral blood flow compared with controls, but this difference was not significant. We conclude that linsidomine decreases portal venous pressure by reducing portocollateral resistances without affecting liver blood flow. These effects should be beneficial for patients with cirrhosis and portal hypertension.     

Early chronic administration of propranolol reduces the severity of portal hypertension and portal-systemic shunts in conscious portal vein stenosed rats.

We investigated the effects of early chronic administration of propranolol on systemic and splanchnic hemodynamic changes, and the development of portal-systemic shunts in conscious, unrestrained, portal vein stenosed rats. Compared to rats receiving placebo, early chronic propranolol (75 mg kg-1 day-1) administration to rats begun 3 days before portal vein stenosis and then continued for 10 consecutive days, resulted in a significant decrease in both portal pressure (11.8 +/- 1.5 mmHg) and portal-systemic shunts (48 +/- 18%) which were measured 2 to 3 h after the final dose of propranolol (15.2 +/- 1.5 mmHg and 84 +/- 5%, respectively). These beneficial effects were also observed 18 to 24 h after the final dose of chronic propranolol. In rats given propranolol continuously for 5 days starting 5 days after portal vein stenosis, portal pressure (11.8 +/- 1.2 mmHg) was significantly lower than in the placebo group but portal-systemic shunts (76 +/- 14%) were not significantly different. In rats receiving a single dose of propranolol (75 mg/kg) 10 days after portal vein stenosis and measured 2 to 3 h after propranolol administration, portal pressure (12.8 +/- 1.0 mmHg) was significantly lower than in the placebo group. Portal-systemic shunts (72 +/- 17%), however, showed no significant difference from the placebo group. Similar values in portal pressure (13.3 +/- 1.2 mmHg) and portal-systemic shunts (83 +/- 21%) were also observed in rats 18 to 24 h after a single dose of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Echo-Doppler evaluation of acute flow changes in portal hypertensive patients: flow velocity as a reliable parameter

In order to evaluate the behavior of the portal vein cross-sectional area during changes in portal flow, two groups of subjects were analyzed in two blinded cross-over studies using echo-Doppler flowmetry. The first group (I) consisted of 21 patients with cirrhosis and 16 controls. They received a standardized meal which is known to increase portal flow. The second group (II) consisted of 31 patients with cirrhosis who received a dose of propranolol which is known to decrease portal flow. In Group I, 30 min after the meal, the portal vein blood velocity increased by 35 +/- 6% (p less than 0.01) in cirrhotic patients and by 55 +/- 5% (p less than 0.01), in normal subjects. The portal vein cross-sectional area increased significantly in normal subjects (22 +/- 2%, p less than 0.01) but not in cirrhotic patients (4 +/- 2%, n.s.). In Group II, 2 h after propranolol, there was a significant decrease in portal blood velocity (-14 +/- 2%), whereas the portal vein cross-sectional area did not show any significant changes. These data demonstrate that, in portal hypersensitive patients, the portal area measured by echo-Doppler flowmetry can be assumed to be constant and hence its calculation to estimate changes in portal blood flow can be omitted. Therefore, the use of blood velocity alone is suggested to monitor acute changes in flow in portal hypertension using Doppler flowmetry. The elimination of the portal vein cross-sectional area measurement simplifies the quantitative calculation of portal hemodynamics and increases the reliability of the technique by avoiding a source of error.     

Assessment of portal hemodynamics by ultrasound color Doppler and laser Doppler velocimetry in liver cirrhosis.

BACKGROUND: Color Doppler is a noninvasive method for assessing portal hemodynamics. Laser Doppler velocimetry is useful in assessment of microcirculatory abnormalities in portal hypertensive gastropathy (PHG). AIMS: To study portal hemodynamics by color Doppler and gastric mucosal blood flow (GMBF) by laser Doppler velocimetry in patients with cirrhosis. METHODS: Twenty-eight patients with cirrhosis of liver (24 men) and 10 healthy subjects (7 men) were studied. Portal venous blood flow (PVBF) and portal flow velocity (PFV) were assessed by color Doppler at the level where the hepatic artery crosses the portal vein, and GMBF was measured by laser Doppler velocimetry. RESULTS: PVBF (379.5 [102.9] mL/min), PFV (5.3 [1.1] cm/sec) and GMBF (3.5 [0.8] volts) were significantly lower in patients with cirrhosis than in controls. PVBF and PFV were significantly lower in patients in Child class B and C than those in class A. Patients with ascites had significantly lower PVBF, PFV and GMBF than those without; values were also lower in patients with PHG than in those without. History of bleeding had no relation with PVBF and PFV. GMBF showed good correlation with PVBF (r=0.58, p<0.001) and with PFV (r=0.48, p<0.01). CONCLUSIONS: In cirrhosis of liver, PVBF, PFV and GMBF are significantly lower, and the changes increase with increasing severity of liver disease.     

Prediction of the lower esophageal sphincter pressure after oral molsidomine by sydnonimine plasma concentrations.

BACKGROUND/AIMS: Recent studies suggest that endogenous nitric oxide decreases lower esophageal sphincter pressure (LESP). Substances leading to the formation of nitric oxide, such as molsidomine, decreases the human LESP. It is not yet clear whether this reduction is related to plasma concentrations of molsidomine, the nitrate-active substance sydnonimine (SIN-1) or to serum concentrations of nitrate/nitrite (NOx) as a stable end-product of volatile nitric oxide. METHODOLOGY: We performed a double blind controlled crossover trial in 8 healthy male volunteers. Plasma concentrations of molsidomine, SIN-1 and serum concentrations of NOx as well as esophageal manometry were determined. RESULTS: Mean basal LESP was significantly decreased from 25.4 +/- 2.8 mmHg to 21.9 +/- 2.7 mmHg and 21.4 +/- 2.6 mmHg 2 and 3 hours after molsidomine administration, respectively (mean +/- SEM; n = 8; p < 0.05). The maximum decrease of LESP from the baseline within 1-4 hours after molsidomine administration was 7.6 +/- 1.5 mmHg (mean +/- SEM; n = 8; p < 0.01). The decrease of the LESP correlated significantly with plasma concentrations of SIN-1 (r = -0.53; p = 0.002). NOx levels remained unchanged. CONCLUSIONS: Molsidomine decreases the LESP and plasma concentrations of the active metabolite SIN-1 may predict the potency of molsidomine to lower LESP. NOx was useless as a control metabolite to measure the LESP in response to molsidomine in healthy volunteers.     

Propranolol does not alter cerebral blood flow and functions in cirrhotic patients without previous hepatic encephalopathy

Since it has been suggested that propranolol could lead to hepatic encephalopathy, we undertook a study to assess the effects of propranolol on cerebral blood flow and cerebral functions. Sixteen patients with alcoholic cirrhosis and large esophageal varices and without major hepatic dysfunction (Child-Pugh score less than 14) or previous hepatic encephalopathy were randomized to receive either propranolol or placebo. The following measurements were performed before and 15 min after single intravenous administration of 15 mg propranolol or placebo and again 1 week after chronic oral administration of propranolol 160 mg per day or placebo: cerebral blood flow by the xenon-133 inhalation technique, quantitative electroencephalogram, psychometric test (number connection test), arterial ammonia, pH and pCO2, resting and exercise heart rates (after single administration, electroencephalogram, number connection test and biochemical measurements were not performed). Cerebral blood flow was not significantly modified by treatment (propranolol group: 80 +/- 23 vs. 76 +/- 11 and 83 +/- 9; placebo group: 73 +/- 10 vs. 75 +/- 11 and 81 +/- 18 ml per 100 gm per min, respectively, before and after single and repeated administration). Likewise, neither of the two treatments significantly altered number connection test, quantitative electroencephalogram index, arterial ammonia, pH and pCO2. We conclude that, in this population of cirrhotic patients, propranolol did not alter cerebral blood flow or neuropsychological functions. As a consequence, hemodynamic alterations cannot be considered as causes of possible cerebral side effects of propranolol in cirrhotic patients without severe hepatic dysfunction and previous hepatic encephalopathy.     

Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study

OBJECTIVE: To investigate whether isosorbide-5-mononitrate (Is-5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. DESIGN: A randomized controlled trial. PATIENTS: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. INTERVENTION: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. MEASUREMENTS: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. MAIN RESULTS: At 3 months, the hepatic venous pressure gradient decreased more (P less than 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 +/- 3.9 to 14.9 +/- 3.8 mm Hg; 95% CI, -2.4 to -4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 +/- 3.5 to 16.3 +/- 3.1 mm Hg; CI, -1.1 to -2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P less than 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. CONCLUSIONS: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.     

Total effective vascular compliance in patients with cirrhosis. Effects of propranolol

BACKGROUND: Total effective vascular compliance (TEVC), may be increased in cirrhosis. However, its significance is unclear. AIMS: To investigate TEVC in patients with cirrhosis, and the effects of propranolol. METHODS: Seven patients without liver disease and 44 cirrhotic patients were studied before and after double-blind administration of propranolol (n=33) or placebo (n=11). MEASUREMENTS: TEVC (right atrial pressure response to rapid central volume expansion), hepatic venous pressure gradient (HVPG) and systemic hemodynamics. RESULTS: TEVC (ml x mmHg(-1) x kg(-1)) was increased in cirrhotics (1.67 +/- 0.66 versus 1.33 +/- 0.32 in controls; P<0.05). TEVC was not modified by placebo, but was markedly reduced by propranolol (from 1.74 +/- 0.75 to 1.33 +/- 0.56; P<0.01). Propranolol decreased HVPG >10% in 20 patients ('responders': -20 +/- 9%) but <10% in 13 'non-responders'. TEVC was normalized by propranolol in HVPG 'responders' (from 1.76 +/- 0.88 to 1.21 +/- 0.51; P<0.01), but not in 'non-responders' (1.69 +/- 0.48 to 1.52 +/- 0.59; NS). Reduction of TEVC in responders was accompanied by increased free hepatic vein pressure (+21 +/- 20%, P=0.05; approximately 60% of the fall in HVPG), which was not observed in non-responders (+3 +/- 11%, NS). CONCLUSIONS: TEVC is increased in cirrhosis. This abnormality is corrected by propranolol in patients exhibiting a >10% fall in HVPG, suggesting that changes in vascular compliance may influence the portal pressure response to propranolol.     

Beta-adrenoceptor blockade in the treatment of postoperative adynamic ileus

Abdominal trauma, such as surgery and peritonitis, leads to inhibition of intestinal motility, partly mediated by alpha- and beta-adrenoceptors. To investigate the effect of nonselective beta-blockade on adynamic ileus, propranolol was compared with placebo in the postoperative course after elective colonic surgery in a double-blind randomized study. Ten patients received 4 mg propranolol intravenously twice daily, and ten received 10 mg intravenously twice daily. Nineteen patients received placebo. The time to first passage of stool was 110 +/- 9 h in the placebo group and 82 +/- 11 h in the 4-mg propranolol group. In the 10-mg propranolol group, the time was 79 +/- 8 h. The difference between the placebo-treated group and the propranolol-treated groups was significant (p less than 0.01). The effect of propranolol was most marked in older patients and after surgery on the distal colon. In patients older than 60 years the time to first stool in the placebo group was 127 +/- 13 h (n = 8), compared with 73 +/- 8 h (n = 11) in the propranolol group (p less than 0.01). In patients who had undergone surgery on the distal colon the time to first stool was 125 +/- 13 h (n = 8) in the placebo group and 76 +/- 8 h (n = 11) for propranolol (p less than 0.01). Adverse effects on the respiratory or cardiovascular system were not seen during medication. It is concluded that propranolol shortens the period of adynamic ileus after colonic surgery.     

Portal venous flow in response to acute beta-blocker and vasodilatatory treatment in patients with liver cirrhosis

The drugs currently under investigation in the prevention of recurrent gastrointestinal bleeding in cirrhosis are likely to decrease the portal pressure by means of a primary reduction of portal blood flow. The hemodynamic effects of beta-blocking agents and vasodilatory drugs were noninvasively measured in eight patients with cirrhosis by means of pulsed echo-doppler equipment. Portal caliber, blood velocity and flow were recorded hourly after a single dose of propranolol (40 mg p.o.) or atenolol (100 mg p.o.), and every 5 min after treatment with isosorbide dinitrate (5 mg sublingually). The drugs were administered at random with an interval of 2 days or more. The portal caliber decreased after atenolol, but did not change after propranolol and isosorbide. The blood velocity decreased by 29 +/- 2% 3 hr after propranolol, by 26 +/- 2% 3 hr after atenolol and by 31 +/- 3% 15 min after isosorbide. The portal blood flow decreased by 0.29 +/- 0.03 liters per min after propranolol, by 0.34 +/- 0.06 after atenolol and by 0.26 +/- 0.03 after isosorbide, without any difference among the various treatments. beta-blockers and vasodilatory drugs have comparable effects on portal blood flow. beta 1-selective and nonselective beta-blockers are similarly effective in keeping with the hypothesis that changes in portal blood flow are mainly due to the block of beta 1-receptors.     

Duplex-Doppler ultrasonography in the evaluation of cirrhotic patients with portal hypertension and in the analysis of their response to drugs

Sixteen patients (15 males, aged 48-70) affected by liver cirrhosis and oesophageal varices were subjected to duplex-Doppler ultrasonographic study (DDUS). Four patients (three with a portal thrombosis and one with a hepatofugal portal flow) were excluded from the subsequent pharmacological test. The twelve remaining patients took part in a double blind cross-over study that evaluated the variations of heart rate (HR), mean systemic arterial pressure (SAP), portal vein diameter (PVD), maximal and mean portal flow velocity (PFV) after the administration of either 40 mg of propranolol or placebo per os, on two consecutive days. Propranolol caused no significant variation in mean SAP and in PVD, whereas it reduced the HR from 67.7 +/- 8.0 to 58.4 +/- 7.0 beats/min (mean +/- s.d.; P less than 0.001); the maxPFV dropped from 18.2 +/- 5.4 to 14.0 +/- 3.7 cm/s (P less than 0.001) and the meanPFV dropped from 15.3 +/- 4.1 to 13.2 +/- 3.1 cm/s (P less than 0.005). No significant variation was observed with placebo. After propranolol administration eight patients exhibited a significant maxPFV decrease, whereas the other four patients exhibited only a drop in HR, suggesting either drug inefficacy, inappropriate dosage or inadequate duration of treatment. DDUS is the only non-invasive method for the examination of the portal vein system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Propranolol decreases portal pressure without changing portocollateral resistance in cirrhotic rats

Propranolol decreases portal pressure by reducing portal blood inflow. Studies in rats with prehepatic portal hypertension due to portal vein stenosis (a model with extensive portosystemic shunting) have shown that propranolol increases the portocollateral resistance, which hinders the fall in portal pressure. The present study examined the effects of propranolol on splanchnic and systemic hemodynamics in rats with portal hypertension due to cirrhosis of the liver, a model which is characterized by mild portosystemic shunting. Two groups of rats with CCl4-induced cirrhosis were studied: the propranolol group (n = 8), which received a propranolol infusion of 2 mg per 15 min, and controls (n = 9), which received a placebo (saline) infusion. Hemodynamic measurements were done using radiolabeled microspheres. Propranolol-treated rats had significantly lower cardiac output (-31%) and heart rate (-26%) than controls (p less than 0.001). Hepatic artery flow was not modified by propranolol. Propranolol caused splanchnic vasoconstriction, manifested by increased splanchnic resistance (+57%) and by a significant fall in portal blood inflow (4.8 +/- 0.4 vs. 6.3 +/- 0.5 ml per min.100 gm in controls, p less than 0.05). In contrast with rats with prehepatic portal hypertension, propranolol did not increase portal resistance in cirrhotic rats [2.0 +/- 0.2 vs. 2.0 +/- 0.1 mmHg per ml per min.100 gm body weight (not significant)]. Hence, the fall in portal pressure (-19%) was expected from the decrease in portal inflow (-24%). These results suggest that increased portal resistance in rats with prehepatic portal hypertension may represent an intrinsic effect of propranolol on the portocollateral vessels, since beta-blockade does not modify portal vascular resistance in cirrhosis.     

Beta-blockade with propranolol and hepatic artery blood flow in patients with cirrhosis

In patients with cirrhosis and portal hypertension, propranolol administration reduces heart rate and cardiac output and diminishes portal pressure and collateral blood flow. However, there is little information on the possible effects of propranolol on hepatic artery blood flow. The present study addressed this question in 12 cirrhotic patients with end-to-side portacaval shunt, in whom all of the liver blood flow represents the hepatic artery blood flow. Hepatic artery blood flow (continuous infusion of indocyanine green), cardiac output (thermal dilution), heart rate and mean arterial pressure were measured before and 20 min after the intravenous infusion of 10 to 15 mg of propranolol. beta-Adrenergic blockade caused a significant reduction of cardiac output (from 9.1 +/- 2.1 to 7.1 +/- 1.4 liters per min, p less than 0.001) (mean +/- S.D.) and heart rate (from 85 +/- 10 to 71 +/- 7 beats per min, p less than 0.001), and a significant increase of systemic vascular resistance (from 9.0 +/- 2.1 to 11.7 +/- 2.7 mmHg per liter per min, p less than 0.001), whereas mean arterial pressure did not change (77 vs. 78 mmHg). Propranolol significantly reduced hepatic artery blood flow (from 0.65 +/- 0.20 to 0.55 +/- 0.14 liters per min, p less than 0.01). However, reduction of hepatic artery blood flow (-12.9 +/- 7.3%) was significantly less than reduction of cardiac output (-21.1 +/- 5.2%, p less than 0.01). As a result, the fraction of the cardiac output delivered to the liver was significantly greater after propranolol (8.0 +/- 1.7%) than before (7.3 +/- 1.7%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Propranolol and haemodynamic response in cirrhosis.

In the present study, we compared cirrhotic patients who had a decrease in the hepatic venous pressure gradient after propranolol intake to patients without a decrease. Twenty patients with cirrhosis and oesophageal varices were investigated during hepatic vein catheterization before and 90 min after an oral dose of 80 mg propranolol. The hepatic venous pressure gradient decreased by 12.6% (19.0 +/- 4.7 to 16.3 +/- 3.6 mm Hg, p less than 0.05). Eight (40%) out of 20 patients had a decrease of less than 10% in protal pressure (non-responders). Responders had a higher baseline cardiac index than non-responders (3.79 +/- 0.74 vs. 2.83 +/- 0.53 1.min-1.m-2; p less than 0.01). No difference in the effect of propranolol on portal pressure was observed between patients with or without ascites, or between Child-Turcotte A, B, and C class patients. Our results suggest that cirrhotic patients who respond to oral propranolol with a decrease in portal pressure are more hyperdynamic than those without a significant fall in portal pressure.     

Molsidomine and isosorbide dinitrate:/their comparative effectiveness in patients with exertion-induced stenocardia

The markedness and duration of antianginal effects of 2 mg molsidomine and 10 mg isosorbide dinitrate were compared by means of repeated treadmill tests in 37 coronary patients with stable angina of effort. Peak magnitude of the effect was similar with both drugs, while the duration of the effect of isosorbide dinitrate (4.0 +/- 0.3 hrs) was significantly greater than that of molsidomine (3.4 +/- 0.3 hrs). Molsidomine reached its peak effect significantly earlier, as compared to isosorbide dinitrate. There was a significant correlation between the effectiveness of molsidomine and isosorbide dinitrate in the same patients.