Hyperdynamic Circulation In Portal Hypertension Research Articles

Oxidative stress triggers hyperdynamic circulation via central neural activation in portal hypertensive rats.

Hyperdynamic circulation in portal hypertension (PHT) depends on central neural activation. However, the initiating mechanism that signals PHT to the central neural cardiovascular-regulatory centers remains unclear. We aimed to test the hypothesis that oxidative stress in the gut initiates the signal that activates central cardiovascular nuclei in portal hypertensive rats. Two groups of rats were used. One had portal hypertension produced by partial portal vein ligation, while controls underwent sham operation. Hemodynamics including portal pressure, cardiac output, mean arterial pressure (MAP) and peripheral vascular resistance were measured. Activation of central cardiovascular nuclei was determined by immunohistochemical Fos expression in the paraventricular nucleus (PVN) of the hypothalamus. Myeloperoxidase activity, an oxidative stress marker, was measured in the jejunum. Hydrogen peroxide, the antioxidant N-acetyl-cysteine (NAC) or saline controls were administered for 12-14days by gavage or osmotic minipumps placed in the peritoneal cavity. Compared with controls, PHT rats showed increased cardiac output (54.2 ± 9.5 vs 33.6 ± 2.4ml/min/100g BW, p < 0.01), decreased MAP (96.2 ± 6.4mmHg vs 103.2 ± 7.8, p < 0.01) and systemic vascular resistance (1.84 ± 0.28 vs 3.14 ± 0.19mmHg/min/ml/100g BW, p < 0.01). PHT rats had increased jejunal myeloperoxidase and PVN Fos expression. NAC treatment eliminated the hyperdynamic circulation, decreased jejunal myeloperoxidase and PVN Fos expression in PHT rats, but had no effect on sham controls. H2O2 significantly increased PVN Fos expression and decreased MAP. These results indicate that in PHT, mesenteric oxidative stress is the initial signal that activates chemoreceptors and triggers hyperdynamic circulation by central neural cardiovascular-regulatory centers.

Systemic and pulmonary hyperdynamic circulation in portal hypertension

Systemic and pulmonary hyperdynamic circulation in portal hypertension

Myocardial late gadolinium enhancement cardiovascular magnetic resonance in patients with cirrhosis.

BackgroundPortal hypertension and cardiac alterations previously described as "cirrhotic cardiomyopathy" are known complications of end stage liver disease (ELD). Cardiac failure contributes to morbidity and mortality, particularly after liver transplantation and transjugular intrahepatic portosystemic shunt (TIPS). We sought to identify myocardial tissue characterization and evaluate cardiovascular magnetic resonance (CMR) for diagnosis of cardiac impairment.ResultsTwenty ELD patients underwent CMR for morphological, functional and tissue characterization by late gadolinium enhancement (LGE). Based on extent of LGE, patients were dichotomized into high and low LGE groups and analyzed regarding liver, cardiocirculatory and renal functions. CMR demonstrated hyperdynamic left ventricular function and a patchy pattern of LGE of the myocardium to a variable extent (range 2-62%) in all patients. There were no significant differences in Model for End-Stage Liver Disease (MELD), Child-Pugh score or the left ventricular ejection fraction between high and low LGE groups. QTc-interval was prolonged in 25% of the patients. E/A ratio was at the upper limit of norm; no difference between groups. Patients showing high LGE had a higher CI (p < 0.05). Biomarkers of myocardial stress were elevated. While NT-proBNP and c-Troponin-T showed no differences, PLGF and sFLT1 were lower in the high LGE group.ConclusionCMR shows myocardial involvement in patients with ELD resembling appearance of myocarditis. The hyperdynamic circulation in portal hypertension may be an important factor. Larger prospective trials are warranted to confirm the association with severity and outcome of liver disease and to test the predictive power of CMR for patients listed for liver transplantation.

Portal Hypertension and Blood Viscosity

Previous studies, exploring the effect of blood viscosity on portal pressure in portal hypertensive humans and animal models, have shown conflicting results. In a series of studies, in portal vein constricted rats, we investigated effects of reduced blood viscosity on the hyperdynamic circulation, portal pressure, and vascular geometry. Blood was withdrawn at a rate of 0.3 mL/min for 15 minutes followed by 15 minutes of stabilization. The shed blood or Haemaccel was infused at the same rate and volume as used for withdrawal. Hemodynamic measurements were performed using radioactive microspheres. Blood viscosity was measured with an Ostwald viscometer. Vascular hindrance (reflecting vessel geometry) was calculated as resistance/viscosity ratio. In normal and portal hypertensive rats, acute volume replacement with Haemaccel, induced increase in systemic and splanchnic blood flows reflecting mainly changes in viscosity and not in blood vessel geometry. However, 24 hours later, in Haemaccel treated animals, an increased splanchnic arteriolar and porto-collateral vascular hindrance were observed. This indicated vasoconstriction in the porto-collateral vascular bed. The increase in portal venous inflow after acute volume restitution with Haemaccel was prevented by pretreatment with propranolol. Although, caution should be taken in extrapolating these results to humans, we would like to speculate that during a portal hypertensive-related bleeding episode: (1) volume replacement with low viscosity plasma expanders may aggravate the hyperdynamic circulation of portal hypertension. (2) Slow rate volume replacement enables hemodynamic adaptation to occur. (3) Volume replacement maybe more safe in a subject pretreated with propranolol.

Endothelial nitric oxide synthase is not essential for the development of fibrosis and portal hypertension in bile duct ligated mice

It is postulated that nitric oxide (NO) is responsible for the hyperdynamic circulation of portal hypertension. Therefore, we investigated induction of fibrosis and hyperdynamic circulation in endothelial NO synthase knock-out (KO) mice. Fibrosis was induced by bile duct ligation. Hemodynamic studies were performed after portal vein ligation. All studies were performed in wild-type (WT) and KO mice. Three to 4 weeks after bile duct ligation (BDL), both WT and KO groups had similar degrees of portal hypertension, 12 (9-14) and 11(8-15) mmHg, median (range), and liver function. Fibrosis increased from 0.0% in sham operated to 1.0 and 1.1% in WT and KO mice, respectively. Cardiac output was similar after portal vein ligation (20 and 17 ml/min in WT and KO mice, respectively). There was no difference in liver of mRNA for endothelin 1, inducible NO synthase (iNOS) and hem-oxygenase 1 (HO1); proteins of iNOS, HO1 and HO2; nor in endothelin A and B (EtA and EtB) receptor density between WT and KO mice after BDL. These results suggest that endothelial NO synthase is neither essential for the development of fibrosis and portal hypertension in bile duct ligated mice, nor for the hyperdynamic circulation associated with portal hypertension in the portal vein ligated mice.

Up-regulation of nNOS and associated increase in vasorelaxation in superior mesenteric arteries in portal hypertension

Splanchnic arterial vasodilatation is the pathophysiological hallmark in the development of the hyperdynamic circulation in portal hypertension. This has been attributed largely to vascular NO overproduction. Three NO-synthase-(NOS)-isoforms have been identified of which e(ndothelial)-NOS has been found up-regulated and I(nducible)-NOS not expressed in the splanchnic circulation in portal hypertension. N(euronal)-NOS so far has not been investigated and hence, the current study evaluates in a model of portal vein-ligated rats (PVL) nNOS-expression and nNOS-mediated vasorelaxation. Methods: Mesenteric vasculature of PVL and sham rats was stained for nNOS immunohistochemically and analyzed for nNOS-protein level by western blots. In-vitro perfused de-endothelialized mesenteric arterial vasculature were preconstricted with norepinephrine (EC80) and tested for nNOS-mediated vasorelaxation by periarterial nerve stimulation (PNS, 2–12 Hz, 45V) before and after incubation with the NO-inhibitor L-NAME (10-4 M). Results: nNOS was localized to the adventitia of the mesenteric arterial tree showing more intense staining in PVL as compared to sham rats. Correspondingly, nNOS protein expression was markedly up-regulated in mesenteric arteries in PVL rats. PNS induced a frequency-dependent vasorelaxation which was more pronounced in PVL rats (Fig.1A). This difference in nerval-mediated vasorelaxation was abolished by incubation with L-NAME (Fig.1B). The effect of NO-inhibition on vasorelaxation, representing nNOS-mediated vasorelaxation, was significantly greater in PVL rats than in sham animals (Fig.1C). Conclusion: Perivascular nNOS protein expression is enhanced in mesenteric arteries in portal hypertension mediating an increased nerval NO-mediated vasorelaxation. This nNOS-derived NO overproduction may play an important role in the pathogenesis of arterial vasodilation and hyperdynamic circulatory syndrome in portal hypertension.

Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats.

To examine the participation of HSP90 in portal hypertensive rat mesentery in vitro. Immunohistochemistry and Western-blot were used to examine the expression of HSP90 in mesenteric vasculature. HSP90 mRNA was detected by RT-PCR, and the role of HSP90 in hyperdynamic circulation was examined by in vitro mesenteric perfusion studies. HSP90 was overexpressed in endothelium of mesentery vasculature in animals with experimental portal hypertension induced by partial portal vein ligation (PVL) compared with normal animals. Geldanamycin (GA), a special inhibitor of HSP90 signaling, attenuated ACh-dependent vasodilation but did not affect vasodilation in response to sodium nitroprusside in normal rats. In PVL animals, the perfused mesentery was hyporesponsive to vasoconstrictor methoxamine. GA significantly potentiated methoxamine-induced vasoconstrictor after PVL. HSP90 plays a key role in NO-dependent hyperdynamic circulation in portal hypertension and provides a novel method for future treatment of portal hypertension.

Bile acids stimulate adrenomedullin production in rat aorta: a novel mechanism contributing to hyperdynamic circulation in portal hypertension

Bile acids stimulate adrenomedullin production in rat aorta: a novel mechanism contributing to hyperdynamic circulation in portal hypertension

Hyperdynamic circulation in portal hypertension: a comparative model of arterio-venous fistula

Complications of portal hypertension remain perplexing physiologic phenomena in the understanding of shunt hemodynamics with multiple theories. Hyperdynamic circulation was also found in sepsis, chronic anemia and arterio-venous (A-V) fistula which relate to an increase in nitric oxide. We hypothesize that portosystemic collaterals may mimic an A-V fistula in which the high-pressure portal blood connects with the lower pressure systemic venous circulation. Although these collaterals decompress the portal circulation, a number of secondary hemodynamic phenomena occur which increase portal blood flow and tend to counteract the portal hypotensive effect of the portosystemic shunt. The consequent increases in cardiac output and portal blood flow perfuse the compromised liver. As portal blood flow increases, collateral flow increases and is nearly totally shunted in the systemic circulation. This shunt may eventually introduce a vicious cycle of hyperdynamic circulation into a compromised host. Ultimately, high-output cardiac failure occurs, leading to cirrhotic cardiomyopathy.

A selective cyclo-oxygenase-2 inhibitor, NS-398, may improve portal hypertension without inducing gastric mucosal injury.

Prostacyclin has been shown to play a role in hyperdynamic circulation in portal hypertension. Recently, a new subtype of cyclo-oxygenase (COX), COX-2, which acts as an inducible synthase in response to various stimuli. The aim of this study was to investigate whether COX-2 contributes to portal hypertension and whether a COX-2 blockade induces the same sort of gastric mucosal injury as a COX-1 blockade. Portal hypertension (PHT) in rats was induced by a two-step ligation of the portal vein. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), serum levels of 6-keto-prostaglandin F1alpha (PGF1alpha), thromboxane B2 (TXB2) and gastric mucosal injury induced by pure ethanol were all measured in PHT rats receiving different inhibitors (indomethacin, a highly selective COX-1 inhibitor; NS-398, a highly selective COX-2 inhibitor). Control rats treated by a sham operation were also studied. The NS-398 administration significantly decreased PP to the same extent as indomethacin at doses of 5 and 10 mg/kg in PHT rats after a 60 min administration, while neither inhibitor affected the control rats. Both inhibitors significantly increased PP after a 30 min administration in the PHT and control rats at a dose of 5 mg/kg while both inhibitors significantly decreased PP after 60 min administration only in the PHT rats. Portal vein ligation treatment induced a significant increase in PP and BFV of the portal vein, gastric mucosa, oesophageal mucosa and the serum levels of 6-keto-PGF1alpha and TXB2, while portal vein ligation treatment induced a significant decrease in BFV of the liver. Both blockades increased MAP and decreased PP and BFV in the splanchnic area and decreased the serum level of 6-keto-PGF1alpha and TXB2 in the PHT rats, while neither blockade modified any parameters in the control rats, except that indomethacin administration significantly decreased the BFV of the gastric mucosa. Indomethacin administration significantly increased the ulcer index (UI). The NS-398 had no effect on UI in either the PHT or control rats. Only indomethacin significantly increased the number of rats demonstrating gastric mucosal long lesions (> 2 cm) in the PHT rats. In the PHT rats, prostaglandin seemed to contribute to portal hypertension. Both COX blockades reduced PP and BFV of the portal vein and gastric mucosa. NS-398, a selective COX-2 inhibitor, may, therefore, improve portal hypertension without inducing gastric mucosal injury.

Enhanced release of nitric oxide in response to changes in flow and shear stress in the superior mesenteric arteries of portal hypertensive rats.

Increased nitric oxide (NO) release has been implicated in the pathogenesis of the hyperdynamic circulation in portal hypertension. NOS 3 (eNOS) causes NO release from the endothelium in response to physical stimuli, such as increased blood flow and shear stress. We evaluated the functional activity of the endothelium in the superior mesenteric arterial bed of portal hypertensive rats through direct measurement of NO metabolites (NOx) during changes in flow and shear stress. The in vitro perfusion system (McGregor) was used in sham and portal vein-ligated (PVL) rats. Shear stress was applied gradually to superior mesenteric arterial beds by increasing the perfusion rate. Flow studies were performed serially before and after incubation with either Krebs solution alone or with the NO-inhibitor, NG-monomethyl-L-arginine (L-NMMA). NOx concentrations in the perfusate were measured using chemiluminescence. The slope of NOx release versus flow-induced shear stress was calculated. Before L-NMMA administration, NOx concentrations and release of NO in PVL rats were significantly elevated in comparison with sham rats at flow rates of 32, 40, and 48 mL/min. The slope of NOx production versus shear stress index was significantly higher in PVL than in sham rats. After L-NMMA incubation, the decrease in slope was significantly larger in PVL rats. This study provides direct evidences of an increased NO synthesis by the superior mesenteric arterial vascular endothelium of PVL animals in response to shear stress. The increased NO output in response to shear stress suggests an adaptative mechanism developed by the vascular endothelial cells in response to a chronic increase in flow-mediated shear stress.

Recent advances in the pathophysiology of portal hypertension.

Portal hypertension is a common complication of chronic liver disease. Increased resistance to portal blood flow through a cirrhotic liver initiates the development of portal hypertension. In addition, alteration of neural and humoral regulations, endothelins, and stellate cells all contribute to the increased intrahepatic resistance. Moreover, the collateral circulation represents an additional site of increased resistance to portal blood flow. Increased splanchnic blood flow appears to play an important role in the maintenance of chronic portal hypertension. Several mechanisms have been proposed to explain this haemodynamic derangement including increased circulating vasodilators, endothelial-derived vasodilators, and decreased vascular reactivity to vasoconstrictors. Finally, the development of portal hypertension induces peripheral arterial vasodilation. The arterial vasodilatation may result in an increase in vascular underfilling which in turn leads to sodium retention and plasma volume expansion. The increased plasma volume is necessary for the development of increased cardiac output and the full expression of hyperdynamic circulation in portal hypertension.

Tumor necrosis factor-alpha regulates inducible nitric oxide synthase gene expression in the portal hypertensive gastric mucosa of the rat

Increased expression of both nitric oxide synthase (NOS) and tumor necrosis factor-alpha (TNF-α) have been implicated in the hyperdynamic circulation of portal hypertension. Since overexpression of these proteins would affect gastric mucosal defenses, which are impaired in portal hypertension, we examined the expression and interrelationships of TNF-α and NOS in the gastric mucosa of portal hypertensive rats. Following staged portal vein ligation, gastric strips from portal hypertensive rats were incubated in organ culture medium with or without TNF-α antibody. The expression of TNF-α and NOS mRNAs was assessed by reverse transcription—polymerase chain reaction (RT-PCR) at baseline and after 1, 2, and 6 hours of incubation. RT-PCR demonstrated a threefold increase in inducible NOS mRNA and a 50% increase in TNF-α mRNA expression at baseline in portal hypertensive animals as compared to sham-operated animals. In tissue incubated with TNF-α neutralizing antibody, inducible NOS mRNA expression was significantly decreased by 40%, 70%, and 80% after 1, 2, and 6 hours, respectively. Since increased TNF-α and NOS production could potentially impair gastric mucosal defenses, our findings suggest a major role for these proteins in the development of portal hypertensive gastropathy.

The Hemodynamic Effects of AT-112, an Analog of Ketanserin, in Portal Hypertensive Rats

A serotonin mechanism has been reported to contribute to the hyperdynamic circulation of portal hypertension. Different studies have demonstrated that serotonin antagonists decrease portal pressure in portal hypertensive patients and animals. The present study was undertaken to investigate the effect of AT-112, an analog of ketanserin, on portal hypertension induced by partial portal vein ligation in rats. Since ketanserin is known to possess alpha 1-adrenergic antagonistic activity, the effect of AT-112 was compared to that of prazosin. A single dose (prazosin 4.2 micrograms/kg, AT-112 1 mg/kg) was chosen to produce a similar hypotensive effect (-20 +/- 4% for prazosin and -24 +/- 4% for AT-112). At this dose, prazosin significantly decreased total peripheral resistance whereas AT-112 significantly decreased cardiac index and heart rate. Both agents significantly decreased the portal tributary blood flow and portal pressure. In rats receiving AT-112, a significant correlation was found between the magnitudes of decrease in cardiac index and the decrease in portal tributary blood flow. We also found that the magnitude of reduction in portal pressure was greater following AT-112 administration. This study suggested that AT-112 may have more beneficial hemodynamic effects than prazosin in portal hypertensive rats. Our results provide further support for the serotonergic mechanism in the pathogenesis of hyperdynamic circulation in portal hypertension.

Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats

Background/Aim: Portal hypertension is characterized by splanchnic hyperemia due to a reduction in mesenteric vascular resistance. Mediators of this hyperemia include nitric oxide. This is based on several reports indicating a marked splanchnic hyporesponsiveness in portal hypertension to vasoconstrictor stimuli both in vitro and in vivo, and a subsequent reversal using specific inhibitors of nitric oxide synthase. The objective of this study was to determine firstly whether the functional activity and/or expression of nitric oxide synthase is altered in portal hypertensive vasculature and secondly which isoenzyme form was responsible for the preferential response to nitric oxide blockade in these animals. Methods: We compared nitric oxide synthase functional activity in the hyperemic vasculature of sham and portal hypertensive rats (following partial portal vein ligation). Nitric oxide synthase activities were determined by measuring the conversion of L-arginine to citrulline using ion-exchange chromotagraphy and the amount of immunodetectable nitric oxide synthase in sham and portal hypertensive vessels was determined by Western blot. Results: Ca 2+-dependent nitric oxide synthase activity was significantly elevated ( p<0.05) in portal hypertensive particulate fractions from the superior mesenteric artery, thoracic aorta and portal vein. Vascular tissue cGMP levels and plasma nitrite levels were both significantly elevated in portal hypertension. Immunodetection with specific antisera raised against the inducible nitric oxide synthase demonstrated a lack of induction within the hyperemic vasculature. Immunodetection with antisera against endothelial nitric oxide synthase showed a significant increase in portal hypertensive portal vein only. These results demonstrate enhanced calcium-dependent nitric oxide synthase activity in portal hypertension hyperemic vessels concurrent with elevated tissue cGMP levels. Conclusion: We conclude that enhanced endothelial nitric oxide synthesis may in part contribute to the hyperdynamic circulation of portal hypertension.

The role of inducible no synthase (iNOS) in the hyperdynamic circulation of portal hypertension

The role of inducible no synthase (iNOS) in the hyperdynamic circulation of portal hypertension

Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Background/Aims Excessive nitric oxide biosynthesis caused by expression of inducible NO synthase has been implicated in the hyperdynamic circulation of portal hypertension. The aim of the study was to investigate whether inducible NO synthase is expressed in portal hypertension and accounts for the hyperdynamic circulation. Methods In study 1, NO synthase activities were measured by the conversion of l-arginine to citrulline in tissues from portal-hypertensive, cirrhotic, and sham-operated rats and from normal rats pretreated with endotoxin and after long-term administration of dexamethasone, which inhibits the expression of inducible NO synthase. In study 2, systemic and splanchnic hemodynamics (radiolabeled microspheres) and gastric blood flow (hydrogen gas clearance and reflectance spectrophotometry) were measured in portal-hypertensive rats after long-term administration of dexamethasone (0.25 mg·kg −1·day −1) or vehicle. Results In study 1, constitutive and inducible NO synthase activities in portal-hypertensive or cirrhotic rats were similar to those observed in sham-operated rats. The significant increase in the inducible activity observed after endotoxin injection was prevented when rats received long-term treatment with dexamethasone. In study 2, cardiac index, portal-pressure, portal venous inflow, and gastric blood flow were similar in dexamethasone or vehicle-treated portal-hypertensive rats. Conclusions These results do not support a role for an increased expression of the inducible NO synthase in the hyperdynamic circulation of portal hypertension.

Role of prostacyclin in hemodynamic alterations in conscious rats with extrahepatic or intrahepatic portal hypertension

Although prostaglandins are thought to be involved in the hyperdynamic circulation of portal hypertension, the role of this substance has not been elucidated. Dose-response curves, the hemodynamic effects of prostacyclin (20 micrograms/kg) and its inhibitor indomethacin and measurements of plasma and urinary levels of 6-keto-prostaglandin F1 alpha were compared in three groups of six rats each: normal, with portal vein stenosis and with secondary biliary cirrhosis. Plasma and urinary levels of 6-keto-prostaglandin F1 alpha were higher in rats with portal vein stenosis and cirrhotic rats than in normal rats. Dose-response curves showed similar maximal decreases in arterial pressure in the three groups, whereas the maximal increase in portal pressure was less marked in cirrhotic rats than in normal rats and rats with portal vein stenosis. In normal rats, prostacyclin increased cardiac output by 21% and portal pressure by 41%. Similar increases were observed in rats with portal vein stenosis. In contrast, prostacyclin did not affect cardiac output and portal pressure in cirrhotic rats. Indomethacin induced a more marked vasoconstrictive effect in normal rats than in cirrhotic rats. This study shows that prostacyclin plays a role in the hemodynamic alterations in portal hypertension. Moreover, the hyporeactivity observed in cirrhotic rats suggests that prostacyclin plays a major role in the circulatory changes of portal hypertension due to chronic liver disease.

Capsaicin treatment blocks development of hyperkinetic circulation in portal hypertensive and cirrhotic rats.

To investigate a possible role of primary afferent innervation in the pathogenesis of hyperkinetic circulation in cirrhosis or portal hypertension, we used capsaicin to denervate the primary afferent nerves. Rat pups were injected with capsaicin (50 mg/kg) or a vehicle and were allowed to grow. When they reached young adulthood, operations to induce portal hypertension by portal vein stenosis or cirrhosis by bile duct ligation were performed. A control group had sham operation. Cardiac output and regional blood flows were measured in unrestrained conscious rats by radioactive microspheres. Capsaicin-treated portal hypertensive and cirrhotic rats had cardiac output and systemic vascular resistance similar to sham-operated rats, whereas the vehicle-treated portal hypertensive and cirrhotic rats showed the hyperkinetic circulation. No hemodynamic effect of capsaicin on sham-operated rats was detected. Capsaicin-treated rats did not demonstrate a splanchnic or renal hyperemia, but the percentage of cardiac output in these vascular beds was similar to controls. These results suggest that capsaicin treatment blocked the generalized vasodilatation in cirrhotic and portal hypertensive rats. Arterial pressure and heart rate were not modified in any group. These results show that denervation of capsaicin-sensitive primary afferent nerves in cirrhotic and portal hypertensive rats blocked the expected development of hyperkinetic circulation. We conclude that primary afferent innervation may be important in the genesis of hyperdynamic circulation in portal hypertension and cirrhosis.

Nitric oxide and hyperdynamic circulation in portal hypertension.

ABSTRACT 1 The effects of inhibiting endogenous nitric oxide (NO) synthesis with NG–monomethyl–L–arginine (L–NMMA) on the systemic and splanchnic circulation have been investigated in rats with experimental chronic portal hypertension, anaesthetized with ketamine. 2 Portal hypertension was induced by partial portal vein ligation, 2 weeks prior to study. This procedure induced a reduction in systemic arterial blood pressure (MAP), an increase in cardiac output as measured by radiolabelled microspheres, a reduction in peripheral and splanchnic vascular resistance and an increased portal venous inflow (PVI) and portal pressure, as compared to control non–ligated rats. 3 l–NMAA (6.25 and 50 mg kg-1, i.v.) dosedependently increased MAP, reduced cardiac output and PVI, and increased peripheral and splanchnic vascular resistance. With l–NMMA (50 mg kg-1), PVI and the vascular resistances returned to values comparable to those determined in control non–ligated anaesthetized rats under resting conditions. 4 Porto–collateral resistance was also increased by these doses of l–NMMA, whereas portal pressure was unchanged. The increase in renal blood flow and decrease in renal vascular resistance also seen in portal–hypertensive rats was reversed by l–NMMA (50 mg kg-1). 5 These effects of l–NMMA (50 mg kg-1) were inhibited by prior administration of l–arginine (300 mg kg-1, i.v.). 6 These findings indicate that the chronic hyperdynamic circulatory characteristics following portal vein stenosis can be attenuated by l–NMMA. Thus, the excessive formation of endogenous NO may be implicated in the pathogenesis of the haemodynamic disturbances and splanchnic vasodilatation associated with chronic portal hypertension.