The gene encoding the catalytic subunit C alpha of cAMP-dependent protein kinase (locus PRKACA) localizes to human chromosome region 19p13.1

OBJECTIVE: The importance of portal hypertensive gastropathy, as a potentially bleeding lesion in cirrhotics with portal hypertension, has recently been appreciated. Histologically, dilation of the mucosal and submucosal vessels of the stomach is noted in this entity. The possibility of nitric oxide acting as a mediator for this mucosal vascular dilation has not been explored. METHODS: We determined, in a group of 10 male cirrhotic patients with esophageal varices and endoscopic changes consistent with severe portal hypertensive gastropathy (Group A), the gastric mucosal nitric oxide synthase activity. This was determined by measuring the rate of conversion of [3H]-arginine to [3H]-citrulline. Serum levels of nitrates and nitrites, the end products of nitric oxide, were also measured. The results were compared with those of a group of 10 male controls with no liver disease (Group B). RESULTS: Gastric mucosal constitutive and inducible nitric oxide synthase levels were significantly higher in group A (125.4 +/- 4.3 and 259.7 +/- 5.5 pmol/mg protein/minute, respectively) than in group B (88 +/- 8.6 and 130.8 +/- 6.6 pmol/mg protein/minute, respectively) ( p < 0.002 and < 0.0001, respectively). Serum nitrate/nitrite levels were 30.1 +/- 3.2 nmol/ml in group A and 15.5 +/- 0.09 nmol/ml in group B (p < 0.001). CONCLUSIONS: We conclude that the significantly increased gastric mucosal nitric oxide synthase activity, in patients with portal hypertensive gastropathy, suggests an important role for nitric oxide in the pathogenesis of this mucosal lesion.     

Antifibrotic and hemodynamic effects of the early and chronic administration of octreotide in two models of liver fibrosis in rats

The aim of this study was to assess the effect of the early and chronic administration of octreotide in the prevention of hepatic fibrosis and portal hypertension (PHT). Two experimental models of liver fibrosis caused by bile duct ligation (BDL) or CCl4 were divided into 4 rat groups: sham, placebo, and octreotide (10 and 100 micrograms/kg twice daily, subcutaneously). Liver fibrosis was assessed by the area of fibrosis (image analysis), liver hydroxyproline and fibronectin mRNA contents, and serum hyaluronate. Systemic and splanchnic hemodynamic changes were also evaluated, including the splenorenal shunt blood flow by the transit-time ultrasound (TTU) technique. In both models, splenorenal shunt blood flow was significantly lower in the octreotide groups than in the placebo group (P <.05), while portal pressure was not significantly decreased. There was a significant decrease in fibrosis by octreotide in the CCl4 model only: area of fibrosis: 13.9% +/- 3.7% vs. 9.8% +/- 2.5% (P <.01), hydroxyproline: 1.8 +/- 0.6 vs. 1.3 +/- 0.4 mg/g wet liver (P <.05), respectively, placebo vs. octreotide 10 micrograms/kg. There was a significant correlation between the area of fibrosis and hydroxyproline liver content (r =.87 in the biliary model and r =.91 in the CCl4 model; P <.0001). The early and chronic administration of octreotide prevents the development of portocollateral blood flow without reducing portal pressure in two models of liver fibrosis and the development of liver fibrosis in the CCl4 model.     

Ameloblastic fibroma: a fine-needle aspiration case report

The aim of this study was to determine the effect of portal hypertension (PHT) on gastric mucosal glycoproteins in rats. PHT was induced experimentally by partial ligation of the portal vein (PVL) in 20 male Wistar rats: 10 rats (PVL4 group) were analyzed after 4 weeks and the remaining 10 (PVL8 group) after 8 weeks. In another group of 10 rats (control group), sham operations were performed. The severity of gastric mucosal lesions was evaluated macroscopically by a gross ulcer index. The gross ulcer indices in the PVL groups were significantly higher than those in the controls (p < 0.05). Histomorphometric evaluation of the intraepithelial mucin content, with the periodic acid-Schiff-Alcian blue staining technique, confirmed a significant decrease in mucosal glycoprotein production in the PVL groups (p < 0.05). Quantitative changes in gastric mucosal hexosamines were also used for mucosal glycoprotein analyses, and the hexosamine content of the gastric mucosa in the control, PVL4 and PVL8 groups were 300.7 +/- 7.8, 177.2 +/- 4.9 and 169.1 +/- 3.5 micrograms/100 mg dried mucosa, respectively. The gastric mucosal hexosamine content was significantly lower in the PVL groups than in the control group (p < 0.05). No significant differences were observed between the two PVL groups in the above-studied parameters. These findings reveal that PHT causes a decrease in gastric mucosal glycoproteins in rats, and the decreased mucin content may weaken an important defensive factor of gastric mucosa. We suggest that gastric mucosal glycoproteins may play an important role in the pathogenesis of gastric mucosal lesions from PHT.     

Measurement of collateral circulation blood flow in anesthetized portal hypertensive rats

AIMS: The aim of this study was to develop a technique to measure collateral blood flow in portal hypertensive rats. METHODS: Morphological techniques included inspection, casts and angiographies of portosystemic shunts. The main hemodynamic measurements were splenorenal shunt blood flow (transit time ultrasound method), percentage of portosystemic shunts and regional blood flows (microsphere method). In study 1, a model of esophageal varices was developed by ligating the splenorenal shunt. In study 2, morphological studies of the splenorenal shunt were performed in rats with portal vein ligation. In study 3, the relationship between splenorenal shunt blood flow with percentage of portosystemic shunts was evaluated in dimethylnitrosamine cirrhosis. In study 4, secondary biliary, CCl4 and dimethylnitrosamine cirrhosis were compared. In study 5, rats with portal vein ligation received acute administration of octreotide. In study 6, rats with dimethylnitrosamine cirrhosis received acute administration of vapreotide. RESULTS: Blood flow of para-esophageal varices could not be measured. SRS blood flow was correlated with the mesenteric percentage of portosystemic shunts (r = 0.74, P < 0.05), splenic percentage of portosystemic shunts (r = 0.54, P < 0.05) and estimated portosystemic blood flow (r = 0.91, P < 0.01). Splenorenal shunt blood flow was 6 to 12 times higher in portal hypertensive rats, e.g., in portal vein ligated rats: 2.8 +/- 2.7 vs 0.3 +/- 0.1 mL.min-1 in sham rats (P < 0.01), and was similar in the different cirrhosis models but was higher in portal vein ligated rats than in cirrhotic rats (1.2 +/- 0.7 vs 0.6 +/- 0.6 mL.min-1.100 g-1, P = 0.05). Octreotide significantly decreased splenorenal shunt blood flow: -23 +/- 20% (P < 0.01) vs -6 +/- 8% (not significant) in placebo rats. The variation of splenorenal shunt blood flow after vapreotide was significant but not that of the splenic percentage of portosystemic shunts compared to placebo. CONCLUSIONS: The splenorenal shunt is the main portosystemic shunt in rats. The measurement of splenorenal shunt blood flow is easy, accurate and reproducible and should replace the traditional measurement of the percentage of portosystemic shunts in pharmacological studies.     

Bleeding in portal hypertensive gastropathy evaluated in terms of gastric mucosal microcirculation and coagulation-fibrinolysis system

Gastric intramucosal bleeding in portal hypertensive gastropathy was investigated in terms of gastric mucosal microcirculation, coagulation-fibrinolysis factors, and local fibrinolysis in patients with liver cirrhosis. The gastric mucosa was examined by endoscopy, and the patients were classified into two groups with or without bleeding. Gastric mucosal blood flow was measured simultaneously with coagulation-fibrinolysis factors or local fibrinolysis in both groups. As gastric mucosal blood flow, the gastric mucosal blood volume (IHb) and the oxygenated hemoglobin concentration (ISO2) were determined by the organ reflection spectrum method. Coagulation-fibrinolysis factors were measured in the blood. For evaluation of local fibrinolysis, gastric biopsy specimens were placed on a standard fibrin plate, and the fibrinolysis area was measured. Compared with the non-bleeding group, the bleeding group showed increased IHb and decreased ISO2 (p < 0.05), suggesting marked congestion of blood flow. Gastric intramucosal bleeding was frequently observed in patients with marked congestion of blood flow and markedly abnormal values of coagulation-fibrinolysis factors. Gastric local fibrinolysis was also significantly enhanced in the bleeding group (p < 0.05). In addition, local fibrinolysis was correlated positively with the gastric mucosal blood volume (r = 0.68, p < 0.05) and negatively with the oxygenated hemoglobin concentration (r = -0.58, p < 0.05). These results suggest the following mechanism of gastric mucosal bleeding in liver cirrhosis and portal hypertension. Congestion of gastric mucosal blood flow is present in liver cirrhosis and portal hypertension. An increase in the microvascular pressure and hypoxia cause release of tissue plasminogen activators from gastric mucosal cells and vascular endothelial cells. As a result, gastric local fibrinolysis is enhanced, causing gastric mucosal bleeding.     

Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis

Administration of angiotensin II causes an increase in portal pressure, and plasma concentration of angiotensin II is elevated in patients with cirrhosis, suggesting that angiotensin II may be involved in the pathogenesis of portal hypertension in cirrhosis. We evaluated the effect of the orally active angiotensin II receptor antagonist, losartan, on portal pressure in patients with cirrhosis and portal hypertension. Thirty patients with severe (hepatic venous pressure gradient [HVPG] >/= 20 mm Hg) and 15 patients with moderate (HVPG < 20 mm Hg) portal hypertension at baseline measurement were treated with an oral dose of 25 mg losartan once daily for 1 week and compared with 15 (HVPG >/= 20 mm Hg) and 10 (HVPG < 20 mm Hg), respectively, cirrhotic controls. On the seventh day, HVPG was determined again, and blood pressure, heart rate, body weight, and parameters of liver and kidney function were recorded. Losartan induced a significant (P <.001) decrease of HVPG in the patients with severe (-46.8% +/- 15.5%) and moderate (-44.1% +/- 14.7%) portal hypertension, while no significant change was seen in the controls. Losartan caused a slight but significant (P <.01) fall in mean arterial blood pressure (-3.1 +/- 5.0 and -3.5 +/- 4.3 mm Hg, respectively). One patient treated with losartan had a short symptomatic hypotensive reaction after the first dose of losartan that did not recur despite continued treatment. No deterioration of liver or kidney function was observed. The present study indicates that angiotensin II blockade with orally administered losartan is safe and highly effective in the treatment of portal hypertension.     

Reduced left ventricular hypertrophy in type 1 diabetic patients with end-stage renal failure. A comparison between groups investigated 1977-80 and 1991-93

BACKGROUND: During the last decade, control of hypertension, oedema, anaemia, uraemia, and blood glucose has improved in patients with diabetic nephropathy. We have investigated whether this has influenced cardiac function at the time of end-stage renal failure. STUDY DESIGN: Echocardiographic investigations were performed in 26 type 1 diabetic patients evaluated for kidney transplantation and the results compared with those obtained in healthy controls and in a similar group of patients investigated in 1977-1980. RESULTS: Blood pressure was 153 +/- 21/85 +/- 12 mmHg versus 174 +/- 17/91 +/- 9 (recent group versus early group). The left ventricular (LV) diameter index, a measure of volaemia, was increased in systole and diastole in the early but not in the recent group. Both groups had LV hypertrophy, but this was much less pronounced in the recent group; posterior wall thickness was 1.1 +/- 0.16 cm versus 1.3 +/- 0.26 cm (P = 0.0001) and LV mass index 132 +/- 43 g/m2 versus 166 +/- 44 g/m2 (P = 0.009). Blood pressure correlated significantly with indices of LV hypertrophy in the recent group. Systolic function was normal in both groups but diastolic function was disturbed in both and to the same extent, atrial systole contributing by 27 +/- 14% to ventricular filling. CONCLUSION: Better treatment of hypertension, fluid overload, and uraemia has led to less pronounced LV hypertrophy. The remaining correlation with blood pressure suggests that more could be gained by intensified antihypertensive treatment.     

Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation

Recent observations showed an improvement of hepatic macro- and microhemodynamics as well as survival rates after warm ischemia of the liver following treatment with N-acetylcysteine (NAC). In this study we assessed the influence of NAC on the hepatic microcirculation after orthotopic liver transplantation (OLT) using intravital fluorescence microscopy. OLT with simultaneous arterialization was performed in 16 male Lewis rats following cold storage in University of Wisconsin solution for 24 hr. Within the experimental group (n = 8) donors received NAC (400 mg/kg) 25 min before hepatectomy. In addition, high-dose treatment of recipients with NAC (400 mg/kg) was started with reperfusion. Control animals (n = 8) received an equivalent amount of Ringer's solution. Intravital fluorescence microscopy was performed 30-90 min after reperfusion assessing acinar and sinusoidal perfusion, leukocyte-endothelium interaction, and phagocytic activity. Treatment with NAC reduced the number of nonperfused sinusoid from 52.4 +/- 0.8% to 15.7 +/- 0.5% (p = 0.0001) (mean +/- SEM). Furthermore, we achieved a significant reduction of leukocytes adhering to sinusoidal endothelium (per mm2 liver surface) from 351.9 +/- 13.0 in controls to 83.6 +/- 4.2 in the experimental group (P = 0.0001). In postsinusoidal venules, treatment with NAC decreased the number of sticking leukocytes (per mm2 endothelium) from 1098.5 +/- 59.6 to 425.9 +/- 37.7 (P = 0.0001). Moreover, bile flow was significantly increased after therapy with NAC (4.3 +/- 1.2 vs. 2.2 +/- 0.7 ml/90 min x 100g liver) (P < 0.05). Phagocytic activity was not influenced by application of NAC. We conclude that high-dose therapy with NAC in OLT attenuates manifestations of microvascular perfusion failure early after reperfusion and should be considered as a means to reduce reperfusion injury.     

Massive lymphocytic infiltration of uterine leiomyomas associated with GnRH agonist treatment

OBJECTIVE: This study was designed to clarify how thrombopoietin (TPO) functions in and, to some extent, causes thrombocytopenia complicating liver cirrhosis and portal hypertension. METHODS: Our study population consisted of 19 cirrhotic and six noncirrhotic patients who underwent percutaneous transhepatic portography (PTP) and hepatic venography. RESULTS: The platelet counts of the cirrhotic patients were significantly lower than those of the noncirrhotic patients (8.7 +/- 4.1 vs 17.4 +/- 7 x 10(4)/microl; p < 0.01). The flow direction in the splenic vein was confirmed by PTP. Ten hepatofugal and nine hepatopetal flow directions in the splenic vein were noted among the cirrhotics. The hepatofugal group showed lower portal venous pressure (20 +/- 10 vs 32 +/- 4 cm H2O; p < 0.01) than the hepatopetal group and had a higher incidence of hepatic encephalopathy (six of 10 vs zero of nine; p < 0.01). The hepatic vein-portal difference in TPO did not differ substantially between the cirrhotics and noncirrhotics (0.12 +/- 0.04 vs 0.24 +/- 0.07 fmol/ml). Comparisons of this value among the three groups showed the TPO difference to be lowest in the hepatofugal group (hepatofugal: 0.04 +/- 0.03, hepatopetal: 0.21 +/- 0.07, noncirrhotic: 0.24 +/- 0.07; p < 0.05). CONCLUSIONS: Our findings suggest that TPO production in the cirrhotic liver is regulated by the portal blood supply to the liver. Thus, portal hemodynamics may play a critical role in the development of thrombocytopenia.     

Bone mineral density in pediatric patients with idiopathic hypercalciuria

Between October 1993 and April 1995, a total of 77 neonates requiring mechanical ventilation were enrolled in this study and were randomly divided into two groups. Group A consisted of 31 premature infants (mean birthweight 1.36 +/- 0.29 kg) with respiratory distress syndrome (RDS) and seven neonates (mean birthweight 3.2 +/- 0.5 kg) with meconium aspiration syndrome (MAS). Group B consisted of 31 premature infants (mean birthweight 1.31 +/- 0.3 kg) with RDS and eight neonates (mean birthweight 3.3 +/- 0.5 kg) with MAS. Infants in group A received synchronized intermittent mandatory ventilation (SIMV) and infants in group B received conventional intermittent mandatory ventilation (CIMV) therapy. In premature infants with RDS, our data showed: (i) the duration of ventilation was significantly shorter (P < 0.05) in the synchronized group (156 +/- 122 h) compared to the conventional group (242 +/- 175 h); (ii) significantly fewer (P < 0.05) patients required reintubation in the synchronized group than in the conventional group (three vs 11 patients); (iii) incidence of severe intraventricular hemorrhage (grades 3 and 4) was significantly lower (P < 0.05) in the synchronized group compared to the conventional group (one vs seven patients); (iv) incidence of bronchopulmonary dysplasia was significantly lower (P < 0.05) in the synchronized group than in the control group (one vs seven patients). In neonates with MAS, our data showed no significant difference (P < 0.05) on duration of ventilation, incidence of reintubation, incidence of pneumothorax or mortality rate between synchronized and control groups.     

Endoscopic assessment of variceal volume and wall tension in cirrhotic patients: effects of pharmacological therapy

BACKGROUND & AIMS: Variceal rupture is believed to occur when variceal wall tension is excessive. The combined use of endosonography, allowing the objective measurement of variceal radius, and endoscopic measurement of transmural variceal pressure may enable assessment of this important parameter. The aim of this study was to assess the effects on variceal hemodynamics of drugs acting through different mechanisms: decreasing portocollateral blood flow (propranolol) or resistance (isosorbide-5-mononitrate [ISMN]). METHODS: Repeated measurements of variceal radius, volume (by endosonography), and transmural pressure (using endoscopic gauge) were performed in 27 cirrhotic patients at baseline and 40 minutes after double-blind administration of placebo (n = 9), propranolol (n = 9), or ISMN (n = 9). RESULTS: Placebo had no effect. Propranolol significantly reduced variceal volume (-32% +/- 26%; P = 0.01), radius (-12% +/- 9%; P < 0.005), and pressure (-26% +/- 10%; P < 0.0001). The resulting decrease in wall tension (-34% +/- 13%; P < 0.0005) exceeded that in transmural pressure (P < 0.01). ISMN reduced transmural variceal pressure (-26% +/- 21%; P < 0.005), but not radius (-3% +/-14%; NS) and volume (-9% +/- 31%; NS). CONCLUSIONS: The combination of endosonography and endoscopic measurement of transmural variceal pressure allows quantitative estimation of variceal wall tension. Propranolol and ISMN reduce similarly transmural variceal pressure. Propranolol, but not ISMN, reduces variceal volume and radius. Therefore, despite similar decreases in variceal wall tension, propranolol may offer a greater therapeutic effect than ISMN in portal hypertension.     

Effect of endoscopic sphincterotomy on gallbladder motility

In experimental animals, sphincterotomy facilitates passage of solids from the gallbladder and inhibits gallstone formation apparently by improvement in gallbladder emptying. In humans, however, gallbladder emptying has not been studied following endoscopic sphincterotomy (ES) in patients with gallstones. We therefore prospectively studied resting and cerulin-stimulated gallbladder volumes by real time ultrasonography in 15 patients of choledocholithiasis with gallbladder in situ (eight with and seven without gallbladder calculi) before and after (after bile duct clearance) ES. ES significantly lowered resting gallbladder volume (21.2 +/- 10.6 vs 11.1 +/- 5.0; P < 0.0001) and cerulin-stimulated residual gallbladder volume (10.8 +/- 5.6 vs 4.4 +/- 2.1; P < 0.0001). ES also significantly increased the gallbladder ejection fraction (47.3 +/- 12.1% vs 58.8 +/- 11.1%; P < 0.0001). The rate constant for gallbladder emptying after cerulin infusion also increased significantly after ES (-0.022/min vs -0.031/ min; P < 0.0001). Significant improvement in gallbladder motility was observed in both groups of patients with and without gallbladder calculi. ES significantly improves gallbladder motility in humans.     

Establishment of uterine cell lines from p53-deficient mice

OBJECTIVE: To evaluate the relationship of E-cadherin (E-CD) expression to cellular DNA content and biological behavior of gastric cancer. METHODS: E-CD expression and cellular DNA content were quantitatively measured by flow cytometry and immunofluorescence methods in 80 cases of formalin-fixed, paraffin-embedded gastric cancer. Systematic pathological examinations and follow up were performed for all cases. RESULTS: E-CD expression was significantly reduced in all cases of gastric cancer, fluorescence Index (FI) of E-CD expression was 0.67 +/- 0.11 in gastric cancer, 1.0 +/- 0.07 in normal gastric mucosa (P < 0.001). The reduction of E-CD expression was also found in 2 cases of early gastric cancer. Tumors with a decrease in E-CD expression occurred significantly more frequently in undifferentiated, diffuse growth pattern Borrmann 4 type, positive lymph node (LN) metastasis and infiltrated serosa type gastric cancer, of which survival time was within 5 years (P < 0.001). E-CD expression was also reduced in gastric cancer with the number of LN metastasis above 5, metastasis to more than group 2. E-CD expression was lower in uneuploid cancer than that in diploid cancer (P < 0.01). The value of DI and PI with negative E-CD expression was significantly higher than that of positive E-CD expression (P < 0.01). CONCLUSION: Down-regulation of E-CD expression correlates with bad biological behavior and poor prognosis of gastric cancer. The reduction of E-CD expression may take place during early time of gastric cancer. Quantitative analysis of E-CD expression may have some value in evaluating the intensity of LN metastasis of gastric cancer.     

Imaging evaluation of subluxation in Legg-Calvé-Perthes disease: magnetic resonance imaging compared with the plain radiograph

Angiotension-II (A-II) receptor maximal binding capacity (Bmax) and dissociation constants (Kd) of different blood vessels in rats with prehepatic portal hypertension were studied by radioligand binding analysis. The results showed that the A-II receptor Bmax in the thoracic aorta, superior mesenteric artery and portal vein of portal hypertensive animals (113.7 +/- 19.4 fmol/mg protein, 206.9 +/- 39.3 fmol/mg protein and 31.5 +/- 9.2 fmol/mg protein respectively) was all significantly lower than that of controls (146.8 +/- 24.5 fmol/mg protein, 297.2 +/- 44.7 fmol/mg protein and 53.4 +/- 12.1 fmol/mg protein respectively, P < 0.01). The A-II receptor Kd in the superior mesenteric artery was markedly increased in portal hypertensive animals (1.03 +/- 0.11 nmol/L) compared with that in controls (0.88 +/- 0.08 nmol/L, P < 0.05). In the thoracic aorta and portal vein, the A-II receptor Kd in portal hypertensive animals was slightly higher than that in controls, but no significant difference was observed between the two groups. The results suggested that the vascular hyporesponsiveness to A-II in portal hypertension was caused partially by a reduction in number and a decrease in affinity of vascular A-II receptors, and these changes might possibly lead to the formation of hyperdynamic circulation.     

Effect of spinal cord injury on the permeability of the blood-brain and blood-spinal cord barriers to the neurotropin PACAP

BACKGROUND & AIMS: The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN). METHODS: Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. RESULTS: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (-24.2% +/- 11% vs. -16.1% +/- 11%; P < 0.01). A reduction in HVPG of > 20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%; P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (P = 0.16). CONCLUSIONS: Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.     

Endothelin-1 receptor antagonism does not influence myocardial function in hypertensive dogs

BACKGROUND: As endothelin-1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin-1 receptor antagonist bosentan were partially related to a decrease in myocardial performance. METHODS: In group I, eight anaesthetized open-chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1-B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure-length loops obtained during vena cava occlusion. RESULTS: In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 +/- 8 to 150 +/- 5 mmHg, P < 0.001; MAP from 167 +/- 7 to 128 +/- 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 +/- 83 to 446 +/- 53 mmHg mL-1 min-1 x 10(4); P < 0.05), and the end-systolic pressure-length relationship (ESPLR) remained unchanged (4.0 +/- 0.4 vs. 4.3 +/- 0.7 mmHg mm-1 kg-1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 +/- 4 to 156 +/- 6 beats min-1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 +/- 0.9 vs. 3.1 +/- 0.5mmHg-1 mm kg-1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 +/- 4 to 110 +/- 6 beats min-1, P < 0.001). CONCLUSIONS: Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.     

The effect of hepatocyte enlargement on the hemodynamic characteristics of the isolated perfused rat liver preparation

The influence of hepatocyte enlargement on intrahepatic hemodynamics was assessed in the isolated perfused rat liver preparation (IPRL) using two experimental models: hypotonic liver cell swelling and phenobarbitone-induced hepatocyte hypertrophy. The analysis of pressure-flow data obtained from the portal vascular bed over a flow range of 0 to 70 mL/min in the presence of a maximally-effective concentration of the vasodilator agent papaverine hydrochloride (6 x 10(-4) mol/L) enabled the calculation of P0, an estimate of the pressure required to passively distend the intrahepatic vasculature, and Gmax, the maximal portal vascular conductance. By comparison with an isotonic perfusion medium (Krebs-Henseleit buffer [KH] containing 2.5% bovine serum albumin [BSA]), perfusion with a hypotonic medium induced a significant increase in mean hepatocyte cross-sectional area (H(A)) (590 +/- 21 vs. 324 +/- 23 microm(-2), p < .05), a fall in Gmax (0.39 +/- 0.08 vs. 2.02 +/- 0.18 mL/min/g/mm hg, P < .001), and an increase in P0 (2.96 +/- 0.38 vs. 1.58 +/- 0.07 mm hg, P < .001). Phenobarbitone administered in drinking water (0.5 g/L) over a period of 60 days also induced a significant degree of hepatocyte enlargement (HA, 510 +/- 29 microm2, P < .05). On day 7, portal pressure measured in vivo in this group was significantly elevated compared with untreated controls (10.5 +/- 0.3 vs. 8.4 +/- 0.2 mm hg, P < .001), while in the IPRL Gmax was reduced (0.48 +/- 0.01 mL/min/g/mm hg, P < .001), and P0 was increased (2.23 +/- 0.17 mm hg, P < .05). However, with continued phenobarbitone treatment portal pressure, Gmax and P0 returned toward control values. The results confirm that hepatocyte enlargement is associated with a significant disturbance of intrahepatic hemodynamics but also that some adaptation occurs if hepatocyte enlargement is sustained over a prolonged period of time.     

Structured patient education for out-patients with hypertension in general practice: a model project in Germany

In a model project, office-based physicians in two regions of Germany provided a structured treatment and teaching programme for out-patients with hypertension. The project was carried out in co-operation with the German Hypertension League and designed to evaluate the practicability and efficacy of the implementation in routine primary health care. A total of 111 primary health care practices in two German districts who had participated in a training course were interviewed. In 43 of these offices documented data of all patients who had received the standardised treatment and teaching were evaluated. The programme was well received by the physicians of which 81% rated the training course and 93% the teaching material as 'very good' or 'good'. A total of 466 patients were trained. Data collected on 272 patients (22 weeks after the intervention) demonstrated the efficacy of the programme at treatment level: reduction of body weight (2 kg, P < 0.001) and blood pressure (from systolic 158+/-18 to 148+/-17 mm Hg, P < 0.001; diastolic 91 +/-9 to 86+/-9, P < 0.001). Sixty-five per cent of patients learned for the first time how to perform blood pressure self-monitoring during the programme. The number of blood pressure readings by the patients' increased significantly from 1+/-3 measurements per week before, to 8+/-7 measurements per week after the programme (P < 0.001). The results of the study demonstrate the practicability and efficacy of the implementation of the programme for patients with hypertension into routine primary health care.     

A new method of high-dose intraarterial chemotherapy of the pancreas using direct hemoperfusion (DHP) under portal venous isolation (PVI)

Surgical resection for pancreatic cancer is severely limited by the extent of the disease at the time of diagnosis. Chemotherapy has been the treatment of choice for unresectable cases. We developed a new method of intraarterial chemotherapy for pancreatic body and tail cancers using direct hemoperfusion (DHP) under portal venous isolation (PVI). Adriamycin (ADR, 3 mg/kg) was infused into the splenic arteries of mongrel dogs for 5 min after clamping off blood flow to the stomach and the duodenum. In group A (n = 5), this was simply done, and in group B (n = 5) the portal venous blood was isolated by clamping at the porta hepatis and pumped through the DHP circuit to the jugular vein for 20 min from the start of drug infusion. The peak systemic level (microgram/ml) of group B (0.78 +/- 0.03) was significantly reduced by PVI.DHP as compared to that of group A (3.49 +/- 1.15, P < 0.01). The pancreatic tissue levels (microgram/g. tissue) 30 min after drug infusion of group A (61.2 +/- 13.4) were slightly lower than those in group B (88.9 +/- 27.8), although not statistically significant. However, tissue levels of group B in the liver (27.3 +/- 9.2) and heart (1.8 +/- 0.8) were significantly lower than those of group A (liver; 52.3 +/- 18.5, heart; 4.9 +/- 0.6, P < 0.05). In conclusion, PVI.DHP achieved a significant reduction in systemic drug exposure during intraarterial chemotherapy. Therefore, we consider that this system will allow dose escalation of ADR during intraarterial chemotherapy for pancreatic body and tail cancers.