Effect of ethanol on splanchnic hemodynamics in awake and unrestrained rats with portal hypertension

Alcoholic liver disease is frequently accompanied by portal hypertension. We have previously shown that alcohol intake in awake, unrestrained rats is followed by an increase in portal tributary blood flow. In this study, the effect of ethanol on splanchnic hemodynamics in rats with portal hypertension was analyzed. Portal hypertension was induced by partial ligation of the portal vein. This procedure resulted in an increase in portal tributary and hepatic arterial blood flows compared to sham-operated animals. Ethanol (2 gm per kg, oral) increased portal tributary blood flow in both sham-operated and portal vein-ligated rats (sham + water = 37.6 +/- 1.4; sham + ethanol = 63.1 +/- 1.9; p less than 0.01; partial portal vein stenosis + water = 53.2 +/- 3.3; partial portal vein stenosis + ethanol = 69.5 +/- 2.2 ml.kg-1.min-1; p less than 0.01). In sham-operated rats, hepatic artery blood flow was unchanged following ethanol (sham + water = 6.6 +/- 0.7; sham + ethanol = 7.1 +/- 1.0 ml.kg-1.min-1), whereas in portal vein-ligated rats, flow was increased (partial portal vein stenosis + water = 13.7 +/- 1.4; partial portal vein stenosis + ethanol = 19.8 +/- 1.1 ml.kg-1.min-1; p less than 0.025). The adenosine receptor blocker 8-phenyltheophylline suppressed only the ethanol-induced increase in both portal tributary and hepatic artery blood flows in portal vein-ligated rats. The increases in hepatic artery and portal tributary blood flows observed in portal vein-ligated rats without ethanol were not influenced by 8-phenyltheophylline.(ABSTRACT TRUNCATED AT 250 WORDS)     

The intrahepatic biliary epithelium in the guinea pig: is hepatic artery blood flow essential in maintaining its function and structure?

To determine whether hepatic artery blood flow is essential in maintaining the function and structure of bile ductules/ducts, the acute effects of hepatic artery ligation on bile secretion and hepatic ultrastructure were examined in anesthetized, bile duct-cannulated guinea pigs. Sixty minutes after hepatic artery ligation, spontaneous bile flow (5.08 +/- 0.4 microliter per min per gm liver) was virtually the same as that before hepatic artery ligation (5.31 +/- 0.3 microliter per min per gm), as were the choleretic effects of 10 CU per kg per 30 min secretin (7.14 +/- 0.9 vs. 7.21 +/- 0.9 microliter per min per gm), 300 micrograms per kg per 30 min glucagon (6.72 +/- 0.9 vs. 6.59 +/- 0.8 microliter per min per gm) and 60 mumoles per kg per 30 min glycochenodeoxycholate (6.43 +/- 0.6 vs. 6.45 +/- 0.6 microliter per min per gm). The failure of hepatic artery ligation to affect bile secretory function could not be attributed to the existence of collateral arterial blood flow to the liver. First of all, hepatic artery ligation resulted in diminishing significantly hepatic venous, but not portal, oxygen content. More importantly, in isolated guinea pig livers, perfused through the portal vein alone, secretin, glucagon and glycochenodeoxycholate produced changes in bile flow and composition similar to those seen in vivo. Electron microscopy showed no major ultrastructural changes of hepatic parenchyma and biliary epithelium 2 hr after hepatic artery ligation, or 2 hr after perfusing the liver through the portal vein alone save for some portal edema in the latter instance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenous carbochromen: a potent and effective drug for estimation of coronary dilatory capacity

Systemic and coronary haemodynamic effects of carbochromen (0.125 mg kg-1 min-1 for 40 min i.v.) and dipyridamole (0.05 mg kg-1 min-1 for 10 min i.v.) were investigated in 18 patients without detectable heart disease. Both drugs induced a comparable increase in coronary blood flow (carbochromen: from 82 +/- 23 to 337 +/- 68 ml.100 g-1.min-1; dipyridamole: from 78 +/- 9 to 301 +/- 61 ml.100 g-1.min-1). This resulted in a minimal coronary resistance of 0.23 +/- 0.04 mmHg.ml-1.100 g.min for dipyridamole and of 0.24 +/- 0.04 mmHg.ml-1.100 g.min for carbochromen. In response to dipyridamole (n = 12) heart rate increased from 73 to 94 beats min-1 (P less than 0.005) and mean aortic pressure fell from 89 to 78 mmHg (P less than 0.001). After administration of carbochromen (n = 6) no significant systemic effects occurred. Dipyridamole induced a significant increase in myocardial oxygen consumption by 46% (P less than 0.001); after application of carbochromen myocardial oxygen consumption remained unchanged. From these data it can be concluded that for the evaluation of coronary dilatory capacity carbochromen may be more suitable than dipyridamole because (1) maximal coronary vasodilation is induced without changes in myocardial oxygen consumption and (2) no systemic effects occur.     

Decreased response to catecholamines in the newborn: effect on glucose kinetics in the lamb

Epinephrine, a catecholamine with both alpha (alpha) and beta (beta) adrenergic effects, may produce hyperglycemia in adults by increasing glucose production and decreasing glucose clearance. To document the degree of sensitivity and characterize maturation of neonatal glucose control, glucose kinetics were measured in 14 term newborn lambs (weight 4.5 +/- 0.3 kg [mean +/- SEM] and aged 4.1 +/- 0.4 days). Following infusion of 0.9% NaCl at 0.06 mg.kg-1 min-1 plus 100 microCi/kg D[6-3H] glucose by prime plus constant infusion, rate of production (Ra) and glucose clearance were measured during administration of epinephrine. The responses in the newborns were compared with those in six adult sheep. Under conditions of epinephrine infusion, the plasma glucose concentration in the newborn lambs increased to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine), P less than .0001, and 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine), P less than .0001, compared with 95 +/- 8 mg/dL (controls, no epinephrine). Comparable values for Ra were 6.5 +/- 1.6 mg.kg-1 min-1 (50 ng.kg-1 min-1 epinephrine), P = NS, and 18.5 +/- 3.0 mg.kg-1 min-1 (500 ng.kg-1 min-1 epinephrine), P less than .0001, compared with 5.3 +/- 0.5 mg.kg-1 min-1 (controls, no epinephrine).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethanol-induced increase in portal hepatic blood flow: interference by anesthetic agents

While a number of studies show that acute oral administration of ethanol results in increases in liver blood flow, a large body of evidence has also been presented in which such an effect is not observed. To shed light on this discrepancy, we have studied in rats, a number of variables that might modulate or inhibit the effect of ethanol. These included the use of three anesthetic agents studied at two different times after anesthetic administration and the effect of animal age, gender, batches and seasonal variation. Portal blood flows were determined by the radiolabeled microsphere method in 12 separate experiments in awake rats. Ethanol given at doses ranging from 0.5 to 4.0 gm per kg consistently increased portal vein blood flow by approximately 50% (42.2 +/- 3.5 to 63.4 +/- 6.5 ml per min per kg). The interexperiment variation was 2.4 to 3.0%, showing remarkable consistency, typical of an all-or-none effect at the doses employed. On the other hand, the ethanol-induced increase in portal blood flow was completely suppressed by ketamine (75 mg per kg), thiopental (50 mg per kg) and fentanyl (15 micrograms per kg) when given 15 min prior to blood flow determinations. This suppression was dependent on the dose and duration of anesthesia. These anesthetic agents had no effect on basal hepatic arterial or portal blood flows. Ethanol or the anesthetics were without effects on hepatic artery blood flow. Neither gender, weight (150 to 350 gm) nor animal batch had effect on the response to ethanol. Similarly, there was no effect of seasonal variation.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Cimetidine does not reduce liver blood flow in cirrhosis

Cimetidine has been shown to reduce liver blood flow, as measured by indocyanine green clearance, in normal subjects. Concern over the potential deleterious effects of such reduction in cirrhosis led to the measurement of blood flow in 14 cirrhotics receiving oral or intravenous cimetidine. Liver blood flow was measured by the clearance of galactose at steady state during infusion of 40 mg per min. In six patients receiving 300 mg cimetidine by mouth each 6 hr for 4 days, basal flow (1,019 +/- 186 ml per min) was not significantly altered by cimetidine (1,087 +/- 156 ml per min). Intravenous infusion of cimetidine (300 mg) did not significantly alter flow in five patients between the basal (1,096 +/- 334 ml per min) and treatment periods (1,051 +/- 383 ml per min). Hepatic extraction of galactose in three patients (82 +/- 19%) was not significantly altered by cimetidine infusion (81 +/- 13%). The failure to reduce liver blood flow with cimetidine in this population may be due to their diminished proportion of portal venous flow, or alternatively suggests that histamine is not an important modulator of flow via H2 receptors. At a clinical level, the use of cimetidine in this population can continue without fear of further reduction in liver blood flow.     

Influence of insulin treatment on insulin sensitivity in insulin requiring type 2 diabetes patients

Insulin resistance in type 2 diabetes subjects was investigated before and 6 months after insulin administration in 43 type 2 diabetes patients (28 females and 15 males). Their age was 56.1+/-8.6 years, diabetes duration 11.7+/-6.8 years, BMI 29.5+/-5.3 kg/m2. All patients were on maximal dosage of oral hypoglycaemic agents and had poor metabolic control (HbA1c 11.2+/-1.6%). Insulin sensitivity was measured by euglycaemic clamp (insulin infusion rate 1 mU kg-1 min-1). The glucose disposal rate (M-value) was considerably lower in patients (2.4+/-1.6 mg kg-1 min-1, 0.2-8.1) compared with healthy subjects (7.1+/-0.2 mg kg-1 min-1, p<0.01). M-value was strongly associated with WHR (r=-0.41, p<0.05). The patients with poorest insulin sensitivity had the highest level of total cholesterol (r=-0.41, p=0.02) and LDL-cholesterol (r=-0.38, p=0.03). After 6 months of insulin treatment BMI was 30.3+/-4.2 kg/m2 (p<0.05), mean weight increase was 2.7+/-0.8 kg. M-value was substantially increased to 4.5+/-2.3 mg kg-1 min-1 (p<0.001), the degree of improvement depended on basal insulin sensitivity (r=-0.55, p<0.01). HbA1c was reduced to 7.7+/-1.4% (p<0.01), the correlation M-value with change of HbA1c (r=-0.59, p<0.01) was shown. Total cholesterol decreased from 6.3+/-1.1 to 5.4+/-1.1 mmol/l, LDL-cholesterol from 4.1+/-1.1 to 3.4+/-1.0 mmol/l, triglycerides from 2.6+/-1.6 to 1.6+/-0.7 mmol/l (p<0.001). In conclusion, insulin treatment of type 2 diabetes patients leads to decrease in insulin resistance due to reduction in glucose toxicity and plasma atherogenicity despite weight gain.     

Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study.

Inotropic support is often required for post-operative management of patients following mitral valve operation. The use of positive inotropes is limited by tolerance development and increase in myocardial oxygen demand. We have compared i.v. enoximone (E) (group E, n = 13), a recently developed phosphodiesterase (PDE) inhibitor, to the conventional i.v. therapeutics dopamine (D) and glyceroltrinitrate (G) in patients following mitral valve operation. The two groups were comparable in terms of physical and pre-operative haemodynamic data. Haemodynamic measurements including cardiac index (CI) determinations were recorded for the first 18 h post surgery in both groups. Group E received a bolus of 1 mg.kg-1 E followed by 4-20 micrograms.kg-1.min-1 (mean = 5 +/- 2 micrograms.kg-1.min-1) for 14 h according to therapeutic requirements, while group D received dopamine (4-10 micrograms.kg-1.min-1, mean = 3.8 +/- 1.9 micrograms.kg-1.min-1) and glyceroltrinitrate (0.5-5 micrograms.kg-1.min-1; mean = 4 +/- 2 micrograms.kg-1.min-1). Adrenaline was added if the MAP was below 60 mmHg or the CI was below 2.5 in both groups (range 50-500 ng.kg-1.min-1; mean E = 0.7 +/- 2 ng.kg-1.min-1; mean D = 2 +/- 2.8 ng.kg-1.min-1). Bolus injection of E resulted in a rise in CI from 2.6 to 3.21.min-1.m-2 (P less than 0.05) within 30 min, followed by a further rise to a maximum of 3.51.min-1.m-2 6 h post bolus. Termination of the E drip resulted in a drop of CI to baseline values (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamics during liver transplantation: the interactions between cardiac output and portal venous and hepatic arterial flows.

Liver blood flow and systemic hemodynamics were measured intraoperatively in 34 patients after liver transplantation. Ultrasound transit-time flow probes measured hepatic arterial and portal venous flow over 10 to 75 min 1 to 3 hr after reperfusion. Cardiac output was measured by thermodilution. Mean cardiac output was 9.5 +/- 2.8 L/min; the mean total liver blood flow of 2,091 +/- 932 ml/min was 23% +/- 11% of cardiac output. Mean portal flow of 1,808 +/- 929 ml/min was disproportionately high at 85% +/- 10% of total liver blood flow. Correlation analysis showed a significant (p less than 0.01; r = 0.42) correlation between cardiac output and portal venous flow and a trend toward negative correlation (p = 0.087) between cardiac output and hepatic arterial flow. These data show that increased flow in the newly transplanted liver is predominantly portal venous flow and is associated with high cardiac output and reduced hepatic arterial flow. In the last 13 patients studied, portal flow was reduced by 50% and the hepatic artery response was measured. We saw a significant (p less than 0.05) increase in hepatic artery flow from 322 +/- 228 to 419 +/- 271 ml/min, indicating an intact hepatic arterial buffer response. The hepatic artery response also showed that it is a reversible rather than a fixed resistance that contributes to the low hepatic artery flow in these patients.     

Alpha-adrenergic agonists stimulate neonatal glucose production less than beta-adrenergic agonists in the lamb

Epinephrine, a catecholamine with both alpha (alpha)- and beta (beta)-adrenergic agonist effects, may produce clinical hyperglycemia in the adult by increasing glucose production and decreasing glucose clearance. However, the relative contribution of alpha v beta adrenergic agonists in control of neonatal glucose kinetics has not been defined. Twenty-three term lambs (weighing 4.4 +/- 0.2 kg, mean +/- SEM, and aged 3.8 +/- 0.4 days) were infused with 0.9% NaCl at 0.6 mL.kg-1 min-1 + 100 microCi/kg D[6-3H]-glucose by prime plus constant infusion for 210 minutes. Ra (rate of production) was measured during infusion of variable doses of epinephrine with or without variable doses of propranolol, a competitive beta-adrenergic antagonist to isolate the alpha-adrenergic agonist effects. All basal kinetic data were comparable. Under conditions of epinephrine infusion, the plasma glucose concentration increased from 95 +/- 10 mg/dL to 129 +/- 18 mg/dL (50 ng.kg-1 min-1 epinephrine; P less than .0001) and from 85 +/- 6 mg/dL to 253 +/- 8 mg/dL (500 ng.kg-1 min-1 epinephrine; P less than .00001) compared with controls (96 +/- 7 mg/dL to 95 +/- 8 mg/dL). When epinephrine and propranolol were infused simultaneously, plasma glucose concentration increased from 95 +/- 10 mg/dL to 122 +/- 12 mg/dL (50 ng.kg-1 min-1 epinephrine + 1.1 micrograms.kg-1 min-1; P less than .0001) and from 78 +/- 9 mg/dL to 134 +/- 12 mg/dL (500 ng.kg-1 min-1 epinephrine + 11 micrograms.kg-1 min-1; P less than .0001) compared with controls (no epinephrine, no propranolol).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hyperkinetic circulatory syndrome in patients with presinusoidal portal hypertension : Effect of propranolol

This study evaluates systemic and splanchnic haemodynamics and the effect of propranolol in 15 patients with presinusoidal portal hypertension (portal vein obstruction, n = 11; schistosomiasis, n = 4). These patients exhibited a hyperkinetic circulatory syndrome characterized by high cardiac index (4.4 +/- 1.61.min-1.m-2, mean +/- S.D.) and by low systemic vascular resistance despite normal liver function and sinusoidal pressure. Hepatic blood flow was decreased in half of the patients with portal vein obstruction. Azygos blood flow, an estimate of superior portal-systemic collateral circulation, was markedly increased in all patients (0.46 +/- 0.19 l/min, upper limit of normal: 0.19 l/min). Therefore, in these patients with normal hepatic venous pressure gradient, azygos blood flow measurement provides an index of splanchnic haemodynamic changes. Propranolol administration (15 mg, i.v.) reduced the hyperkinetic circulatory syndrome, with a significant decrease in heart rate (-17 +/- 6%), cardiac index (-25 +/- 12%) and azygos blood flow (-40 +/- 26%) and a significant increase in systemic vascular resistance (+40 +/- 40%). These results suggest that the hyperkinetic circulatory syndrome observed in these patients, could be related to an increase in beta-adrenergic activity. The decrease in azygos blood flow, after propranolol administration, was significantly correlated (r = 0.94) with the increase in right atrial pressure. This finding suggests that propranolol may act through an increase in portal-systemic collateral venous tone. These haemodynamic results justify, in patients with presinusoidal portal hypertension, clinical trials investigating the beneficial effect of beta-blockers on gastrointestinal bleeding caused by portal hypertension.     

Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension

The effects of verapamil on hepatic and systemic hemodynamics and on liver function were investigated in 10 patients with portal hypertension due to advanced micronodular cirrhosis to verify whether, as it has been suggested, this calcium channel blocker may improve liver function and reduce portal pressure in these patients. The oral administration of 100 mg of verapamil caused systemic vasodilation, evidenced by a significant reduction in mean arterial pressure (-8.1 +/- 7.6%, p less than 0.025) and systemic vascular resistance (-12.5 +/- 9.5%, p less than 0.001), and increased heart rate (+13.9 +/- 10.4%, p less than 0.01). However, no beneficial effect was noted on portal pressure evaluated by hepatic vein catheterization (baseline 19.8 +/- 4.0, verapamil 20.2 +/- 3.6 mmHg, NS), hepatic blood flow (1.45 +/- 0.64 vs. 1.47 +/- 0.62 liters per min, NS) and hepatic vascular resistance (1.314 +/- 611 vs. 1,266 +/- 513 dyn per sec per cm-5, NS). Similarly, no change was observed in portal blood flow, measured in six patients by pulsed Doppler flowmeter (0.94 +/- 0.30 vs. 0.89 +/- 0.35 liter per min, NS). In addition, verapamil did not increase the hepatic intrinsic clearance of these patients (0.20 +/- 0.07 vs. 0.19 +/- 0.06 liter per min, NS). This study suggests that verapamil is of no beneficial effect in patients with advanced cirrhosis of the liver.     

Hemodynamic effects of dopamine in conscious rats with secondary biliary cirrhosis

Dopamine may be used in cirrhotic patients with renal or circulatory failure, but this drug can also increase the degree of portal hypertension. Hence, the systemic and splanchnic hemodynamic effects of dopamine have been studied in portal hypertensive rats with secondary biliary cirrhosis. The dose-response curves showed that dopamine significantly increased portal pressure at the same dose (80 micrograms min-1 kg-1 body wt.) in normal and biliary cirrhotic rats. Arterial pressure only increased with higher doses of dopamine in rats with biliary cirrhosis (160 micrograms min-1 kg-1 body wt.) while in normal animals it increased (80 micrograms min-1 kg-1 body wt.). Dopamine (160 micrograms min-1 kg-1 body wt.) significantly increased mean arterial pressure in normal and biliary cirrhotic rats. It significantly increased cardiac output in biliary cirrhotic rats from 134 +/- 6 to 153 +/- 7 ml/min but not in normals. Accordingly, systemic vascular resistance increased significantly in normal rats but not in cirrhotics. Portal pressure increased significantly in normal rats from 8.0 +/- 0.3 to 12.1 +/- 0.6 mmHg and in rats with biliary cirrhosis from 15.9 +/- 1.0 to 19.0 +/- 1.3 mmHg. Portal tributary blood flow increased significantly in normal and biliary cirrhotic rats (14.1 +/- 1 to 20.9 +/- 2.3 ml/min and 18.0 +/- 0.9 to 25.5 +/- 1.8 ml/min, respectively). This study shows that an elevated dose of dopamine increases the hyperkinetic syndrome in rats with secondary biliary cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of phase of menstrual cycle on insulin sensitivity, peripheral blood flow and cardiovascular responses to hyperinsulinaemia in young women with type 1 diabetes

Disturbances of blood glucose control around the time of menstruation are often reported by women with Type 1 diabetes. To investigate the possibility that such changes may be due to alterations in insulin sensitivity or peripheral blood flow we have studied 9 women with Type 1 diabetes during the follicular and luteal phases of the menstrual cycle. Insulin sensitivity was assessed by the glucose clamp technique with insulin doses of 40 (low dose) and 100 (high dose) mU m-2 min-1. Glucose disposal rates were 2.5 +/- 0.3 (mean +/- SE) mg kg-1 min-1 during the follicular phase and 3.2 +/- 0.3 mg kg-1 min-1 in the luteal phase with low dose insulin, and 5.9 +/- 0.4 and 6.4 +/- 0.6 mg kg-1 min-1, respectively, with high dose insulin. These differences were not statistically significant. Forearm blood flow, heart rate, and blood pressure were similar during both phases.     

Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension

BACKGROUND/AIMS: To assess the effects of the early and chronic administration of losartan--a specific angiotensin II receptor antagonist--in the prevention of hepatic fibrosis and portal hypertension. METHODS/RESULTS: (1) In CCl(4) rats, losartan at 5 and 10 mg/kg per day significantly decreased portal pressure (-11, -18%, respectively), splenorenal shunt blood flow (-60, -80%) and liver fibrosis (liver hydroxyproline and area of fibrosis) without significant changes in mortality and mean arterial pressure (MAP). (2) In bile duct ligated (BDL) rats, losartan at 5 mg/kg per day significantly decreased portal pressure (-14%), splenorenal shunt blood flow (-70%) and liver fibrosis. Losartan at 10 mg/kg per day significantly worsened liver and renal functions, mortality and liver fibrosis, without significant changes in portal pressure and splenorenal shunt blood flow. Losartan at 5 and 10 mg/kg per day significantly decreased MAP (-24, -30%). (3) In portal vein ligated (PVL) rats, losartan significantly decreased MAP (-12%) but did not change portal pressure or splenorenal shunt blood flow. CONCLUSIONS: In BDL and CCl(4) rats, losartan has beneficial effects on splanchnic hemodynamics and liver fibrosis. Losartan might decrease hepatic resistances in fibrotic liver. Losartan decreased MAP except in CCl(4) rats. Higher dosage of losartan had deleterious effects in BDL rats.     

Effects of acute normovolemic anemia on gastric mucosal blood flow in rats: role of nitric oxide.

The present study investigates the effects of acute normovolemic anemia induced by isovolemic hemodilution on gastric mucosal blood flow (GMBF), measured by hydrogen gas clearance, and on the oxygen and hemoglobin content in the gastric mucosa, estimated by reflectance spectrophotometry. GMBF significantly increased after 3 and 6 mL of isovolemic hemodilution (from 50 +/- 5 to 70 +/- 7 and 77 +/- 6 mL.min-1.100 g-1, respectively; P less than 0.05) compared with basal values (50 +/- 5.mL-1.min-1.100 g-1; P less than 0.05). Oxygen content remained unchanged, whereas hemoglobin concentration decreased in parallel with the decrease in hematocrit. In a second set of experiments, the role of endogenous nitric oxide (NO) as a possible mediator of the gastric vascular changes induced by hemodilution was investigated by using the specific inhibitor of NO biosynthesis, NG-monomethyl-L-arginine (L-NMMA). The increase in GMBF induced by 3 mL of isovolemic hemodilution (delta 23 +/- 7 mL.min-1.100 g-1) was attenuated in a dose-related manner with L-NMMA, 6.25 mg/kg IV (delta 15 +/- 4 mL.min-1.100 g-1) or 50 mg/kg IV (delta 5 +/- 2 mL.min-1.100 g-1 g; P less than 0.05). The concurrent administration of L-arginine (the precursor of NO biosynthesis) abolished the effects of L-NMMA on GMBF changes. The current findings show that acute normovolemic anemia causes an increase in GMBF that is dependent on the endogenous formation of NO.     

Quantitative liver function in the elderly assessed by galactose elimination capacity, aminopyrine demethylation and caffeine clearance

Hepatic function was assessed in 13 healthy elderly subjects, 71-88 years of age, with three quantitative tests of liver function. The galactose elimination capacity was significantly (P less than 0.05) lower in the elderly (6.08 +/- 1.30 mg X min-1 X kg-1, mean +/- SD) than in a group of 70 subjects under 40 (7.48 +/- 0.94 mg X min-1 X kg-1) and 11 subjects between the age of 40 and 70 (7.08 +/- 0.68 mg X min-1 X kg-1). The demethylation of aminopyrine as assessed by the aminopyrine breath test, and the systemic clearance of caffeine, two measures of microsomal function, demonstrated a comparable decrease but showed much more interindividual variation. Caffeine clearance decreased from 1.49 +/- 0.44 ml X min-1 X kg-1 in young adults to 0.97 +/- 0.39 ml X min-1 X kg-1 (P less than 0.01) in the elderly, and the demethylation of aminopyrine decreased from 0.79 +/- 0.15 to 0.62 +/- 0.20% dose X kg X mmol-1 (P less than 0.05). Our data indicate that aging is associated with a loss of the functioning mass of hepatocytes. The decrease in drug metabolism parallels the loss of functional mass but shows more interindividual variation probably reflecting the many genetic and environmental factors influencing these tests of microsomal function.     

Glucose and lactate interrelations during moderate-intensity exercise in humans

To evaluate circulating lactate and glucose kinetics during moderate-intensity exercise, we studied ten healthy endurance-trained men (aged 25 +/- 6 years) during 30 to 50 minutes of supine cycle ergometer exercise at 43% +/- 5% of maximal oxygen consumption (VO2 max) using isotopic tracer techniques. Seven subjects received [U-13C]-lactate and [6-14C]-glucose, and three received [1-14C]-lactate and [U-13C]-glucose. Arterial glucose and lactate concentrations were 94.0 +/- 4.1 and 5.66 +/- 0.87 mg/dL at rest, and 95.7 +/- 3.4 and 8.38 +/- 3.87 mg/dL, respectively, after 25 minutes of exercise. The rate of glucose disappearance (RdG) increased from 2.41 +/- 0.40 at rest to 3.38 +/- 0.77 mg x kg-1 x min-1 during exercise, compared with the much larger rise in the rate of lactate appearance (RaL), which increased from 1.25 +/- 0.20 to 3.47 +/- 0.79 mg x kg-1 x min-1. During exercise RaL was 103% of RdG, compared with only 52% at rest. The rate at which the blood was cleared of lactate increased from 22.7 +/- 2.2 at rest to 44.2 +/- 11.2 ml x kg-1 x min-1 after 25 minutes of exercise. From secondary labeling of lactate with glucose carbons, the rate of glucose conversion to lactate was estimated to be 0.65 +/- 0.16 mg x kg-1 x min-1 during exercise. Twenty percent of the glucose utilization went to lactate formation during exercise, and 20% of the blood lactate appearance came from blood glucose, with the balance presumably coming from muscle glycogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic and extrahepatic splanchnic glucose metabolism in the postabsorptive and glucose fed dog

In awake dogs we measured the glucose balance across the liver and extrahepatic splanchnic tissues in the postabsorptive state and during two hours of IV infusion of glucose or for three hours following ingestion of oral glucose and during four hours of sequential intraportal followed by oral glucose. The IV glucose infusion rate was adjusted to maintain a steady state glucose concentration of either euglycemic levels (insulin clamp, group 1, N = 4), 125 mg/100 mL above the postabsorptive glucose concentration (+125 mg glucose clamp, group 2, N = 3) or 200 mg/100 mL above basal glucose levels (+200 mg glucose clamp, group 3, N = 7). Oral glucose was given at a dose of either 1.5 g/kg (group 4, N = 7) or 2.5 g/kg (group 5, N = 12). In dogs that received IV glucose, basal gut glucose uptake (0.5 +/- 0.1 mg/min X kg) was stimulated by hyperglycemia (1.5 +/- 0.5 and 1.4 +/- 0.1 mg/min X kg for group 2 and 3, respectively, P less than 0.05). In these same animals basal hepatic glucose output (-2.7 +/- 0.3 mg/min X kg) was promptly suppressed and net hepatic glucose uptake occurred (2.8 +/- 0.2 and 2.4 +/- 0.5 mg/min X kg in group 2 and 3 respectively). Euglycemic hyperinsulinemia (group 1) suppressed postabsorptive hepatic glucose release but did not enhance glucose removal by either the liver or gut tissues. After oral glucose gut tissues released absorbed glucose into portal blood. Over three hours following the glucose meal 74% and 59% of the ingested glucose was absorbed in group 4 and 5, respectively. As with IV glucose, postabsorptive hepatic glucose production was suppressed and over the first two hours after feeding the liver took up glucose (3.4 +/- 1.0 and 3.1 +/- 0.7 mg/min X kg groups 4 and 5, respectively) at a rate similar to that seen with IV glucose. To further examine the effect of the route of glucose administration on liver glucose handling, hepatic glucose balance was measured serially over four hours in three dogs that received IV glucose into a mesenteric vein to produce portal hyperglycemia (+125 mg/dL portal glucose clamp N = 3). Oral glucose (2.5 mg/kg) was given at two hours, and the rate of the mesenteric glucose infusion adjusted to maintain portal glycemia constant. The hepatic glucose balance averaged 5.5 mg/min X kg over the 0 to 2 hour period and 4.2 +/- 1.0 mg/min X kg over the 2 to 4 hour time.(ABSTRACT TRUNCATED AT 400 WORDS)