Reduction In Liver Blood Flow Research Articles

Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase*

To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.

Inhaled Nitric Oxide Improves Hepatic Tissue Oxygenation in Right Ventricular Failure

Inhaled Nitric Oxide Improves Hepatic Tissue Oxygenation in Right Ventricular Failure

Hypoxic hepatitis in patients with cardiac failure

Hypoxic (HH) commonly called ischemic hepatitis or refers to a sharp but transient increase in serum activity of one or both of the aminotransferases (AST and/or ALT) of at least 20 times the upper limit of normal following circulatory failure. The definition of the syndrome in patients with previously healthy livers was reviewed by Gibson & Dudley in 1984 (I). HH is characterized by a rapid fall in transaminases if the causing condition is treated successfully. HH has been described in cardiogenic shock, after hemorrhage, and with sepsis, postoperative hypotension and pulmonary embolism, although the cause of appears to be irrelevant for the development of the syndrome. The patlaophysiological mechanisms of HH are still not well known. Most published papers describe patients with diseases and consider the relative contributions of HH (hepatic ischemia, hypoxia and congestion) to be relevant. Hepatic injury of HH may thus occur as a result of a reduction in liver blood flow followed by ischemia. Another study, however, showed that there was a higher incidence of passive venous congestion and hypoxemia in patients who developed HH, compared with patients with cardiogenic shock who did not develop HH (2). The role of hypoxemia is controversial since it has been reported that hyperbaric oxygen does not prevent hepatic necrosis in experimental models of shock (3). Further contributing factors may be the simultaneous administration of different drugs (e.g., vasoconstrictor inotropes which may impair hepatic blood flow by splanchnic vasoconstriction, or cardiodepressing drugs like calcium channel blockers or anti-arrhythmic agents) (4,5), It might be useful to summarize briefly the wide spectrum of hepatic complications due to heart failure syndromes. Chronic heart failure, which may exacerbate to acute heart failure (2), can cause cardiac with the typical nutmeg appearance, but the more common finding and the first step which normally occurs in cirrhosis is simple congestive hepatomegaly (6). This disorder is usually recognized by elevated serum transaminases, high bilirubin levels, up to 20 mg/dl, due to an increase in both direct and indirect fractions, and jaundice. The serum transaminases may be increased I0to 15-fold and serum alkaline phosphatase is increased. When the prothrombin time is substantially prolonged, congestive hepatopathy is usually severe and the prognosis poor. The development of end-stage cirrhosis will produce all of the findings associated with chronic liver failure, including hypoalbuminemia, hypoglycemia, ascites, and hepatic coma. Hepatic disorders due to acute failure can be caused by sudden low output syndromes or may arise also as a consequence of aggravation of chronic heart failure. In one study (2), the onset of HH was usually preceded by an acute complicaton, e.g., arrhythmia, provoking a sudden decrease in output. Fig. 1 and 2 depict the histological correlates of two typical hypoxic states in the liver. In the article by Henrion and coworkers, published in this issue of the journal (7), the authors present for the first time a prospective study on the incidence of HH in a European coronary care unit and measure the effective hepatic blood flow in patients with low output and HH, using the method of galactose clearance at low concentration. In this setting, low output was defined clinically by: I) Existence of disease (chronic or acute); 2) Cutaneous signs of circulatory failure; and 3) Intravenous inotropic treatment with dobutamine. Shock (defined in Henrion's paper as a fall of systolic blood

Liver Blood Flow as a Major Determinant of the Clearance of Recombinant Human Tissue-Type Plasminogen Activator

The influence of changes in liver blood flow on the clearance of rt-PA was studied both in healthy subjects and in a perfused rat liver model. Liver blood flow in healthy subjects was documented indirectly by the clearance of indocyanine green (ICG). Exercise reduced liver blood flow on average by 57% with a 95% confidence interval (95% CI) ranging from 51% to 62% (n = 5) and increased plasma levels of rt-PA activity (after an i.v. infusion of 18 mg of rt-PA over 120 min) by 119% (95% CI, 58%-203%) and rt-PA antigen by 91% (95% CI, 30%-140%). In the perfused rat liver model it was shown that halving or doubling of the physiological flow rate of a perfusate, containing rt-PA caused a proportional change in the clearance of rt-PA, while the extraction of rt-PA by the liver remained similar. In conclusion, liver blood flow is a major determinant of the clearance of rt-PA. This may have important implications for dosage of rt-PA in patients with myocardial infarction.

Effects of anesthetic agents and abdominal surgery on liver blood flow

The cause of postoperative liver dysfunction is often unclear, but a decrease in liver blood flow during anesthesia and/or major surgery may be important. Plasma half-life and clearance of indocyanine green were therefore measured in 42 patients before, during and after anesthesia and abdominal surgery. In 13 patients, liver blood flow was also estimated from indocyanine green extraction using hepatic vein catheterization. The major finding was an early decrease in estimated liver blood flow after induction of anesthesia, but not later during or after surgery. Mean indocyanine green half-life increased by 26% (p less than 0.005), mean indocyanine green plasma clearance decreased by 19% (p less than 0.01) and mean estimated hepatic blood flow decreased by 36% (p less than 0.005) during the first 30 min of anesthesia. These changes were greater in males and in patients older than 55 yr, but changes were similar with each of three anesthetic groups. Half-life, but not indocyanine green clearance, was also significantly prolonged by mid-operation in the older (greater than 55 yr) patients and in those undergoing lower abdominal surgery. We suggest that this period of reduced liver blood flow during anesthesia is caused by the effects of neuromuscular blocking agents and may contribute to postoperative liver damage.

Experimental study of iron effect on the liver function.

The effect of iron on the liver function was studied in rats. A total of 40 rats were divided into four groups. Group 1 was given iron; Group 2, carbon tetrachloride; Group 3, a combination of iron and carbon tetrachloride; and Group 4 was the control. The changes in liver function were evaluated by using hepatobiliary and liver scintigraphy as the index of hepatocyte function and reticuloendothelial system function, respectively. Determination of liver CT number and a histological study were made at the same time. The administration of iron activated the reticuloendothelial system function per unit of liver weight. However, because of the decrease in liver weight, the total reticuloendothelial system function did not change at all. In the group given iron and carbon tetrachloride, liver cirrhosis and siderosis in the reticuloendothelial system occurred. Dysfunction in the reticuloendothelial system was more severe in this group than in the group given carbon tetrachloride only, by hepatocyte dysfunction was more mild. It is doubtful that the administration of iron after liver dysfunction had developed, which caused acceleration of fibrosis and reduction of liver blood flow, led to the enhancement of the reticuloendothelial system dysfunction.

Pentopril-cimetidine interaction caused by a reduction in hepatic blood flow.

The interactive effects of the coadministration of steady-state cimetidine and single-dose pentopril, an angiotensin converting enzyme inhibitor, on the pharmacokinetic disposition of each other were studied in humans. Cimetidine reduced the clearance of pentopril by 11 to 14%. This reduction in clearance was shown to be caused by a reduction in liver blood flow probably mediated through H2 receptor blockade. Meanwhile pentopril induced the oral clearance of cimetidine by 21%, presumably by a reduction in the bioavailable fraction of cimetidine. The mechanism of this interaction is unknown.

The hepatic and renal mechanisms of drug interactions with cimetidine.

Cimetidine is one of the most frequently prescribed drugs with a known potential to interfere with the metabolic disposition of numerous other medications. Some of these drug interactions may be hazardous to patients. The hepatic and renal mechanisms of drug interactions with cimetidine are discussed in this article. The interactive processes include inhibition of hepatic microsomal enzyme activity, reduction of liver blood flow, and competition for renal tubular secretory sites. The clinical significance and proposed mechanisms of interaction for individual drugs are also presented.

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.

Kinetic interactions of nadolol and propranolol with cimetidine.

British Journal of Clinical PharmacologyVolume 17, Issue 4 p. 486-487 Free Access Kinetic interactions of nadolol and propranolol with cimetidine. KL Duchin, KL DuchinSearch for more papers by this authorMA Stern, MA SternSearch for more papers by this authorDA Willard, DA WillardSearch for more papers by this authorDN McKinstry, DN McKinstrySearch for more papers by this author KL Duchin, KL DuchinSearch for more papers by this authorMA Stern, MA SternSearch for more papers by this authorDA Willard, DA WillardSearch for more papers by this authorDN McKinstry, DN McKinstrySearch for more papers by this author First published: April 1984 https://doi.org/10.1111/j.1365-2125.1984.tb02379.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Feely, J., Wilkinson, G. R. & Wood, A. J. J. (1981). Reduction of liver blood flow and propranolol metabolism by cimetidine. New Engl. J. Med., 304, 692– 695. Funke, P. T., Malley, M. F., Ivashkiv, E. & Cohen, A. I. (1978). Determinations of serum nadolol levels by GLC-selection monitoring mass spectrometry: comparison with a spectrofluoro-metric method. J. pharm. Sci., 67, 653– 657. Gibaldi, M. & Perrier, D. (1982). Pharmacokinetics. New York: Marcel Dekker, Inc. Kirch, W., Spahn, H., Kohler, H., Ohnhaus, E. E. & Mutschler, E. (1982). Interactions of metoprolol, propranolol, and atenolol with concurrent administration of cimetidine. Klin. Wochenschr., 60, 1401– 1407. Pelkonen, O. & Puurunen, J. (1980). The effect of cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochem. Pharmac., 29, 3075– 3080. Reimann, I. W., Klotz, U., Siems, B. & Frohlich, J. C. (1981). Cimetidine increases steady-state plasma levels of propranolol. Br. J. clin. Pharmac., 12, 785– 790. Shand, D. G., Nuckolls, E. M. & Oates, J. A. (1970). Plasma propranolol levels in adults with observations in four children. Clin. Pharmac. Ther., 11, 112– 120. Citing Literature Volume17, Issue4April 1984Pages 486-487 ReferencesRelatedInformation

The effect of ranitidine on the plasma clearance and hepatic extraction of indocyanine green in patients with chronic liver disease.

Since hepatic clearance of ICG is reduced by H2-receptor antagonists in normal subjects, it has been suggested that they reduce liver blood flow. We have studied the effect of intravenous ranitidine on ICG clearance in twelve patients with chronic liver disease. Wedged and free hepatic venous pressure were measured before and after intravenous ranitidine in nine of the patients, and the hepatic extraction of ICG was determined in six patients. ICG clearance fell by 22 +/- 11% (s.e. mean) 60 min after ranitidine. In patients in whom ICG clearance fell after intravenous ranitidine the hepatic extraction of ICG was also reduced. There was no significant change in the gradient between wedged and free hepatic venous pressure after ranitidine. It is therefore unlikely that ranitidine lowers liver blood flow.

Effect of somatostatin on liver blood flow in the rat.

The effect of portal and systemic intravenous boluses of somatostatin on total liver blood flow in rats was studied using the xenon-133 clearance technique. No change in liver blood flow was found when somatostatin was delivered into the portal circulation, but there was a significant reduction in liver blood flow when somatostatin was delivered into the systemic venous circulation. The results suggest that somatostatin exerts its effect on liver blood flow through the pre-hepatic splanchnic circulation rather than directly on the portal vein.

Improved blood flow and protein synthesis in the postischemic liver following infusion of dopamine

To study the effects of dopamine on hepatic blood flow and protein synthesis in a condition with reduced liver blood flow, dopamine (5 μg × kg −1 × min −1) or saline was infused intravenously following a period of liver ischemia in rats. Hepatic blood flow was measured by xenon washout technique and protein synthesis by leucine incorporation into proteins in incubated liver slices. Blood flow and protein synthesis in the postischemic liver were restituted faster and more completely in dopamine-treated rats suggesting that dopamine infusion can be of beneficial effect on liver metabolism in situations with reduced hepatic blood flow.

Tolerance of the liver to ischemia in the pig

The effect of liver blood flow occlusion was studied in pigs under general anesthesia at normal body temperature. Portal venous blood flow was diverted to the systemic circulation during the period of liver ischemia. A 90% reduction in liver blood flow was produced during the period of ischemia as measured by 127Xe washout. Animals subjected to 90 min of liver ischemia had uniform survival and only moderate disturbance in liver function tests. Extension of the ischemic period to 180 min produced greater disturbances in liver function tests, more hepatocellular injury histologically, and two deaths occurred. It is concluded that the pig liver can tolerate profound reductions in blood flow for extended periods of time without developing massive liver necrosis. The clinical relevance of the findings is discussed.

Reduction of Liver Blood Flow and Propranolol Metabolism by Cimetidine

Reduction of Liver Blood Flow and Propranolol Metabolism by Cimetidine

Reduction of liver blood flow and propranolol metabolism by cimetidine.

We studied the influence of cimetidine on liver blood flow in eight normal subjects. Cimetidine acutely reduced liver blood flow during fasting by almost 25 per cent, as measured by indocyanine green clearance. Chronic cimetidine therapy (300 mg four times daily for seven days) reduced the flow by 33 per cent, as measured over eight hours by calculating the relative disposition of oral and intravenous propranolol. In addition to reducing the clearance of intravenous propranolol by decreasing live blood flow, cimetidine also inhibited the metabolism of oral propranolol and thereby further reduced elimination. The reduction in clearance of oral propranolol correlated positively (r = 0.87, P less than 0.05) with the average steady-state concentration of plasma cimetidine, suggesting that the inhibition of drug metabolism by cimetidine is dose related. Pulse rates at rest were markedly lower after propranolol plus cimetidine than after propranolol alone. The reduction in liver blood flow produced by cimetidine has important therapeutic implications for patients with alterations in liver and gastrointestinal blood flow and when drugs are used whose hepatic elimination depends on liver blood flow.

CHANGES IN LIVER BLOOD FLOW WITH DEVELOPMENT OF BILIARY OBSTRUCTION IN THE RAT

As well as causing retention of biliary secretory products, bile duct obstruction is associated with other hepatic and systemic effects which are poorly understood. These latter changes contribute to the increased morbidity and mortality associated with surgery for biliary obstruction. This study examines the changes in liver blood flow occurring after common bile duct (CBD) ligation in the belief that relative hepatic ischaemia may contribute to dysfunction. A new method for measuring liver blood flow (LBF) based on the clearance of 133Xe from the liver following injection into the portal vein is described. With this new development, serial measurements of LBF can be performed in the conscious, unfasted rat. With the development of jaundice, a highly significant reduction in LBF is seen which is first evident 36 hours after CBD ligation. By the third day after ligation, LBF is only 54% of the control value. No fall in LBF is seen in rats subjected to sham ligation. The mechanism for the reduction in LBF is uncertain, but the delayed onset makes any relfex autonomic reaction unlikely.

Liver blood flow and oxygen consumption during hypocapnia and IPPV in the greyhound

Pentobarbital-anesthetized greyhounds were passively hyperventilated using intermittent positive-pressure breathing (IPPV) and the effects of raised airway pressure, accompanied by hypocapnia and then by normocapnia, on liver blood flow and oxygen consumption were studied. Electromagnetic flowmeters were used to measure hepatic arterial, portal venous, and splenic venous blood flow. Studies were carried out at three levels of raised airway pressure, both at normocapnia and hypocapnia. It was found that hypocapnic hyperventilation produced a decrease in portal venous and hepatic arterial blood flow. Normocapnic hyperventilation resulted in a restoration of portal venous blood flow but with a further decrease in hepatic arterial blood flow. A decrease in oxygen consumption with hypocapnia, returning to control values with normocapnia, was seen. It is suggested that the reduction in liver blood flow and oxygen consumption seen with passive hyperventilation is chiefly an effect of hypocapnia and is largely reversed by restoration of normocapnia.

Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.

Mechanism for reduced drug clearance in patients with cirrhosis

The mechanism responsible for reduced drug clearance in patients with cirrhosis was investigated using d-propranolol as an example of a drug that is highly extracted by the liver in the normal subject. The pharmacokinetics of d-propranolol, 0.4 mg · kg−1, was studied after intravenous injection in 26 subjects: the total clearance (mean ± SD) of the drug was not different in 6 subjects with normal liver (21 ± 7 ml · min−1 · kg−1) and in 6 patients with alcoholic fibrosis of the liver, without cirrhosis (18 ± 8 ml · min−1 · kg−1); the total clearance of the drug was significantly lower in 14 patients with alcoholic cirrhosis (8 ± 5 ml · min−1 · kg−1). Concomitantly with the pharmacokinetic study, a hepatic vein was catheterized, and indocyanin green was infused in the 6 patients with fibrosis of the liver and in 6 of the 14 patients with cirrhosis; information provided by these techniques allowed measurement of the hepatic clearance of d-propranolol and estimation of its contributing factors: the hepatic clearance of d-propranolol was 18 ± 6 ml · min−1 · kg−1 in patients with fibrosis and only 6 ± 3 ml · min−1 · kg−1 in patients with cirrhosis; the liver blood flow was 25 ± 9 ml · min−1 · kg−1 in the former and 14 ± 6 ml · min−1 · kg−1 in the latter patients; the hepatic extraction ratio of d-propranolol was 0.73 ± 0.09 in patients with fibrosis of the liver and 0.41 ±0.17 in patients with cirrhosis; the intrinsic hepatic clearance of d-propranolol, a mathematical concept expressing the maximal ability of the liver to remove the drug from the blood, was 72 ± 30 ml · min−1 · kg−1 in the former and only 12 ± 7 ml · min−1 · kg−1 in the latter patients. It is concluded that, in patients with cirrhosis, (1) the total clearance of d-propranolol is reduced, (2) the reduced total clearance is a consequence of a reduced hepatic clearance, and (3) the reduced hepatic clearance results mainly from an impaired ability of the liver to remove the drug from the blood and secondarily from a reduced liver blood flow.