Portal Pressure Blood Research Articles

Blood pressure and hepatocellular effects of the cyclic heptapeptide toxin produced by the freshwater cyanobacterium (blue - green alga) Microcystis aeruginosa strain PCC-7820

Laboratory rats and mice were used to investigate the hepatotoxicity caused by the cyclic heptapeptide (mol. wt 994) termed microcystin-LR. Microcystin-LR (also known as cyanoginosin-LR) is produced by the freshwater cyanobacterium (blue - green alga) M. aeruginosa strain PCC-7820. In time course histopathology studies with mice significant liver damage, with an absence of pulmonary emboli, were observed after 15 min. Pulmonary emboli did not appear until 1 hr. In rats, significant liver damage and the presence of occasional emboli were observed at 20 min. Pulmonary emboli did not contain fibrin nor appear life-threatening in any case and resembled the globular eosinophilic debris found in the liver sinusoids and central veins. Measurements of rat femoral arterial, jugular venous and hepatic portal venous blood pressures during the course of toxicity revealed a slowly declining arterial pressure and stable, normal venous pressures. Blood lactic acid levels rose in parallel with the fall in arterial pressure, a pattern typical of hemorrhagic shock. There was no indication of venous congestion that would accompany right heart failure. Isolated, perfused rat livers dosed with toxin showed rapid changes in the liver, including cessation of bile flow within 10 min and complete obliteration of normal lobular architecture within 60 min. No effect of the toxin was observed in isolated perfused rat heart. We conclude that in the mouse and rat, microcystin-LR is a potent, rapid-acting, direct hepatotoxin, with the immediate cause of death in acute toxicities being hemorrhagic shock secondary to massive heptocellular necrosis and collapse of hepatic parenchyma.

Physiological effects of portal ligation on the longitudinal and circular muscles of the dog portal tree.

We studied physiological effects of portal vein ligation on the longitudinal and circular muscles of the dog portal tree. Portal venous blood pressure after portal ligation was higher in dogs that died than in those that survived. The portal veins isolated from dogs that died after portal ligation exhibited both lower rate of onset and decreased intensity of spontaneous activity, compared with those from dogs that survived. Responsiveness of longitudinal muscles of each of the four portal segments to noradrenaline, acetylcholine, histamine and KCl was markedly reduced in dogs that died, compared with those that survived, although the responsiveness of circular muscle was nearly equal in both groups of dogs. The longitudinal muscle of the truncal portal vein from dogs that died responded less strongly to electrical transmural stimulation than that from surviving dogs. The nonadrenergic, noncholinergic response was almost abolished in dogs that died rapidly. The degree of spontaneous activity or responsiveness to various stimulations in smooth muscles of the portal tree is considered to reflect muscular development. The degree of development of the longitudinal muscle of the portal tree may determine the survival of dogs after portal ligation.

Characteristics of contractile response of isolated portal veins from chronic portal hypertensive rats under altered levels of external K+, Ca2+, and norepinephrine concentrations: a comparison with normal Wistar rats.

We studied contractile properties of portal veins isolated from chronic portal hypertensive rats (PHR) resulting from liver cirrhosis, a model obtained by repeated subcutaneous injections of CCl4 (2 mg/kg) twice weekly for over 45 weeks. Portal venous pressure in vivo was significantly higher in PHR (167.0 +/- 38.7 mmH2O) than in the control normal Wistar rats (NWR) (102.0 +/- 25.5 mmH2O). A pair of portal veins from PHR and NWR were mounted longitudinally in an organ bath and perfused with Tyrode's solution with different K+, Ca2+, and norepinephrine concentrations. The isometric tension was measured by a strain-gauge. Under control conditions, spontaneous phasic contractile force, corrected by cross-sectional area, was greater, and the frequency was lower in PHR than in NWR preparations. The averaged peak contractile force measured at different [K]o (5.4-86.4 mM) was also greater in PHR than in NWR. Force of the tonic contraction measured at different [Ca]o (0.45-5.4 mM), under conditions of 86.4 mM [K]o was significantly larger in PHR than in NWR preparations. However, the Ca2+ sensitivity of both preparations was the same. D-600 (greater than or equal to 0.1 microM) inhibited the tonic contraction in both preparations with an identical sensitivity to the drug. In the presence of norepinephrine (10 microM), the Ca2+ sensitivity of the tonic contraction increased both in PHR and NWR preparations. The increase was more pronounced in PHR and was completely reversed in the presence of the alpha 1-adrenoceptor blocker, prazosin (0.1 microM). The alpha 1-adrenoceptor sensitivity to norepinephrine was not altered in PHR preparations. The rate of Ca2+ release and uptake of intracellular Ca2+ seemed identical in both preparations. Thus, in the absence of norepinephrine, the phasic and tonic contractile forces of portal veins from PHR are larger than that of NWR, probably due to increased membrane Ca2+ permeability. The PHR preparations have a higher affinity for external Ca2+ in the presence of norepinephrine, an additional factor contributing to elevation of portal blood pressure in the presence of chronic liver cirrhosis.

Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients.

Different and contradictory results concerning the use of propranolol in the treatment of portal hypertension have been reported. This study was designed to investigate the hemodynamic effects of short- and long-term administration of propranolol in portal hypertensive patients. Portal pressure, cardiac index, heart rate and blood pressure were obtained in 18 unselected alcoholic cirrhotic patients with esophageal varices before and 60 min after the oral administration of 40 mg propranolol and again after 106 +/- 35 days of continuous oral administration (mean dose = 158 +/- 63 mg per day). Baseline portal pressure was 21.7 +/- 7.2 mm Hg. It decreased after 60 min to 17.2 +/- 5.5 mm Hg (p less than 0.01) and after long-term administration of propranolol to 16.1 +/- 5.7 mm Hg (p less than 0.01). No decrease in portal pressure was noted in 9 of 18 (50%) patients after acute administration and 5 of 17 (30%) patients after long-term administration. Baseline cardiac index was 5.1 +/- 1.2 liters X min-1 X m-2. It decreased after 60 min to 3.9 +/- 1.4 liters X min-1 X m-2 (p less than 0.01) and to 3.6 +/- 1.0 liters X min-1 X m-2 after long-term administration (p less than 0.001). Baseline heart rate was 85 +/- 11 beats per min. It decreased after 60 min to 75 +/- 9 (p less than 0.001) and after long-term administration to 62 +/- 6 (p less than 0.001) beats per min. Baseline mean arterial pressure was 108 +/- 11 Hg. It decreased after 60 min to 97 +/- 14 mm Hg (p less than 0.01) and after long-term administration to 103 +/- 14 mm Hg (not statistically significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandins in Diagnostic and Therapeutic Superior Mesenteric Artery Pharmacoangiography

The hemodynamic effects of prostaglandins PGA1, PGE1, PGE2, and PGF2 alpha on the splanchnic circulation were evaluated in five chronic dogs with portal hypertension, periportal fibrosis, and portosystemic venous shunting. The maximum effect was achieved with dosages of 2 micrograms/kg/min after bolus injection into the superior mesenteric artery. With this dosage a monophasic increase of portal blood flow and pressure was found with PGA1, PGE1, and PGE2, whereas PGF2 alpha caused a biphasic response: an initial decrease in portal blood flow and pressure was followed by an increase in these parameters. The average peak increase in portal blood flow and pressure was similar for PGE1 and PGF2 alpha, and significantly smaller for PGA1 and PGE2. Average peak iodine concentrations in the portal blood after superior mesenteric angiography were highest with PGF2 alpha, similar for PGE1 and tolazoline, and lowest in controls. The vasoconstrictor effect of PGF2 alpha is, overall, reduced and less reproducible when compared with vasopressin. This investigation suggests that both PGE1 and PGF2 alpha are effective for improved arterial portography, the latter agent appearing superior. On the other hand, PGF2 alpha cannot be recommended as a therapeutic agent for the treatment for gastrointestinal and particularly variceal bleeding.

Circulatory actions of vasopressin in anaesthetized rats with portal hypertension subjected to haemorrhage

To assess the influence of vasopressin on splanchnic and renal circulatory changes induced by haemorrhage in portal hypertension, we studied 4 groups of 7 rats with chronic portal vein stenosis. Two groups received saline (C and H) and two groups vasopressin, 0.01 IU/kg/min (VP and VP-H). Ten minutes after starting drug infusion, group H and VP-H animals were allowed to bleed from the superior mesenteric vein. Both haemorrhage and vasopressin alone, decreased portal venous tributary blood flow and pressure but their association was not additive (as reflected by comparable bleeding rate in groups H and VP-H). By contrast, vasopressin increased renal perfusion in bleeding and non-bleeding animals whereas haemorrhage alone decreased renal perfusion. These results indicate that the effects of vasopressin on the splanchnic circulation in bleeding anaesthetized animals differ from the effects observed when blood volume is normal. Therefore, in patients with cirrhosis the effects of vasopressin during bleeding might also differ from those observed in patients in stable condition.

Hemodynamic actions of nicotine on the canine stomach.

Acute effects of nicotine were determined in the circulation of the stomach in which measurements of gastric blood flow, systemic arterial and portal venous blood pressures, and the arteriovenous oxygen content difference were made. From these measurements gastric vascular resistance and oxygen consumption were calculated. Nicotine was infused for 10-min periods in two doses intraarterially (ia) and intravenously (iv) alone and following adrenergic receptor blockade with either propranolol or phentolamine or both agents. With ia nicotine alone, gastric blood flow and oxygen consumption increased. The effect of nicotine on blood flow was enhanced by prior treatment with phentolamine. The effects of nicotine on both blood flow and oxygen consumption were abolished in the presence of combined phentolamine plus propranolol. With iv nicotine alone, gastric blood flow, oxygen consumption, and arterial pressure increased transiently. Phentolamine enhanced the effect of nicotine on oxygen uptake and prevented the pressor response. Propranolol enhanced the pressor effect of nicotine but abolished the blood flow and oxygen consumption responses. Combined treatment with both adrenergic antagonists abolished nicotine effects on blood flow and oxygen consumption. These findings indicate that nicotine alters gastric hemodynamics and oxygen consumption during acute intravascular infusions of the drug. The vasodilator and metabolic effects of nicotine appear to be mediated via beta-adrenergic receptors. These findings provide little basis for implicating a local ischemic mechanism in the ulcerogenic effects of nicotine on the stomach.

Evaluation of topical phenol as a means of producing autonomic denervation of the liver.

Topical application of 90% phenol around the bile duct, portal vein, and hepatic artery, as well as along each of the three hepatic ligaments was tested for effectiveness of rapid and chronic denervation in cats. Because phenol produces nonselective nerve degeneration, it was assumed that proof of functional sympathectomy was adequate proof of disruption of parasympathetic and afferent nerves as well. Functional sympathetic neurons were evaluated by measuring physiological responses to direct electrical stimulation of the anterior hepatic plexus. Acute or rapid denervation was assessed by the degree of rise in portal blood pressure produced by nerve stimulation. Complete denervation appeared within 20 min and was still present by 80 min postapplication. Chronic denervation was tested by applying the phenol and recovering the cats for 6-14 days. An equal number (n = 6) of sham-denervated cats were compared. Phenol denervation did not alter basal glucose, insulin or glucagon levels, hematocrit, blood pressure, or hepatic glycogen levels. These variables are a good index of stress and metabolic status. Nerve stimulation in the chronic sham group raised portal pressure, arterial pressure, and blood glucose levels, whereas the chronic-denervated group showed no responses. The health of the two groups appeared normal with the sole difference being that the painted tissues were mildly discolored and more adhesions appeared in the phenol-denervated set. Thus phenol is a useful tool for producing hepatic denervation. It is less traumatic, faster, and more certain than surgical denervation. In addition, the hepatic lymphatics can be preserved using the topical application of phenol.

Acute portal hypertension after gastric administration of ethanol in the pig.

A single gastric administration of 15 ml/kg of 40% ethanol to anesthetized pigs resulted in an increased portal venous blood pressure which increased with increasing blood alcohol levels. For the first 2 h there was no significant alteration in liver blood flow, but 3 h after the administration of ethanol, when portal blood pressure reached its highest values, liver blood flow had decreased. This was probably caused by increased hepatic vascular resistance as shown in electron thin-section phase-contrast microscopy which at this time showed marked hepatocyte swelling, narrowing of the sinusoids and platelet aggregates in small portal branches.

Gallbladder wall thickening: patients without intrinsic gallbladder disease.

Retrospective analysis of 22 patients with increased gallbladder wall thickness (4--10 mm) in the absence of gallbladder disease revealed that 19 were hypoalbuminemic (albumin less than 3.6 g/dl). To test the hypothesis that hypoalbuminemia was a causal factor, gallbladder wall thickness was measured in 40 patients selected prospectively solely on the basis of hypoalbuminemia. This group was compared to 25 normal volunteers. Hypoalbuminemic patients had significantly thickened gallbladder walls compared to volunteers (p less than 10(-9)). This thickening was associated not only with hypoalbuminemia, but also with increased main portal vein diameter, which reflects portal venous blood pressure. Gallbladder wall thickening unrelated to intrinsic gallbladder disease seems to be influenced by the same parameters as ascites formation--plasma colloid oncotic pressure and portal venous pressure.

Relationship between acquired resistance, portal hypertension, and lung granulomas in ten strains of mice infected with Schistosoma mansoni.

Pronounced differences in resistance to reinfection and pathology were observed among various strains of mice infected with Schistosoma mansoni. When comparing strains, the level of resistance induced by a 12-week infection correlated closely with the degree of portal blood pressure elevation and number of lung egg granulomas, but did not correlate with other pathological parameters or with the number of worms or tissue eggs. Among individual mice of the same strain, however, resistance was proportional to the number of worms and tissue eggs. Nmri strain mice infected for more than a year remained highly resistant to reinfection and continued to shunt eggs into the lungs, but showed considerable resolution of portal hypertension, hepatomegaly and splenomegaly. No association was observed among mouse strains between the mortality resulting from a primary infection and the severity of any of the pathological parameters which were measured.

Effect of stimulation of hepatic nerves on hepatic O2 uptake and blood flow.

Acute denervation of the liver did not result in changes of oxygen uptake or hemodynamics in the intact liver of the cat. Stimulation of the hepatic nerves resulted in a marked reduction of vascular conductance of the hepatic artery and portal vein (intrahepatic) resulting in almost complete cessation of arterial flow and increased portal blood pressure. The hepatic artery showed a more complete escape from the neurogenic vasoconstriction than did the portal vein. During the stable "escape phase" oxygen delivery was 86% of control, but hepatic extraction of oxygen increased so that oxygen uptake was not altered from control values. The return of oxygen consumption to normal during nerve stimulation suggests that redistribution of hepatic blood flow did not occur. In spite of arterial and portal venous blood pressure changes and changes in gut conductance, oxygen extraction of the gut did not change.

Similarity of Arterial and Intravenous Vasopressin on Portal and Systemic Hemodynamics

The effects of superior mesenteric arterial and intravenous infusions of vasopressin and low and high dose intravenous infusions of vasopressin on splanchnic and systemic hemodynamics were compared in 20 anesthetized dogs. The following parameters were evaluated: flow in the superior mesenteric artery and portal vein, portal and systemic blood pressure, and cardiac output. In the comparison of selective arterial and intravenous infusions, no statistically significant difference was found between the degree of changes in portal flow, portal and systemic blood pressure, and cardiac output. Only the superior mesenteric artery flow showed a greater decrease with the selective arterial injection. In a comparison of intravenous high dose (corresponding to that used clinically) and low dose (one-fifth) infusions of vasopressin, a relatively high splanchnic and low systemic effectiveness of the low dose was found. It resulted in only a 15 to 20% smaller effect on flow in the superior mesenteric artery and portal vein and portal pressure; however, about 40% lesser systemic effect on arterial blood pressure and cardiac output than the high dose. The results of this experimental work warrant exploration in clinical practice, preferably by a controlled study. If clinical success in controlling hemorrhage confirms these hemodynamic results, an intravenous. low dose infusion of vasopressin would appear to be the method of choice in the vasoconstrictive therapy of gastrointestinal bleeding from varices.

Prostaglandin E1 as a pharmacoangiographic agent for arterial portography.

The effects of increasing single selective doses of prostaglandin E1 (PGE1) on superior mesenteric arterial flow and portal and systemic blood pressures were studied in dogs to assess its value as a vasodilatory agent for pharmacoangiography. PGE1 consistently increased blood flow, with an average increase of 187%, but had minimal effect on portal and systemic blood pressure. 25 mug of PGE1 gave an ideal flow curve for pharmacoangiography, with a maximum effect 30 seconds after injection.

Effect of substance P on various vascular beds in the dog.

Using the electromagnetic flowmeter technique, the blood flow in the aorta, carotid, hepatic, superior mesenteric, renal and femoral arteries and portal vein was recorded during continuous i.v. infusion of synthetic Substance P (SP) in 8 dogs. Systemic and portal blood pressures were recorded. A significant decrease in mean arterial blood pressure was recorded at infusion of SP in the femoral vein at a rate of 2.5 ng x min-1 x kg b.w.-1 or higher. Portal venous blood pressure increased. A rapid increase in the carotid, hepatic, mesenteric and portal blood flow was obtained at infusion rates of 1.2 ng x min-1 x kg b.w.-1 or higher. The femoral artery responded with a late, transient increase in flow, with a return to the base level while the infusion was still in progress. The renal artery 0lood flow decreased slightly at low infusion rates and increased at higher. At SP infusions in the portal vein the infusion rate had to be increased to 20 ng x min-1 x kg b.w.-1 or higher before any general vascular reactions lere recorded, indicating that the liver has a high capacity for inactivating SP.

Reduction of portal hypertension by ganglionic blockade.

The effect of the ganglionic blocking agent, trimethaphan camsylate, on the portal venous and systemic arterial blood pressure was evaluated in 58 cirrhotic patients who had esophageal varices secondary to portal hypertension. Portal venous pressure was monitored by splenic-pulp manometry. Trimethaphan induced a mean decrease of 31.0% in portal pressure and 39.3% in arterial pressure. Both decrements were highly significant (P<0.005). Pressure decrements generally were greater in those patients whose initial pressure readings were higher. Reduced levels of portal and arterial blood pressure were maintained throughout the period of drug infusion.

The portal blood pressure and its influence upon diuresis in unanesthetized rats

The portal blood pressure and its influence upon diuresis in unanesthetized rats

Hemodynamic changes in the hepatectomized liver of the rat and their relationship to regeneration

Summary The blood flow, vascular space and portal pressure were measured in the liver of partially hepatectomized rats. The first 24 hour period after partial hepatectomy was characterized by a severe reduction in vascular space, increase of portal blood pressure, increase in the blood flow per gram liver tissue and decrease in liver blood flow per 100 gm. body weight. During the rest of the two months' experimental period, all the hemodynamic parameters were below preoperative levels with the exception of portal blood pressure, which remained higher than initial values. When related to regeneration, the blood flow per gram liver tissue and the portal blood pressures of the residual liver were increased in the first 24 hours after partial hepatectomy. The vascular space and liver blood flow per 100 gm. body weight were markedly decreased. During the remaining phase of active liver growth all hemodynamic parameters showed decreased values with the exception of portal blood pressures, which remained constantly above initial values.

Liver haemodynamics and age.

Variations in the pattern of liver circulation in the rat have been observed in different age groups. Hepatic blood flow decreased as age of the animal increased and was not dependent on vascular space and portal blood pressure. Vascular space values were higher in the middle age group but portal vein blood pressures were unaffected by variations in age.

Pathogenesis of esophageal varix rupture.

Clinical, pathological, and hemodynamic studies indicate that peak elevations in portal blood pressure, coupled with flooding of the cardioesophageal pathways by blood precipitously mobilized from the stagnant splanchnic basin, underlie the pathogenesis of varix rupture. Retching, vomiting, straining, coughing, etc., influence the magnitude and integrity of the varicosities and are often the mechanisms that trigger such vascular accidents. Several facts argue against the hypothesis of erosion by acid and pepsin, especially when the site of hemorrhage is located out of range of the corrosive gastric juice. Prophylactic and therapeutic considerations of the patient with esophageal varices must take into account all of the varied factors which determine blood flow in that region.