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Background: Arterial vasodilatation, which is a major factor in the pathogenesis of the hyperkinetic circulatory state and portal hypertension in cirrhosis, is due to arterial nitric oxide (NO) overproduction secondary to endothelial NO synthase (eNOS) and inducible NOS (iNOS) upregulation. However, in cirrhosis, the respective roles of eNOS and iNOS isoforms in NO overproduction are still unknown and the effect of iNOS modulation on eNOS activity and expression has not been evaluated in the systemic or splanchnic vessels. The aim of this study was to evaluate the effects of modulating aortic and superior mesenteric arteries (SMA) iNOS on arterial eNOS activity and expression in rats with cirrhosis., Methods: eNOS and iNOS protein expression and eNOS activity (assessed by its phosphorylation at serine 1177) were measured in the aortas and SMA in untreated and treated cirrhotic rats with lipopolysaccharide (LPS), N-iminoethyl-L-lysine (L-NIL), a selective iNOS inhibitor, and LPS plus L-NIL., Results: LPS administration significantly increased eNOS and iNOS protein expression and eNOS activity in the aortas of both sham-operated and cirrhotic rats. However, in SMA, LPS administration induced a decrease in eNOS protein expression and activity and an increase in iNOS protein expression., Conclusion: The results of this study may explain the worsening of the hyperdynamic state in cirrhosis during septic shock by direct LPS-induced eNOS activation in large systemic vessels, and its inhibition in concomitant small splanchnic vasculature by iNOS synthesized NO.

In splanchnic arteries, vasodilators decrease the cytosolic free calcium concentration ([Ca(2+)]i) by inducing Ca(2+)sequestration and extrusion, by limiting the entry of extracellular Ca(2+)via L-type Ca(2+)channels and by decreasing the agonist-induced mobilization of intracellular Ca(2+). Cyclic GMP kinase and membrane hyperpolarization are important mediators of the decrease in [Ca(2+)]i. Vasoconstrictors increase [Ca(2+)]i by mobilizing intracellular Ca(2+)from the sarcoplasmic reticulum and by stimulating extracellular Ca(2+)entry via L-type Ca(2+)channels. Activation of G proteins, inositol trisphosphate, diacylglycerol and membrane depolarization are important mediators of the increase in [Ca(2+)]i., (Copyright 2001 Harcourt Publishers Ltd.)

Aims: In cirrhosis, the effects of selective activation of atrial natriuretic peptide (ANP) R2-receptors on haemodynamics, endogenous ANP (ANP1-28) and sodium excretion are unknown. The aim of the present study was to examine the effects of selective activation of ANP-R2 receptors by ANP4-23 (a ring-deleted analogue of endogenous ANP) on haemodynamics, plasma ANP1-28 concentrations and urinary sodium excretion in conscious cirrhotic and normal rats., Methods: Haemodynamics and sodium excretion were measured prior to and following administration of ANP4 23. Plasma ANP1-28 concentrations were also measured., Results: In cirrhotic rats, ANP4-23 significantly decreased portal pressure and tributary blood flow by 15% and 25% respectively but significantly increased portal territory vascular resistance by 30%. Systemic and renal haemodynamics were not altered by ANP4-23. In normal rats, ANP4-23 did not significantly change splanchnic, renal and systemic haemodynamics. In both groups of rats, ANP4-23 increased plasma ANP1-28 concentrations but did not change sodium excretion., Conclusions: ANP4-23 administration induced splanchnic vasoconstriction in cirrhotic but not in normal rats. ANP4-23-elicited vasoconstriction caused a portal hypotensive effect in cirrhotic rats. Finally, in both groups, ANP4-23 caused an increase in plasma ANP1-28 concentrations but did not increase sodium excretion.

Hemodynamics and oxygen variables, plasma cytokines, and histological features of a liver tissue sample obtained by transvenous biopsy were evaluated during 65 episodes of acute rejection. The hepatic venous pressure gradient was significantly higher in patients with acute rejection than in those without (5.1+/-0.3 vs. 3.1+/-0.2 mmHg, P<0.01). The increase in pressure gradient was related to the severity of rejection lesions. Hepatic blood flow was significantly lower in patients with than in those without acute graft rejection (1.28+/-0.11 vs. 1.75+/-0.13 L/min, P<0.05). Plasma interleukin-6 levels were significantly increased in patients with acute rejection and positively correlated with pressure gradient values. In patients with acute rejection, a significant decrease in hepatic venous oxygen content (-16%) was associated with a significant increase in hepatic oxygen consumption (+24%), whereas hepatic oxygen transport did not change significantly. In treated patients with a favorable response, the pressure gradient decreased significantly by 46%, but it remained elevated in patients who later developed chronic graft rejection. In conclusion, this study confirms that acute graft rejection may induce an increase in portal pressure, which is related to the severity of rejection lesions. It also shows that acute rejection decreases hepatic blood flow and increases hepatic oxygen consumption. In addition, it suggests that the hepatic venous pressure gradient might be useful to determine the outcome of rejection.

Background: The aim of this study was to investigate short-term effects of propranolol (a non-selective beta-adrenergic antagonist), octreotide (a long-acting somatostatin analogue), or a combination of these substances on splanchnic and systemic haemodynamics and arterial blood gases in rats with portal vein stenosis., Methods: Splanchnic and systemic haemodynamics were measured using the radioactive microspheres method. Eight rats first received an i.v. infusion of isotonic saline (10 microL/min for 15 min) and then an i.v. infusion of octreotide (8 micrograms.h/kg for 15 min). Eight other rats first received a bolus i.v. injection of propranolol (2 mg) and an i.v. infusion of octreotide 15 min later., Results: Propranolol or octreotide alone significantly decreased portal pressure (both by 23%), portal tributary blood flow (35 and 10%, respectively) and cardiac index (36 and 26%, respectively). Octreotide administration in rats pretreated with propranolol significantly decreased cardiac index but did not change portal and arterial pressures or portal tributary blood flow. Propranolol significantly increased arterial oxygen tension. Octreotide alone or combined with propranolol significantly decreased oxyhaemoglobin saturation and pH and increased carbon dioxide tension., Conclusions: In rats with portal vein stenosis, the somatostatin analogue, octreotide, accentuates the short-term decrease in cardiac index due to propranolol. In addition, octreotide altered arterial blood gases and acid-base status. In contrast, octreotide does not further decrease portal pressure in animals receiving propranolol.

Background/aims: Refractory ascites, which occurs in certain patients with cirrhosis, is associated with a blunted natriuretic response to exogenous atrial natriuretic peptide (ANP). Since this blunting seems to be related to ANP-induced arterial hypotension, a vasoconstrictor, such as terlipressin (a vasopressin analogue), may restore natriuresis to exogenous ANP. Moreover, since cirrhosis-elicited vasodilation is thought to play a role in sodium retention, a vasoconstriction caused by terlipressin alone may lead to an increase in sodium excretion. This study aimed to evaluate the natriuretic response to either a combination of ANP with terlipressin or terlipressin alone in patients with cirrhosis and refractory ascites., Methods: Sixteen consecutive patients with cirrhosis and refractory ascites were randomly assigned to receive either a combination of terlipressin (1-2 mg, i.v. bolus) with ANP (35 ng/kg, i.v. bolus followed by 15 ng x kg(-1) x min(-1) for 60 min) (n=8) or terlipressin alone (1-2 mg, i.v. bolus) (n=8). Sodium excretion and urine output, systemic, splanchnic and renal hemodynamics and renal oxygen consumption were measured before and during treatments., Results: Combined therapy did not change arterial pressure but significantly increased urinary sodium excretion and urine output. These effects were associated with a significant increase in glomerular filtration rate and a decrease in renal oxygen consumption. Terlipressin alone significantly increased arterial pressure but did not change urinary sodium excretion or urine output. Moreover, terlipressin did not change either glomerular filtration rate or renal oxygen consumption., Conclusions: The combination of exogenous ANP with terlipressin, but not terlipressin alone, increases sodium excretion in patients with cirrhosis and refractory ascites.

Although hepatic schistosomiasis is a common cause of portal hypertension, only a few hemodynamic studies, in humans, have been published on this subject. The aim of this study was to determine the systemic and splanchnic hemodynamic changes in hepatic schistosomiasis and to evaluate the influence of liver fibrosis on these changes. A retrospective analysis of a series of 13 patients with hepatic schistosomiasis who had undergone hemodynamic studies was performed. Portal or perisinusoidal fibrosis was present at liver biopsy in 8 patients. The control group included 22 patients with chronic hepatitis and normal hepatic venous pressure gradients. Patients with schistosomiasis exhibited high cardiac index (4.11 +/- 1.15 l.min-1.m-2 vs 2.99 +/- 0.85 l.min-1.m-2; p < 0.05) and low systemic vascular resistance (1039 +/- 316 dyn.s.cm-5 vs 1334 +/- 336 dyn.s.cm-5; p < 0.05). The hepatic venous pressure gradient and hepatic blood flow were normal. Azygos blood flow was markedly increased (0.90 +/- 0.66 l.min-1 vs 0.13 +/- 0.04 l.min-1; p < 0.05). Hemodynamic values were not significantly different between patients with liver fibrosis and those without fibrosis at liver biopsy. In conclusion, patients with hepatic schistosomiasis had a hyperkinetic systemic and splanchnic circulation. In patients with esophageal varices, a normal hepatic venous pressure gradient confirmed presinusoidal portal hypertension. The presence of portal or perisinuoidal fibrosis did not influence hyperdynamic splanchnic state.

The role of nitric oxide (NO) in the hyperkinetic circulation in portal hypertension has not been clearly elucidated. Different doses of NO inhibitors, haemodynamic values and experimental conditions might explain the discrepant results. The aim of the present study was to investigate the acute effects of a specific biosynthesis inhibitor of NO, Nomega-nitro-L-arginine (L-NNA), on the systemic and splanchnic circulation in normal conscious rats and rats with portal hypertension due to either partial portal vein stenosis or secondary biliary cirrhosis. The administration of L-NNA (15 to 960 micrograms.kg-1.min-1) induced a significant dose dependent increase in arterial pressure which was not different among the three groups of rats. Following an acute and maximal vasopressive dose of L-NNA (1 mg.kg-1.min-1) cardiac index decreased more in portal vein stenosed and cirrhotic rats (-45 +/- 3% and -45 +/- 2%, respectively) than in normal rats (-31 +/- 2%), and systemic vascular resistance increased more in the two groups of portal hypertensive rats than in normals (+ 161 +/- 13% and + 154 +/- 10% vs + 85 +/- 6%, respectively). L-NNA caused a greater decrease in portal tributary blood flow in portal vein stenosed and cirrhotic rats (-63 +/- 4% and -55 +/- 4%, respectively) than in normal rats (-45 +/- 6%). Similarly, the increase in portal territory vascular resistance was significantly more marked in portal vein stenosed and cirrhotic rats (+ 337 +/- 62% and + 214 +/- 24%, respectively) than in normal rats (+ 153 +/- 23%). Portal pressure did not change. Following the acute administration of L-NNA, no significant difference in splanchnic and systemic haemodynamics were noted between portal vein stenosed and normal rats, except for portal pressure. In cirrhotic rats, splanchnic and systemic values remained different from normal rats. This study confirms that NO plays a role in the haemodynamic changes in portal hypertension, and shows that NO inhibitors have a dose-dependent effect in conscious portal hypertensive rats.

Background/aims: Since portal tributary blood flow is increased in portal hypertension due to cirrhosis, a reduction in mesenteric arterial blood flow should decrease portal pressure., Methods: Calibrated stenosis of the superior mesenteric artery was performed in bile duct ligated rats, using a 22-gauge needle. Arterial stenosis was performed 4 weeks after bile duct ligation. Hemodynamic studies were performed in the 5th week following bile duct ligation in conscious rats., Results: At that time, no digestive tract alterations were observed. In rats with mesenteric arterial stenosis, portal pressure was 12.2 +/- 2.0 mmHg; this value was lower than in rats with cirrhosis without arterial stenosis (14.5 +/- 1.1 mmHg) but higher than normal rats (5.8 +/- 0.7 mmHg). In rats with cirrhosis with mesenteric arterial stenosis, portal tributary and mesenteric blood flows were lower than in rats with cirrhosis without arterial stenosis and not significantly different from normal rats. In rats with mesenteric stenosis, cardiac index was significantly lower than in rats with cirrhosis and not significantly different from normal rats., Conclusion: This study shows that calibrated superior mesenteric arterial stenosis normalized portal tributary blood flow and reduced but did not normalize the degree of portal hypertension.

1. The effects of the sulphonylurea, glibenclamide (20 mg kg-1, i.v.), at a dose that blocks vascular potassium channels, on systemic and splanchnic haemodynamics (radioactive microspheres) were studied in conscious rats. 2. Glibenclamide significantly decreased cardiac index and hepatic artery blood flow while it significantly increased vascular resistance in systemic, portal and hepatic arterial territories. 3. In rats with suppressed cardiovascular reflexes, glibenclamide induced vasoconstriction in systemic, portal and hepatic arterial territories. 4. Intracerebroventricular administration of glibenclamide did not alter systemic or regional vascular tone. 5. Glibenclamide blunted the vasodilator effect of the potassium channel opener, diazoxide but not that of the L-type calcium channel blocker, nicardipine. 6. Another sulphonylurea, glipizide (20 mg kg-1, i.v.), induced significant systemic and splanchnic vasoconstriction. 7. Thus, the glibenclamide-induced blockade of vascular potassium channels caused a vasoconstriction in the systemic and splanchnic vascular beds. In these territories, therefore, the opening of glibenclamide-sensitive potassium channels might be responsible for a basal vasodilator tone.

The effects of clonidine, vasopressin or a combination of both substances on splanchnic and systemic haemodynamics were measured in conscious rats with portal vein stenosis. Clonidine alone significantly decreased portal pressure, portal tributary blood flow and cardiac index, but did not change arterial pressure. Vasopressin alone significantly increased arterial pressure and significantly decreased portal pressure, portal tributary blood flow and cardiac index. Changes in portal tributary blood flow, arterial pressure and cardiac index were significantly higher with vasopressin than with clonidine alone. Vasopressin infusion in rats pretreated with clonidine significantly increased arterial pressure and significantly decreased portal pressure, portal tributary blood flow and cardiac index. Changes in arterial and portal pressures and portal tributary blood flow were significantly higher with combined therapy than with clonidine alone. Changes in arterial and portal pressures and portal tributary blood flow did not differ between combined therapy and vasopressin alone. Changes in cardiac index were significantly higher with combined therapy than with clonidine or vasopressin alone. Hepatic artery blood flow was not affected by either clonidine or vasopressin but significantly declined with combined therapy. In conclusion, this study suggests that a combination of vasopressin and clonidine accentuates the portal hypotensive action of clonidine but not the action of vasopressin. Moreover, this study suggests that a combination of vasopressin and clonidine may have deleterious effects on systemic and hepatic artery vascular beds.

Systemic, splanchnic and renal hemodynamic responses to saline, physiological (25 ng.kg-1.min-1) and pharmacological (100, 300 and 600 ng.kg-1.min-1) doses of alpha human atrial natriuretic peptide were measured in normal (n = 7 for saline and 7-8 for each dose of atrial natriuretic peptide) and cirrhotic (n = 7 for saline and 7-8 for each dose of atrial natriuretic peptide), conscious, unrestrained rats. In addition, plasma norepinephrine concentrations were measured in normal and cirrhotic rats, before and following a 300-ng.kg-1.min-1 dose of atrial natriuretic peptide. In cirrhotic rats, splanchnic, renal and systemic hemodynamics were not significantly affected by either physiological or pharmacological doses of atrial natriuretic peptide. In normal rats, a 300 ng.kg-1.min-1 dose of atrial natriuretic peptide significantly decreased cardiac index, portal tributary blood flow and renal blood flow, and significantly increased vascular resistance in the systemic, portal, and renal territories. The other doses of atrial natriuretic peptide did not significantly change regional and systemic hemodynamics. Atrial natriuretic peptide-induced changes in plasma norepinephrine concentrations were significantly higher in normal than in cirrhotic rats (1827 +/- 834 vs. 59 +/- 46 pg/ml, mean +/- S.E., respectively). In conclusion, this study shows that the normal cardiovascular response to a 300 ng.kg-1.min-1 atrial natriuretic peptide infusion is blunted in cirrhotic rats. Moreover, in cirrhotic rats, blunting of vasoconstriction following atrial natriuretic peptide administration seems to be due to a lack of increased sympathetic vascular tone.

Portal pressure and portal-systemic collateral circulation after orthotopic liver transplantation have not been investigated. We studied systemic and splanchnic hemodynamics in 17 patients with cirrhosis before and 205 +/- 146 days after orthotopic liver transplantation. Among the 17 orthotopic liver transplantation patients, 12 had undergone hemodynamic study in the 6 mo before orthotopic liver transplantation. Controls were 50 patients with normal liver architecture. Cardiac index remained elevated in orthotopic liver transplantation patients compared with controls (3.6 +/- 0.9 vs 3.1 +/- 0.4 L/min.m2; p < 0.05). Azygos blood flow, which was elevated before orthotopic liver transplantation (585 +/- 402 ml/min), remained elevated after orthotopic liver transplantation (553 +/- 343 ml/min). In transplant patients, hepatic blood flow was higher than it was in controls (2.26 +/- 0.86 vs. 1.38 +/- 0.57 L/min; p < 0.05). Elevated hepatic blood flow correlated with cardiac index (r = 0.647, p < 0.025). In patients with normal graft function, hepatic venous pressure gradient was normal (2 +/- 1 mm Hg). In a patient with acute rejection, a sharp elevation in the hepatic venous pressure gradient was observed; it returned to normal 45 days after treatment. We conclude that despite normal portal pressure, portal-systemic collateral blood flow remains elevated after orthotopic liver transplantation. Possibly because of persistent collateral circulation, which may keep portal tributary blood flow elevated, hepatic blood flow is increased after orthotopic liver transplantation. Elevated splanchnic blood flow, in turn, contributes to the high cardiac index in liver recipients. Finally, a sharp elevation in portal pressure, which may be observed during acute rejection and subsides after treatment, merits further study.

Decreased pressor reactivity to angiotensin II has been demonstrated in portal hypertension due to cirrhosis. The present study investigated the respective roles of portal hypertension and cirrhosis and the hemodynamic mechanisms of the depressor response in different models of portal hypertension in conscious rats. Dose-pressor curves were studied in sham-operated, portal vein stenosed (portal hypertension without cirrhosis) and biliary cirrhotic rats following angiotensin II administration. Decreased pressor response was observed in cirrhotic rats but not in portal vein stenosed rats. The hemodynamic effects of angiotensin II administration (11 ng.100 g-1 body wt.min-1, i.v.) were studied in conscious sham-operated and biliary cirrhotic rats (radioactive microsphere method). The percentage of change from basal values following angiotensin II administration were significantly more marked in sham-operated rats than in cirrhotic rats for mean arterial pressure (+34 vs. +6%), cardiac index (-36 vs. -22%), systemic vascular resistance (+117 vs. +40%). After angiotensin II, portal tributary and hepatic artery blood flows significantly decreased in sham-operated rats (-31 and -14%, respectively) but not in cirrhotic rats (+1 and +23%), whereas changes in renal blood flow were not significantly different between the two groups (-44 vs. -34%). In conclusion, in biliary cirrhotic rats, decreased pressor response to angiotensin II depends on the presence of liver disease rather than on portal hypertension or basal hemodynamic alterations. It also depends on the decreased vasoconstrictive effect which predominates in the splanchnic vascular bed.

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.

Because superior mesenteric arterial blood flow is increased in portal hypertension and plays a role in elevated portal pressure, mechanical reduction of artery diameter should induce decreases in portal pressure and superior mesenteric arterial blood flow. In this study, calibrated superior mesenteric artery stenosis (induced with a 22-gauge needle) was performed in rats simultaneously with portal vein stenosis or 2 wk after creation of portal vein stenosis. Hemodynamic studies were performed 3 wk after induction of portal vein stenosis in conscious, unrestrained rats. At that time, neither weight loss nor digestive tract alterations were observed in rats with arterial stenosis. In neither group of rats with arterial stenosis was portal tributary blood flow significantly different from that of normal rats; nor was it significantly lower than in rats with portal vein stenosis without arterial stenosis. In both groups of rats with arterial stenosis, portal pressure was significantly lower (12.1 +/- 1.6 mm Hg and 12.5 +/- 1.8 mm Hg, respectively) than in rats subjected to portal vein stenosis (15.4 +/- 1.5 mm Hg) but significantly higher than in controls (7.2 +/- 1.0 mm Hg). In rats with arterial stenosis, cardiac index was also significantly lower than that in rats with portal vein stenosis but higher than that in controls. In conclusion, this study shows that both early and late superior mesenteric artery stenosis significantly reduce the degree of portal hypertension and the hyperkinetic state of rats with extrahepatic portal hypertension. Thus we can speculate that superior mesenteric artery stenosis might provide a new therapeutic approach for portal hypertension.

We studied the hemodynamics in four groups of rats with combinations of mesenteric hypertension and portal diversion. Operations created three groups with mesenteric hypertension and different degrees of portal venous diversion: mesenteric vein stenosis, portal vein stenosis and end-to-side portacaval anastomosis with mesenteric vein stenosis, the fourth group had only portacaval anastomosis. A control group had sham operations. Cardiac output, splanchnic blood flows and portosystemic shunt indices were measured with radioactive microspheres. Mesenteric venous pressures in the mesenteric-stenosed, portal-stenosed, portacaval-shunted and end-to-side portacaval anastomosis with mesenteric vein stenosis rats were, respectively, 13.5 +/- 0.6, 15.3 +/- 0.7, 4.3 +/- 0.5 and 13.0 +/- 0.9 mm Hg, which were all significantly different from controls: 8.3 +/- 0.3 mm Hg. Portosystemic shunt indices were also significantly different from each other: controls, 0.4% +/- 0.02%; mesenteric-stenosed, 5.9% +/- 2.3%; and portal-stenosed, 52.1% +/- 4.9%. Cardiac output and splanchnic visceral blood flows were significantly increased in the portal-stenosed rats and the two groups with portacaval anastomoses, with the latter two groups having the highest values. The addition of mesenteric stenosis did not change the blood flows because mesenteric-stenosed rats did not differ from controls and end-to-side portacaval anastomosis with mesenteric vein stenosis rats did not differ from rats with portacaval anastomosis alone. These results suggest that mesenteric venous hypertension per se does not affect hemodynamics but that diversion of portal venous blood from the liver is a critical factor in the development of hyperkinetic circulation in portal hypertension.

The effects of 1 MAC of either halothane, enflurane or isoflurane on splanchnic haemodynamics were studied in cirrhotic rats that were either normovolaemic or hypovolaemic from haemorrhage. A group of conscious rats acted as the control group. Bile duct ligation had been carried out in all the rats four weeks previously to induce cirrhosis. At the time of the study, all the rats were anaesthetized with ether for catheterization of the left femoral artery and vein, and the left ventricle via the right carotid. The control group was allowed to awake. When the other rats started to recover, they were artificially ventilated with room air and 1 MAC of the halogenated agent. Heart rate and mean arterial blood pressure were monitored continuously. Once the animals had remained steady for one hour, 1.25 ml of blood for 100 g body weight was removed over a 10 min period. PaO2, PaCO2, arterial pH, heart rate, mean arterial blood pressure, cardiac index and regional blood flows (RBF) were measured before, and thirty minutes after the haemorrhage. Cardiac output and RBF were measured using the radioactive-labelled microsphere method. Only 32 animals were finally included, eight in each group. Splanchnic, portal and hepatic arterial blood flows were similar in conscious rats and in those receiving isoflurane or halothane, and were higher than in those receiving enflurane. The lowest splanchnic and portal venous blood flows were found in those rats receiving enflurane. After haemorrhage, these RBF decreased significantly in all groups except in the enflurane group.(ABSTRACT TRUNCATED AT 250 WORDS)

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)

The effects of dopamine on kidney function have not been elucidated in patients with cirrhosis. Moreover, although increased portal pressure has been observed with supradopaminergic doses of dopamine in these patients, the splanchnic hemodynamic effects of low doses of dopamine have not been previously studied. Thus we studied the acute systemic, splanchnic and renal hemodynamic effects of a dopaminergic dose of dopamine (1.5 micrograms/kg body wt min) in nine cirrhotic patients. Plasma dopamine levels increased markedly from 35 +/- 20 pg/ml to 31,400 +/- 4,900 pg/ml during dopamine administration. A significant diastolic pressure decrease of 10% was associated with a 15% increase in heart rate. Cardiac output was not altered. Although dopamine significantly increased azygos blood flow by 16%, wedged and free hepatic venous pressures were not altered. Dopamine significantly increased renal blood flow by 31%, but did not change the glomerular filtration rate. We conclude that a dopaminergic dose of dopamine increases azygos blood flow but not the hepatic venous pressure gradient. Finally, although it increases renal blood flow, dopamine does not seem to have any beneficial effects on glomerular filtration rate in cirrhotic patients.

The splanchnic and systemic hemodynamics of 14 patients with refractory ascites were studied and were compared to those of 15 patients with ascites responding to medical treatment. Among the 14 patients, 10 were grade B and 4 C, according to the Pugh classification. Of the 15 patients, 5 were Pugh B and 10 C. In patients with refractory ascites, free hepatic venous pressure was significantly higher and hepatic venous pressure gradient was significantly lower than in patients with responsive ascites. Hepatic and azygos blood flows were not significantly different between the two groups. Cardiac output was lower in patients with refractory ascites (p less than 0.05) than in those with responsive ascites. In patients with refractory ascites, six months after peritoneovenous shunting, there was a significant reduction of wedged and free hepatic venous pressures and azygos blood flow. Cardiac output increased by 20 % (p less than 0.02). This study shows that hemodynamic alterations in patients with refractory ascites is the consequence of increased intraabdominal pressure due to chronic ascites. Six months after peritoneovenous shunting splanchnic and systemic hemodynamics became similar to those observed in patients without ascites.

The prevalence of pulmonary hypertension in 507 patients hospitalized with portal hypertension but without known pulmonary hypertension who underwent cardiac catheterization was prospectively studied. Ten (2%) of these patients, 6 of whom were clinically asymptomatic, had primary pulmonary hypertension. Second, 26 patients with symptomatic pulmonary hypertension complicating portal hypertension were reviewed. Pulmonary hypertension occurred later after diagnosis of portal hypertension in patients with a surgical shunt (10 patients) than in those without a shunt (147 +/- 49 vs. 44 +/- 27 months; P less than 0.0001). Cardiac index correlated inversely with pulmonary arterial pressure (r = -0.45; P less than 0.01) and was lower in the 5 patients who died of pulmonary hypertension than in the 5 who died of liver failure (1.52 +/- 0.14 vs. 3.69 +/- 1.88 L/min.m2; P less than 0.05). Third, systemic and splanchnic hemodynamics were compared in 285 patients with alcoholic cirrhosis and 29 controls. No significant relation was found between elevated pulmonary vascular resistance and increased portal pressure, zzygos blood flow, or cardiac index. Pulmonary hypertension is considerably more frequent than was previously estimated in patients with portal hypertension. The risk of developing pulmonary hypertension could increase with the duration of portal hypertension without any clear relation to the degree of portal hypertension, hepatic failure, or amount of blood shunted.

The effects of ketamine, halothane, enflurane, and isoflurane on systemic and splanchnic hemodynamics in cirrhotic rats that were either normovolemic or hypovolemic following hemorrhage were characterized. Rats received at random either ketamine (30 mg/kg iv, 1.5 mg.kg-1.min-1 iv), halothane, enflurane, or isoflurane (1 MAC). Conscious rats were considered the control group. Four weeks before hemodynamic studies bile duct ligation was performed in all rats to induce cirrhosis. Hemodynamic measurements were performed using the radioactive microsphere method 1 h after the onset of anesthesia and 30 min after hemorrhage. Anesthetized rat lungs were mechanically ventilated with room air. Before hemorrhage cardiac index was higher in conscious rats and in rats receiving isoflurane than in the other groups (P less than 0.001). Hepatic arterial blood flow was similar in conscious rats and in those receiving isoflurane or halothane and was higher than in those receiving ketamine or enflurane. The lowest splanchnic and portal venous tributary blood flows were observed in rats receiving enflurane. After hemorrhage cardiac index was significantly less than before hemorrhage in all groups, except in rats receiving enflurane. After hemorrhage portal venous tributary blood flow decreased significantly in all groups except in enflurane group. During halothane and enflurane anesthesia hepatic arterial blood flow and hepatic arterial fraction of cardiac output decreased (P less than 0.01) and they were maintained in the other groups. After hemorrhage hepatic arterial fraction of cardiac output in conscious rats was higher than in those receiving ketamine, halothane, or enflurane (P less than 0.05) and was similar to those receiving isoflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic and splanchnic haemodynamics were studied in patients with cirrhosis who had been classified in three groups (A, B, and C) according to the degree of liver failure (modified Pugh's classification). In patients of group A, cardiac index was significantly lower than that of group C and systemic vascular resistance was higher, but not significantly so, than that of patients with liver failure. Wedged hepatic venous pressure was significantly lower in the former group than in the latter. In patients in group B, corresponding values fell between those of groups A and C. Azygos blood flow averaged 0.477 +/- 0.242 l/min (mean +/- SD) in group A and it was significantly lower than in groups B and C (0.642 +/- 0.224 and 1.061 +/- 0.476 l/min, respectively). In the three groups, acute administration of propranolol induced statistically significant changes in systemic and splanchnic haemodynamics. In patients of group C but not of group B, the mean value of azygos blood flow after propranolol remained significantly higher than in group A. Moreover, the fraction of azygos blood flow to cardiac output decreased in groups A and B while slightly increased in group C. This study shows that in patients with cirrhosis, the degree of liver failure may be a determinant for the haemodynamic responses to drugs acting on portal hypertension.

Propranolol decreases portal venous pressure in patients with cirrhosis but no method is available in man to study the effect of this beta-blocker on splanchnic organ blood flow. Because in rats, the microsphere method allows evaluation of regional blood flow, the acute effect of propranolol on both splanchnic and systemic circulations was studied in normal rats and in rats with portal hypertension due to portal vein stenosis. Portal venous pressure significantly decreased during propranolol administration in normal (5.6 +/- 1.0-4.7 +/- 1.1 mm Hg; mean +/- SD) as well as in portal hypertensive rats (11.7 +/- 2.3-10.3 +/- 1.8 mm Hg). Propranolol slightly decreased cardiac output and arterial pressure in all rats. Portal tributary blood flow was significantly reduced by propranolol in normal rats (17.4 +/- 3.0-11.3 +/- 2.2 ml/min) and in portal hypertensive rats (23.7 +/- 5.0-16.6 +/- 3.3 ml/min). Accordingly vascular resistance of the different organs in the portal venous territory increased in these rats receiving propranolol. The percentage of the decrease in portal tributary blood flow was significantly more marked than the percentage of reduction in cardiac output in portal hypertensive rats but, in normal rats, these percentages were parallel. Hepatic arterial blood flow did not change or slightly increased and, consequently, hepatic arterial vascular resistance decreased. These findings further clarify the marked effects of propranolol on splanchnic circulation.

The acute effects of 2 doses of the beta-agonist dobutamine on systemic and splanchnic haemodynamics were studied in normal rats and in rats with portal hypertension due to portal vein stenosis. Cardiac output and splanchnic organ blood flow were estimated with the radioactive microsphere method and portal pressure was measured. Low dose (5 micrograms/kg) of dobutamine did not change significantly arterial pressure and portal pressure but, cardiac output was significantly higher after dobutamine than after placebo in both groups of rats. Similar results were observed with 15 micrograms/kg of dobutamine except for a significant decrease in arterial pressure in portal-hypertensive rats. In sham-operated rats, dobutamine significantly increased portal tributary blood flow; this rise was parallel to cardiac output. In contrast, in portal-hypertensive rats, portal tributary blood flow did not change significantly after dobutamine. Accordingly in the former group, portal tributary vascular resistance significantly decreased, whereas in the latter group, no change in this resistance was observed with a low dose and a significant decrease was noted with a high dose. In both groups of rats, hepatic arterial blood flow was not significantly different after dobutamine than after placebo. This study demonstrates that the vasodilatory response of the portal tributary vascular bed to an increase in cardiac output is altered in anaesthetized rats with portal hypertension due to portal vein stenosis.

Although not demonstrated in patients with cirrhosis, it is generally claimed that administration of vasopressin in the form of triglycyl-lysine-vasopressin (glypressin) may prevent untoward systemic effects of this former hormone. The aim of this study was to assess the effects of intravenous administration of 2 mg of glypressin on splanchnic and systemic hemodynamics in 9 patients with cirrhosis under stable circulatory conditions. One hour after the injection, the following statistically significant changes were observed as compared to the baseline values (m +/- SEM): wedged hepatic venous pressure, -9 +/- 2 p. 100; hepatic venous pressure gradient, -16 +/- 3 p. 100; azygos blood flow, -24 +/- 6 p. 100; heart rate, -16 +/- 3 p. 100; cardiac index, -23 +/- 2 p. 100; systemic vascular resistances, +47 +/- 11 p. 100; wedged pulmonary arterial pressure, +44 +/- 15 p. 100. In conclusion, in patients with cirrhosis in a stable hemodynamic condition, intravenous administration of glypressin decreased portal venous pressure and blood flow into the superior portal systemic collateral circulation but did not prevent the untoward systemic hemodynamic effects of vasopressin.

To determine the effect of pentobarbital sodium anesthesia on the rat with portal hypertension due to portal vein stenosis, four groups of rats were studied. Cardiac output and regional blood flow were measured by radioactive microspheres in anesthetized and conscious sham-operated and portal-hypertensive rats. Anesthesia markedly decreased cardiac output in both sham-operated (109.7 +/- 4.6 vs. 77.8 +/- 1.4 ml/min, P less than 0.001) and portal-hypertensive rats (130.1 +/- 7.6 vs. 93.8 +/- 5.3 ml/min, P less than 0.01). In spite of this diminution in cardiac output, pentobarbital did not significantly change absolute blood flow values of splanchnic organs in either group. However, the fractions of cardiac output perfusing the splanchnic organs were significantly increased by pentobarbital in both groups because of the decrease in cardiac output: sham operated, anesthetized, 22.86 +/- 1.19% vs. conscious, 14.83 +/- 1.02%, P less than 0.001; and portal hypertensive, anesthetized, 26.67 +/- 0.71% vs. conscious, 19.07 +/- 1.44%, P less than 0.001. The hyperdynamic circulation of the portal vein-stenosed rat compared with the sham-operated rat continued to manifest itself with significantly increased portal pressure, cardiac output, and splanchnic blood flow, whether the animal was anesthetized or awake. We conclude that, despite marked hemodynamic changes induced by pentobarbital, the rat with portal vein stenosis remains a useful experimental model of portal hypertension.

To elucidate the relationship between the haemodynamic changes and glucagon in cirrhosis, we infused physiologic and supraphysiologic doses of this hormone in conscious rats with portal hypertension due to biliary cirrhosis. Cardiac output and splanchnic organ blood flows were measured by the radioactive microsphere method before and 30 min after glucagon infusion at doses of 2, 5 and 10 ng/min. Serum glucagon increased from a basal level of 92 +/- 17 pg/ml (mean +/- S.E.) to 399 +/- 89, 1151 +/- 136 and 2064 +/- 328 pg/ml, respectively, in sham-operated rats, and from 743 +/- 75 pg/ml to 1497 +/- 197, 1583 +/- 356 and 2957 +/- 649 pg/ml, respectively, in cirrhotic animals at 2, 5 and 10 ng/min doses. In both groups, cardiac output did not change after glucagon infusion at 2 and 5 ng/min doses, suggesting that factors other than glucagon are primarily responsible for the systemic hyperdynamic circulation in cirrhosis. Portal tributary blood flow increased significantly after glucagon infusion in sham-operated rats by 34 and 65% at doses of 5 ng/ml and 10 ng/ml, respectively, and in cirrhotic rats by 29% at a dose of 10 ng/ml. However, portal tributary blood flow did not change after glucagon infusion at the physiologic dose of 2 ng/min. This study shows that glucagon infused at a physiologic dose does not increase splanchnic blood flow, although it increases portal tributary blood flow at supraphysiologic doses. The discrepancy between blood glucagon levels and splanchnic haemodynamic responses suggests that glucagon plays only a minor role and that other factors are primarily responsible for the hyperdynamic state of the splanchnic circulation in rats with biliary cirrhosis.

To delineate the circulatory effects of glucagon in cirrhosis, we infused two moderately supraphysiological doses of this hormone into 19 patients with cirrhosis and determined hemodynamic responses. Patients were divided into a group with good liver function (Pugh Class A, n = 8) and poorer function (Pugh Class B and C, n = 11). All patients received glucagon at 10 ng per kg per min for 20 min, then 20 ng per kg per min for a further 20 min. These doses raised serum glucagon levels to a similar degree in both groups of patients. Serum glucose levels also rose in both groups but to a lesser degree in Class BC patients. Serum noradrenaline and adrenaline remained unchanged in both groups. Heart rate, mean arterial pressure, cardiac index, systemic vascular resistance, hepatic venous pressure gradient and hepatic blood flow were measured basally and during the second glucagon infusion. None of these measurements significantly changed in either group of patients. Azygos and renal venous blood flow were measured basally and during the first and second infusions. Azygos flow increased significantly only in Group A patients: basal, 0.32 +/- 0.03 liter per min; first infusion, 0.40 +/- 0.06 liter per min; second infusion, 0.49 +/- 0.07 liter per min. Corresponding values in Group BC patients were: 0.54 +/- 0.08, 0.54 +/- 0.08 and 0.52 +/- 0.08 liter per min. Renal blood flow did not change significantly. One patient with a portacaval shunt increased superior mesenteric venous flow from 0.78 liter per min to 0.95 liter per min with glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was undertaken to assess splanchnic blood flow in rats with portal hypertension induced by portal vein stenosis. Splanchnic blood flow, estimated by the microsphere method, was significantly higher in portal hypertensive rats than in sham-operated rats: 26.5 +/- 3.9 (mean +/- SD) and 17.5 +/- 3.3 ml/min, respectively (P less than 0.001). Hepatic blood flow, estimated by the clearance method, was significantly lower in portal hypertensive rats than in sham-operated rats: 12.7 +/- 1.1 and 17.3 +/- 2.8 ml/min, respectively (P less than 0.001). It is concluded that splanchnic blood flow is increased in rats with portal hypertension and that hepatic blood flow is different from splanchnic blood flow in these portal hypertensive rats. It is hypothesized that splanchnic blood flow may also be increased in patients with portal hypertension.

Splanchnic organ blood flow and cardiac output were measured by the microsphere method in fasted rats with prehepatic portal hypertension due to portal vein stenosis, in rats with intrahepatic portal hypertension due to bile duct ligation, and in unoperated normal rats. Portal venous pressure was higher in both groups of portal hypertensive rats than in normal rats. Cardiac output was significantly higher in portal hypertensive rats than in normal rats. In rats with portal vein stenosis, splanchnic blood flow was higher than in controls. This increase was caused by increased perfusion of all organs drained by the portal vein, and by increased hepatic arterial blood flow. In rats with bile duct ligation, splanchnic blood flow was not significantly higher than in normal rats: haemoperfusion of all organs contributing to the portal circulation decreased, whereas hepatic arterial blood flow increased. As cardiac output rose similarly, the differences observed between the two types of portal hypertension depend mainly on the difference in distribution of flow within the splanchnic bed.

In animals, there may exist a hyperemic response in the portal circulation during intravenous administration of hypertonic glucose, but a hemodynamic response of this kind has never been described in man. This study was designed to evaluate if hyperglycemia itself could induce systemic or splanchnic hemodynamic changes in patients with cirrhosis. Sixteen patients with cirrhosis were studied before and during i.v. infusions of hypertonic (900 mOsmoles per liter) glucose (n = 8), mannitol (n = 4) or saline (n = 4) at 2 ml per min. In the group receiving glucose, there were significant increases in hepatic venous pressure gradient (+12%), azygos blood flow (+27%) and pulmonary capillary pressure (+32%), while calf blood flow decreased (-26%). No changes occurred in the mannitol or saline groups. Changes in plasma osmolality, plasma volume, splanchnic oxygen extraction and vasoactive hormones, including vasoactive intestinal polypeptide and glucagon, did not appear to be involved in the mechanism of these vasoactive phenomena. It is suggested that the possible deleterious effects of increase in portal pressure and azygos blood flow should be taken into consideration when administering hypertonic glucose to patients with portal hypertension.

High doses of nitroglycerin may decrease portal pressure in patients with cirrhosis with untoward effects such as arterial hypotension and a decrease in systemic O2 uptake. In the present study, low doses of nitroglycerin (7 to 15 micrograms per min, i.v.) were administered in 11 patients with cirrhosis in order to unload cardiopulmonary baroreceptor--one of the possible mechanisms by which nitroglycerin may improve splanchnic hemodynamics--and moreover to avoid deleterious systemic effects. Nitroglycerin significantly decreased right atrial pressure (-35%) and pulmonary wedged pressure (-27%) with significant increase in plasma norepinephrine concentration (+23%), which indicated that cardiopulmonary baroreceptor unloading was achieved. Changes in systemic hemodynamics were slight, although significant, with a decrease in arterial pressure (-8%) and an increase in heart rate (+8%); this indicates a minimal effect on high-pressure baroreflexes. In contrast, no significant change was observed in hepatic venous pressure gradient, hepatic blood flow and azygos blood flow. However, the fraction of cardiac output reaching the azygos system significantly increased by 18%. Plasma renin activity did not change significantly. Moreover, O2 transport and uptake were significantly decreased. These findings show that low doses of nitroglycerin failed to improve splanchnic hemodynamics in patients with cirrhosis. These results suggest an impaired cardiopulmonary baroreflex function which is probably located on the efferent arch.

The acute effects of betaxolol (10 mg, intravenously), a new cardioselective beta-blocker, and propranolol (15 mg, intravenously) on splanchnic and systemic circulations were studied in two matched groups of six patients with portal hypertension due to cirrhosis. Similar decreases in hepatic venous pressure gradient and azygous blood flow--an estimation of superior portosystemic shunts--were observed after both drugs, whereas hepatic blood flow was not modified. The decreases in heart rate and cardiac index were also similar after betaxolol and propranolol. Both drugs induced a significant decrease in the fraction of cardiac output flowing through superior portosystemic shunts. These findings confirm that the marked effect of beta-adrenoceptor blocking agents on splanchnic circulation results both from the reduction in cardiac output and from a vasoconstriction of the portal vein territory, and demonstrate that this vasoconstriction of the portal vein area does not necessitate a beta 2-blocking activity of the drug. The similar efficiency of the two agents in decreasing the hyperkinetic circulation suggests that betaxolol merits further long-term study in the pharmacologic treatment of portal hypertension.

Due to the marked effects of hemorrhage on cardiac output and splanchnic hemodynamics, the circulatory actions of vasopressin may differ during bleeding as opposed to stable conditions. We evaluated this hypothesis in conscious rats with portal hypertension due to chronic portal vein stenosis, by comparing the effects of a vasopressin infusion (0.02 IU per kg per min) to those of a control saline infusion, during and after a hypotensive hemorrhage (25 ml per kg). We also studied unbled portal hypertensive rats receiving an identical infusion of vasopressin or saline. During and after hemorrhage, vasopressin induced significant changes in systemic hemodynamics but had no effect on portal pressure, portal tributary blood flow and nonhepatic splanchnic arteriolar resistance. In unbled animals, by contrast, vasopressin decreased portal pressure and portal tributary blood flow and increased nonhepatic splanchnic arteriolar resistance. Our data further indicate that hemorrhage alone caused an early vasoconstriction in the portal tributaries and a delayed vasoconstriction in the nonsplanchnic vascular bed while vasopressin during hemorrhage induced an early and sustained vasoconstriction in the nonsplanchnic vascular bed as well as in the portal tributaries. The results show that, during and after severe bleeding, vasopressin exerts little influence on portal hemodynamics. Although these data do not allow firm conclusions concerning the therapeutic efficacy of vasopressin in bleeding esophageal varices, they demonstrate that the splanchnic actions of vasoactive substances cannot be readily extrapolated from stable conditions to hemorrhage.

The effect of ascites on splanchnic and systemic hemodynamics was retrospectively studied in 256 patients with alcoholic cirrhosis. The patients were divided into 3 classes: no ascites, moderate ascites, and large ascites. They were also classed into 3 groups according to a modified Pugh classification (ascites was not taken into account). In patients without ascites, cardiac output was positively related to the severity of liver disease. This result was not found in patients with large ascites. Similarly, in patients with no or moderate ascites, the degree of portal hypertension estimated by the hepatic venous pressure gradient was associated with liver failure. In patients with large ascites, hepatic venous pressure gradient was higher than in patients without ascites but this relation was observed only in patients without liver failure. These results show that ascites reduces the relation between cardiac output and liver failure and increases the degree of portal hypertension but not cardiac output.

To determine the reproducibility of splanchnic blood flow measurements by the microsphere method in rats with portal hypertension and the effects of laparotomy with portal vein cannulation, eight groups of 10 rats were studied. Cardiac output and regional blood flows were measured twice, 10 min apart, in pentobarbital anesthetized or awake, sham-operated or portal vein-ligated rats, with or without portal cannulation. Variability between the two successive measurements was not affected by portal hypertension or portal cannulation, and was not different in the splanchnic territory and in other organs. Laparotomy with portal cannulation had no significant effect in sham-operated rats. In awake portal hypertensive rats, cardiac output (53.9 +/- 3.0 vs 45.8 +/- 2.9 ml.min-1.100 g body wt-1, P less than 0.01) and splanchnic blood flow (12.31 +/- 0.72 vs 9.34 +/- 0.85 ml.min-1.100 g body wt-1, P less than 0.01) were lower in portal vein cannulated rats compared with those of non-cannulated animals. In anesthetized portal hypertensive rats blood flows were unaffected by portal cannulation, but arterial pressure (100.2 +/- 4.3 vs 119.9 +/- 3.4 mm Hg, P less than 0.01) and heart rate (366.5 +/- 10.0 vs 405.5 +/- 7.4 beats.min-1, P less than 0.01) were elevated. Anesthesia also decreased portal pressure (14.8 +/- 0.5 vs 12.0 +/- 0.4 mm Hg, P less than 0.05) in portal hypertensive rats. We conclude that the microsphere method remains reproducible in portal hypertensive rat models. Laparotomy with portal cannulation can alter systemic and splanchnic hemodynamics in portal hypertensive rats; these effects can also be changed during pentobarbital anesthesia. Regional blood flow measurements in portal hypertensive rats should be performed in animals without portal cannulation and preferably in the awake state.

The effects of increasing doses of propranolol were studied in awake portal hypertensive rats in order to elucidate the relative effects of the beta-blocker on systemic and splanchnic circulation. Hemodynamic responses to 0.1, 0.2 and 0.4 mg per min infusions of propranolol were compared with placebo in awake rats with portal hypertension due to portal vein stenosis. Heart rate significantly and progressively decreased from 356 +/- 13 to 293 +/- 10 beats per min (mean +/- S.E.). Cardiac output significantly decreased from 54 +/- 3 to 42 +/- 3 ml per min per 100 gm body weight at the highest dose. Significant decrease in portal tributary blood flow from 27 +/- 1 to 18 +/- 1 ml per min, at 0.4 mg per min dose, was due not only to the decrease in cardiac output but also to a significant increase in portal tributary vascular resistance from 269 +/- 17 to 368 +/- 31 dyne per sec per cm5 x 10(3). However, portal pressure showed only an insignificant decrease from 14.9 +/- 1.1 to 14.1 +/- 1.4 mmHg. The reduction in portal pressure being minimal, in spite of a significant decrease in portal tributary blood flow, is explained by an increase in combined hepatic and collateral resistance from 44 +/- 2 to 66 +/- 4 dyne per sec per cm5 x 10(3), p less than 0.05, at 0.4 mg per min dose. We conclude that the systemic and splanchnic effects of propranolol show discrepancy at two levels.(ABSTRACT TRUNCATED AT 250 WORDS)

The splanchnic and systemic haemodynamic effects of mepindolol (0.6 mg, IV), a beta-blocker with a marked beta 2-blockade activity and propranolol (15 mg, IV) were studied in two groups of eight patients with portal hypertension due to cirrhosis. Similar decreases in the hepatic venous pressure gradient were observed after mepindolol and propranolol, whereas hepatic blood flow significantly decreased after mepindolol but did not significantly do so after propranolol. The decreases in cardiac output and heart rate were statistically significant and similar after mepindolol and propranolol. Mepindolol slightly decreased mean arterial pressure and propranolol slightly increased this pressure. Both beta-blockers significantly increased systemic vascular resistance. From these observations, it was not possible to demonstrate that mepindolol offered a beneficial effect on splanchnic haemodynamics in patients with portal hypertension due to cirrhosis.

The radioactive microsphere technique with the reference sample method was used for simultaneous determinations of splanchnic organ blood flow and cardiac output in fed and fasted anesthetized control rats and in rats with portal hypertension due to portal vein stenosis. Portal tributary blood flow was significantly higher in control (27.35 +/- 1.82 versus 14.60 +/- 0.96 ml/min) and in portal hypertensive (25.45 +/- 0.71 versus 20.09 +/- 1.27 ml/min) fed animals than in fasted rats, respectively. This difference was due to an increase in most of the splanchnic organ blood flows expressed in terms of either milliliter per minute or milliliter per minute per gram of tissue. The distribution of the cardiac output to the portal venous territory was also increased in fed animals as compared to fasted rats. In contrast, hepatic arterial blood flow was lower in fed animals than in fasted rats in both groups. Cardiac output was also significantly elevated in fed animals. This study demonstrates that the baseline circulatory state that depends on the digestive condition of these rats must be considered for splanchnic hemodynamic studies.