Fibroblast growth factor receptor is a mechanistic link between visceral adiposity and cancer.

Epidemiological evidence implicates excess adipose tissue in increasing cancer risk. Despite a steeply rising global prevalence of obesity, how adiposity contributes to transformation (stage a non-tumorigenic cell undergoes to become malignant) is unknown. To determine the factors in adipose tissue that stimulate transformation, we used a novel ex vivo system of visceral adipose tissue (VAT)-condition medium-stimulated epithelial cell growth in soft agar. To extend this system in vivo, we used a murine lipectomy model of ultraviolet light B-induced, VAT-promoted skin tumor formation. We found that VAT from mice and obese human donors stimulated growth in soft agar of non-tumorigenic epithelial cells. The difference in VAT activity was associated with fibroblast growth factor-2 (FGF2) levels. Moreover, human and mouse VAT failed to stimulate growth in soft of agar in cells deficient in FGFR-1 (FGF2 receptor). We also demonstrated that circulating levels of FGF2 were associated with non-melanoma tumor formation in vivo. These data implicate FGF2 as a major factor VAT releases to transform epithelial cells-a novel, potential pathway of VAT-enhanced tumorigenesis. Strategies designed to deplete VAT stores of FGF2 or inhibit FGFR-1 in abdominally obese individuals may be important cancer prevention strategies as well as adjuvant therapies for improving outcomes.

Transvaginal uterine cervical dilation with fluoroscopic guidance: preliminary results in patients with infertility.

PURPOSE: To assess efficacy of uterine cervical dilation performed with fluoroscopic guidance to treat patients with infertility who have cervical stenosis, false channels within the endocervical canal, or both. MATERIALS AND METHODS: Fifteen patients in whom infertility was diagnosed were referred because the uterine lumen could not be accessed. Three of the patients had endometriosis. With fluoroscopic guidance, the cervix was cannulated and the endocervical canal was dilated with an angioplasty balloon or with dilators. Five patients underwent simultaneous fallopian tube recanalization. Five of 15 patients who underwent dilation subsequently underwent in vitro fertilization for embryo transfer (IVF-ET) or intrauterine insemination. RESULTS: Four patients became pregnant. Of those four, one underwent IVF-ET and one underwent intrauterine insemination. Two patients became pregnant spontaneously. In the five patients who underwent IVF-ET or intrauterine insemination and in the remaining eight patients, the cervix could be easily cannulated up to 7 months after dilation. CONCLUSION: Dilation of the uterine cervix may provide options for treatment in selected patients with infertility. The effect of dilation on patients with other sequelae of cervical obstruction such as endometriosis remains uncertain.

The effects of chronic administration of indomethacin and misoprostol on renal function in cirrhotic patients with and without ascites.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) often cause renal dysfunction in cirrhotic patients with ascites through inhibition of prostaglandin synthesis. However, their renal effects in cirrhotic patients without ascites are controversial. In addition, the role of prostaglandins in cirrhotic patients with ascites and in non-ascitic cirrhotic patients receiving NSAIDs also remains elusive. Thus we evaluated the chronic renal effects of indomethacin and misoprostol in 9 cirrhotic patients with ascites (protocol 1) and 21 cirrhotic patients without ascites (protocol 2). METHODS: The patients of protocol 1 received 200 micrograms of misoprostol every 6 h for 7 consecutive days. In protocol 2, 11 patients received 25 mg indomethacin three times a day for 7 consecutive days. The other 10 patients received 25 mg indomethacin three times a day plus 200 micrograms misoprostol every 6 h for 7 consecutive days. Renal function tests, plasma renin activity, and plasma aldosterone concentration were measured before and after treatment. RESULTS: In protocol 1, misoprostol tended to reduce the urinary sodium excretion (p = 0.08). In protocol 2, indomethacin alone greatly impaired renal plasma flow (p < 0.05), creatinine clearance (p < 0.05), blood urea nitrogen (p < 0.05), and serum creatinine (p = 0.06) in 11 patients. Similar magnitudes of renal dysfunction were observed in the other 10 patients despite the concomitant misoprostol treatment. CONCLUSION: Chronic administration of misoprostol may have caused a negative natriuretic effect in cirrhotic patients with ascites. In cirrhotic patients without ascites chronic administration of indomethacin may induce a renal dysfunction that cannot be reversed by misoprostol.

Pharmacological characterization of bradykinin receptors in canine cultured tracheal smooth muscle cells.

1. [3H]-bradykinin was used to characterize the bradykinin receptors associated with canine cultured tracheal smooth muscle cells (TSMCs). Receptor binding assay showed that TSMCs had specific, saturable, high-affinity binding sites for [3H]-bradykinin. 2. The specific [3H]-bradykinin binding increased linearly with increasing cell concentrations. The equilibrium for association of [3H]-bradykinin with the bradykinin receptors was attained within 2 h at 4 degrees C and 1 h at room temperature, respectively. 3. Analysis of binding isotherms yielded an apparent equilibrium dissociation constant (KD) of 2.5 +/- 0.3 nM and a maximum receptor density (Bmax) of 25.1 +/- 0.3 fmol mg-1 protein. The Hill coefficient for [3H]-bradykinin binding was 1.00 +/- 0.02. The association (K1) and dissociation (K-1) rate constants were (8.67 +/- 2.60) x 10(6) M-1 min-1 and 0.024 +/- 0.005 min-1, respectively. KD, calculated from the ratio of K-1 and K1 was 2.8 +/- 0.5 nM, a value close to that of KD calculated from Scatchard plots of binding isotherms. 4. The B1 receptor selective agonist, (des-Arg9-bradykinin, 0.1 nM-10 microM) and antagonist ([Leu8, des-Arg9]-bradykinin, 0.1 nM-10 microM) did not did not inhibit the [3H]-bradykinin binding to TSMCs, which excludes the presence of B1 receptors in canine TSMCs. 5. The specific binding of [3H]-bradykinin to canine TSMCs was inhibited by B2 receptor selective antagonists ([D-Arg0, Hyp3, Thi5, D-Tic7, Oicl-bradykinin, Hoe 140, 0.1 nM-10 micro M and [D-Arg0, Hyp3,Thi5,8, D-Phe7-bradykinin, 0.1 nM-10 micro M) and agonists (bradykinin and kallidin, 0.1 nM-10 micro M) with a best fit by a one-binding site model. The order of potency for the inhibition of [3H]-bradykinin binding was kallidin = bradykinin = Hoe 140> [D-Arg0, Hyp3, Thi5,8, D-Phel-bradykinin.6. Preincubation of TSMCs with forskolin for 24 h led to an up-regulation of B2 receptors, increasing in Bmax from 25.1 +/- 0.3 to 218 +/- 24 fmol mg-1 protein without changing the KD values. [3H]-bradykinin binding to TSMCs was inhibited by the B2 receptor selective antagonists and agonists, but not by the B1 receptor selective reagents. The up-regulation of the B2 receptor by forskolin was mediated through protein synthesis, since cycloheximide blocked this response.7 It is concluded that the pharmacological characteristics of the bradykinin receptors in canine cultured TSMCs are primarily of the B2 receptor subtype.

Bradykinin-stimulated calcium mobilization in cultured canine tracheal smooth muscle cells.

Bradykinin (BDK)-induced increases in intracellular Ca2+ concentration ([Ca2+]i) were monitored in cultured canine tracheal smooth muscle cells (TSMCs) using a fluorescent Ca2+ indicator, Fura-2. BDK and kallidin caused an initial transient peak followed by a sustained elevation of [Ca2+]i in a concentration-dependent manner, with half-maximal stimulation (log EC50) obtained at -8.10 M and -8.04 M, respectively. The BDK-induced rise in [Ca2+]i was not affected by the BDK B1 receptor antagonist, des-Arg9[Leu8]-BDK (10 microM). However, the BDK B2 receptor antagonists des-Arg[Hyp3, Thi5,8, D-Phe7]-BDK and Hoe 140 had high affinity in antagonizing BDK with pKB values of 7.5 +/- 0.3 and 8.7 +/- 0.3, respectively. The sustained phase of the rise in [Ca2+]i was dependent on the presence of external Ca2+, as evidenced by a decline to the resting level on addition of EGTA. In the absence of external Ca2+, only an initial transient peak was seen which then declined to the resting level; a sustained elevation of [Ca2+]i could then be evoked by addition of 1.8 mM Ca2+ in the continued presence of BDK. Ca2+ influx was required for the changes in [Ca2+]i, since Ca(2+)-channel blockers, diltiazem, verapamil, and Ni2+, decreased both the initial and sustained elevation of [Ca2+]i in response to BDK. In conclusion, these findings indicate that the initial increase in [Ca2+]i stimulated by BDK acting on BDK B2 receptors is due to the release of Ca2+ from internal stores, followed by the influx of external Ca2+ into the cells. The influx of extracellular Ca2+ partially involves a diltiazem- and verapamil-sensitive Ca2+ channel.

The effect of cyclic AMP elevating agents on bradykinin- and carbachol-induced signal transduction in canine cultured tracheal smooth muscle cells.

1. The effects of cholera toxin (CTX), forskolin and dibutyryl cyclic AMP on bradykinin (BK)- and carbachol-induced accumulation of inositol phosphates (IPs) and Ca2+ mobilization were investigated in canine cultured tracheal smooth muscle cells (TSMCs). The BK-induced responses were mediated via a G protein which was not inhibited by CTX or pertussis toxin treatment. 2. BK-stimulated IPs accumulation and Ca2+ mobilization were potentiated by CTX (10 micrograms ml-1) pretreatment which was time-dependent. Maximal increase of these responses occurred after 24 h treatment with CTX. The concentration-effect relationship of BK-induced responses were shifted to the left and BK was substantially more effective in CTX-treated cells than in the control cells. This enhancing effect of CTX did not occur with carbachol. 3. Short-term (< 4 h) treatment with forskolin (10 microM) or dibutyryl cyclic AMP (1 mM) failed to accentuate BK-induced responses, but long-term (> 4 h) treatment of TSMCs with these agents mimicked the enhancing effect of CTX, suggesting that CTX-induced enhancement of BK responsiveness might be due to a rise in cyclic AMP. 4. Prolonged treatment of TSMCs with these agents was accompanied by an increase in cell surface [3H]-BK binding sites, which was inhibited by concurrent incubation with cycloheximide, an inhibitor of protein biosynthesis. Cycloheximide also abolished the potentiating actions of CTX, forskolin, and dibutyryl cyclic AMP on BK-induced IPs formation and Ca2+ mobilization. 5. The locus of this enhancement was further investigated by examining the effects of CTX, forskolin and dibutyryl cyclic AMP on A1F4(-)-induced IPs accumulation in canine TSMCs. AIF4-induced IPs accumulation was not affected by CTX, forskolin, or dibutyryl cyclic AMP treatment, supporting the contention that this stimulatory effect is located at the BK receptor level.6. These results demonstrate that the augmentation of BK-induced IPs accumulation and Ca2+mobilization produced by CTX, forskolin and dibutyryl cyclic AMP involves a cyclic AMP-dependent mechanism which is induced by a sustained increase in the level of intracellular cyclic AMP. CTX and forskolin may promote an increase of the synthesis of BK receptors, and thereby enhance BK-induced responses.

Relationships between the severity of cirrhosis and haemodynamic values in patients with cirrhosis.

The relationship between the severity of cirrhosis and systemic and hepatic haemodynamic values was evaluated in 193 patients with cirrhosis, most of whom were diagnosed with post-necrotic cirrhosis. It was found that the hepatic venous pressure gradient and cardiac output in Pugh's A patients (13.6 +/- 4.8 mmHg and 6.2 +/- 1.6 L/min, mean +/- s.d.) were significantly lower than in both Pugh's B (16.8 +/- 4.3 mmHg and 7.3 +/- 2.1 L/min) and Pugh's C (18.8 +/- 5.5 mmHg and 7.4 +/- 2.3 L/min) patients (P < 0.01), respectively. In contrast, the systemic vascular resistance in Pugh's A patients (1232 +/- 369 dyn/s per cm5) was significantly higher than in both Pugh's B (1016 +/- 345 dyn/s per cm5) and Pugh's C (935 +/- 234 dyn/s per cm5) patients (P < 0.01), respectively. Additionally, not only was there a positive correlation found between Pugh's score and cardiac output and hepatic venous pressure gradient, but a negative correlation was found between Pugh's score and systemic vascular resistance. It was also confirmed that the degree of portal hypertension and the hyperdynamic circulation were more severe in patients with ascites than in those without ascites. However, there were no statistically significant differences in hepatic venous pressure gradient among patients with F1, F2 and F3 esophageal varices (15.7 +/- 4.0, 17.0 +/- 4.8 and 18.0 +/- 4.8 mmHg, respectively). It is concluded that in those patients with cirrhosis, the severity of cirrhosis is closely related to the degree of the hyperkinetic circulatory state and portal hypertension.

Bradykinin-stimulated phosphoinositide metabolism in cultured canine tracheal smooth muscle cells.

1. Stimulation of bradykinin (BK) receptors coupled to phosphoinositide (PI) hydrolysis was investigated in canine cultured tracheal smooth muscle cells (TSMCs). BK, kallidin, and des-Arg9-BK, stimulated [3H]-inositol phosphates (IPs) accumulation in a dose-dependent manner with half-maximal responses (EC50) at 20 +/- 5, 13 +/- 4, and 2.3 +/- 0.7 nM, (n = 5), respectively. 2. D-Arg[Hyp3, D-Phe7]-BK and D-Arg[Hyp3, Thi5,8, D-Phe7]-BK, B2 receptor antagonists, were equipotent in blocking the BK-induced IPs accumulation with pKB = 7.1 and 7.3, respectively. 3. Short-term exposure of TSMCs to phorbol 12-myristate 13-acetate (PMA, 1 microM) attenuated BK-stimulated IPs accumulation. The concentrations of PMA that gave half-maximal and maximal inhibition of BK-induced IPs accumulation were 15 +/- 4 nM and 1 microM, n = 3, respectively. The inhibitory effect of PMA on BK-induced response was reversed by staurosporine, a protein kinase C (PKC) inhibitor, suggesting that the inhibitory effect of PMA was mediated through the activation of PKC. 4. Prolonged incubation of TSMCs with PMA for 24 h, resulted in a recovery of receptor responsiveness which may be due to down-regulation of PKC. The inactive phorbol ester, 4 alpha-phorbol 12, 13-didecanoate at 1 microM, did not inhibit this response. 5. The site of this inhibition was further investigated by examining the effect of PMA on AlF(4-)-induced IPs accumulation in canine TSMCs. AlF(4-)-stimulated IPs accumulation was inhibited by PMA treatment, suggesting that the G protein(s) can be directly activated by AlF4-, which is uncoupled from phospholipase C by PMA treatment. 6. Incubation of TSMCs in the absence of external Ca2+ or upon removal of Ca2+ by addition of EGTA, caused a decrease in IPs accumulation without changing the basal levels. Addition of Ca2+ (3-620 nM) to digitonin-permeabilized TSMCs stimulated IPs accumulation was obtained by inclusion of either guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) or BK. The combination of GTP gamma S and BK caused an additive effect on IPs accumulation.7. Pretreatment of TSMCs with cholera toxin enhanced BK-stimulated IPs accumulation, whereas there was no effect with pertussis toxin.8. These data suggest that BK-stimulated PI metabolism is mediated by the activation of BK B2 receptors coupling to a G protein which is not blocked by cholera toxin or pertussis toxin treatment and dependent on external Ca2+. The transduction mechanism of BK coupled to PI hydrolysis is sensitive to feedback regulation by PKC.

Hepatic hemodynamic features in patients with esophageal or gastric varices.

One hundred and fifty cirrhotic patients with or without esophageal varices and/or gastric varices were investigated by endoscopy and hepatic venous catheterization to evaluate differences in the degree of portal hypertension, main portal venous diameter and frequency of portal systemic encephalopathy. Hemodynamic values were correlated with varices size as assessed by endoscopy. Patients with large gastric varices had wedged hepatic venous pressures and hepatic venous pressure gradients which were lower than patients with esophageal varices only, but similar to patients without varices. In addition, in patients with large gastric varices, a decrease in the diameter of the main portal vein and an increase in the incidence of chronic portal systemic encephalopathy were noted. Our results implied that patients with large gastric varices presented different hemodynamic features including the degree of portal hypertension and the incidence of portal systemic encephalopathy from patients with esophageal varices only.

Changes of sex hormone levels in patients with hepatitis B virus-related postnecrotic cirrhosis: relationship to the severity of portal hypertension.

The effect of portal hypertension on plasma sex steroid levels was studied in 49 patients with hepatitis B virus-related postnecrotic cirrhosis. In accordance with the Child-Pugh classification, 18 patients were classified as grade A, 15 grade B and 16 grade C. At the same time, 25 males who were admitted for physical check-up served as normal controls. Serum testosterone levels decreased (3.31 +/- 2.03 vs. 5.65 +/- 0.13 ng/ml) and estrone levels increased (0.16 +/- 0.08 vs. 0.09 +/- 0.02 ng/ml) significantly in patients with cirrhosis compared to the levels obtained in the controls. Moreover, these changes were associated with an increased severity of cirrhosis (P < 0.05 when severity increased from grade A to C). Hemodynamic values regarding hepatic venous pressure gradient and cardiac output demonstrated significant differences in patients from grade A to C, but the correlation between these two parameters was poor (r = 0.3242). The hepatic venous pressure gradient, the only direct measurement of portal hypertension, did not correlate with any of the measured hormone levels in patients with cirrhosis. There was, however, a highly significant negative correlation between cardiac output and testosterone levels (r = -0.8754, P < 0.01) and a positive correlation between cardiac output and estrone levels (r = 0.7522, P < 0.05) in grade C patients. On the basis of these results, we concluded that gonadal dysfunction is a common finding in patients with hepatitis B related postnecrotic cirrhosis, especially in those with decompensated liver function. The relationship between cardiac output and severity of liver disease suggests that the degree of portosystemic shunting probably increases as liver disease worsens.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes of hepatic and systemic haemodynamics following somatostatin administration in patients with hepatitis B-related cirrhosis.

Somatostatin has been used to effectively control acute variceal haemorrhage, with conjectured mechanisms on portal hypertension. We, therefore, evaluated the effects of somatostatin on hepatic and systemic haemodynamics in 15 patients with hepatitis B-related cirrhosis and portal hypertension. All patients received an intravenous, continuous infusion of somatostatin 250 micrograms/h, following a bolus injection of 250 micrograms. In systemic haemodynamics, the mean arterial pressure (MAP) increased (P < 0.05), associated with a reflex bradycardia within 3 min following bolus injections, compared with basal values. The right atrial pressure, pulmonary capillary wedge pressure, inferior vena cava pressure, cardiac index, and systemic vascular resistance remained unaffected after drug infusion. In hepatic haemodynamics, the wedge hepatic vein pressure remained unchanged after drug administration. However, there was an increase in free hepatic vein pressure (FHVP; P < 0.05), and a trend toward a decrease in the hepatic vein pressure gradient (HVPG; P = 0.063), within 3 min after bolus injection. Furthermore, the hepatic blood flow decreased significantly at 10 and 30 min after somatostatin infusion (P < 0.05). The effective sinusoidal perfusion assessed by indocyanine green infusion also decreased progressively at 10 min (P = 0.057) and 30 min (P < 0.05). We concluded that somatostatin, at the dose used in this study, caused a transient and bolus-related vasoconstrictive effect, resulting in increases in MAP and FHVP, a decrease in heart rate, and a trend toward lower HVPG. In addition, somatostatin reduced the hepatic blood flow and effective sinusoidal perfusion which may be hazardous to cirrhotic patients during variceal haemorrhage.

A randomized controlled trial comparing octreotide and vasopressin in the control of acute esophageal variceal bleeding.

This randomized controlled trial was conducted to compare the efficacy of intravenous infusion of octreotide (a synthetic long-acting somatostatin analogue) with vasopressin in 48 cirrhotic patients with endoscopically proven bleeding esophageal varices. Twenty-four patients received a continuous infusion of octreotide 25 micrograms/h for 24 h after an initial bolus of 100 micrograms and another 24 patients received a continuous infusion of vasopressin 0.4 U/min for 24 h. Bleeding was initially controlled after 6 h of drug infusion in 88% (21/24) and 54% (13/24) of the patients treated with octreotide and vasopressin respectively (p = 0.03). Complete control of bleeding after 24 h of drug infusion was achieved in 15 (63%) patients receiving octreotide and in 11 (46%) patients receiving vasopressin (p > 0.05). Side effects during drug infusion such as headache, chest pain and abdominal pain were significantly lower in the octreotide group (3/24) than in the vasopressin group (11/24). Serum gastrin and insulin levels fell significantly following octreotide infusion, but plasma glucose levels remained unchanged. Mortality related to bleeding esophageal varices was no different between the two groups. This report showed that octreotide infusion was more effective and had fewer side effects than vasopressin in initial controlling of acute esophageal variceal bleeding until an elective endoscopic sclerotherapy could be performed.

Octreotide decreased liver metabolic activity in patients with hepatitis B surface antigen-positive cirrhosis.

The influence of octreotide and somatostatin on liver metabolic activity were studied in 16 patients with cirrhosis that was positive for hepatitis B surface antigen (HBsAg). In patients receiving a 50 micrograms bolus and a 50 micrograms/hr infusion of octreotide, the hepatic blood flow, hepatic clearance, and the maximum velocity/metabolic elimination rate constant (Vmax/km) were significantly reduced after octreotide infusion compared with basal values. Similarly, the hepatic blood flow, hepatic clearance, and Vmax/km were significantly decreased in patients receiving a 250 micrograms bolus and a 250 micrograms/hr infusion of somatostatin. The extraction ratio and the systemic hemodynamic values, including cardiac index, heart rate, mean arterial pressure, and systemic vascular resistance, showed no significant changes in patients receiving either octreotide or somatostatin. These findings suggest that, as with somatostatin, octreotide reduced hepatic blood flow and impaired liver metabolic activity in patients with HBsAg-positive cirrhosis. These effects may have important clinical implications in the management of bleeding esophageal varices in patients with cirrhosis.

Hemodynamic evaluation of octreotide in patients with hepatitis B-related cirrhosis.

The hemodynamic effects of octreotide were studied in 20 patients with hepatitis B-related cirrhosis. In patients receiving a 100-micrograms bolus and a 100-micrograms/h infusion, heart rate, cardiac index, and systemic vascular resistance showed no significant changes, whereas right atrial pressure, pulmonary capillary wedge pressure, and inferior vena cava pressure decreased significantly after octreotide infusion compared with basal values. In contrast, in patients receiving a 50-micrograms bolus and a 50-micrograms/h infusion, all the systemic hemodynamic values were unaffected. In both groups of patients receiving two different doses of octreotide, the estimated hepatic blood flow, hepatic indocyanine green clearance, and wedge hepatic venous pressure were significantly reduced at 60 minutes after octreotide administration compared with basal values, whereas the hepatic venous pressure gradient remained unchanged. It is concluded that the two different doses of octreotide administration result in the reduction of the wedge hepatic venous pressure and the hepatic blood flow of a similar magnitude, whereas the hepatic venous pressure gradient is unaffected. Octreotide induces discrepant systemic hemodynamic response; this effect is dose related.

Relationship of portal pressure, anorectal varices and hemorrhoids in cirrhotic patients.

In a prospective study of 103 consecutive cirrhotic patients a high prevalence (43%) of anorectal varices was found compared with only 2% in 103 age- and sex-matched control subjects (p less than 0.001). However, there was no significant difference between the prevalences of hemorrhoids in cirrhotic patients and in control subjects (79% vs. 83%, p greater than 0.05). The hepatic venous pressure gradient of cirrhotic patients with anorectal varices was similar to cirrhotic patients without anorectal varices (14 +/- 6 mmHg, n = 22, vs. 16 +/- 7 mmHg, n = 39, p greater than 0.05. There was no significant difference in the hepatic venous pressure gradient between cirrhotic patients with and without hemorrhoids (15 +/- 6 mmHg, n = 47, vs. 16 +/- 8 mmHg, n = 14, p greater than 0.05). The prevalence of anorectal varices and hemorrhoids in cirrhotic patients had no relation to Child-Pugh's grading, esophageal varices with and without sclerotherapy and ascites. We conclude that anorectal varices are common in cirrhotic patients. Anorectal varices and hemorrhoids are not related to the degree of portal pressure.

Hemodynamic effects of a combination of vasopressin and ketanserin in patients with hepatitis b-related cirrhosis.

We measured the hemodynamic effects of intravenous vasopressin, ketanserin (a 5-hydroxytryptamine-2 receptor blocker), and vasopressin plus ketanserin in 33 patients with hepatitis B-related cirrhosis. Thirteen patients received vasopressin alone (0.66 units/min), ten patients ketanserin alone (10 mg), and ten patients vasopressin followed by vasopressin plus ketanserin. Vasopressin alone reduced the hepatic venous pressure gradient (from 18 +/- 5, mean +/- S.D., to 9 +/- 3 mmHg, p less than 0.0001) and cardiac output (p less than 0.0001), but increased mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.0001), pulmonary capillary wedge pressure (p less than 0.0001), and systemic vascular resistance (p less than 0.001). There was no significant change in heart rate. Ketanserin alone produced a significant fall in the hepatic venous pressure gradient (from 16 +/- 4 to 13 +/- 3 mmHg, p less than 0.0001), mean arterial pressure (p less than 0.005), mean pulmonary arterial pressure (p less than 0.005), and pulmonary capillary wedge pressure (p less than 0.005). Heart rate, cardiac output, and systemic vascular resistance were not significantly changed. The addition of ketanserin to vasopressin corrected most of the systemic hemodynamic disturbances produced by vasopressin. This combination did not lead to a further reduction in the hepatic venous pressure gradient. We conclude that intravenous ketanserin reduces portal pressure in patients with hepatitis B-related cirrhosis. The addition of ketanserin to vasopressin improves the detrimental systemic hemodynamic effects of vasopressin without further reducing the portal pressure.

A randomized controlled study of low-dose and high-dose terlipressin in the control of acute oesophageal variceal haemorrhage.

A randomized controlled trial was designed to investigate whether a high dose of terlipressin could control acute variceal haemorrhage more effectively than a low dose of terlipressin. Forty cirrhotic patients with bleeding oesophageal varices were included, with low-dose terlipressin in 21 patients and high-dose terlipressin in 19 patients. The two groups of patients were similarly matched for all parameters on admission. High-dose terlipressin (84%) seemed to be more effective in the initial control of bleeding than low-dose terlipressin (67%); however this difference was not significant. Complete control of bleeding during 24 h of drug infusion was achieved in 53% of patients receiving high-dose terlipressin and in 48% of those treated with low-dose terlipressin (P greater than 0.05). There were no major complications in either group. Mortality in relation to variceal bleeding and transfusion requirements were similar in the two groups. This study shows that high dose terlipressin is not superior to low dose terlipressin in acute variceal bleeding.

Hyposensitivity to vasopressin in patients with hepatitis B-related cirrhosis during acute variceal hemorrhage.

It has been suggested that vasopressin given during hemorrhage may be less effective than when given during a stable state in a portal-hypertensive rat model. This study was designed to evaluate the hemodynamic response to vasopressin infusion in 25 HBsAg-positive cirrhotic patients. Nine patients had active variceal hemorrhage before vasopressin infusion, and the other 16 patients were in a stable condition at the time of infusion. The two groups of patients were similar in baseline values except that a higher heart rate was found in patients with hemorrhage (96 +/- 20 vs. 73 +/- 10 beats/min, mean +/- S.D., p less than 0.01). Thirty minutes after vasopressin infusion (0.66 units/min), hepatic venous pressure gradient significantly decreased in both bleeding and stable patients (from 21 +/- 9 to 18 +/- 9 mm Hg, p less than 0.05; and from 18 +/- 4 to 8 +/- 3 mm Hg, p less than 0.0001, respectively). However, the decrease of hepatic venous pressure gradient was less obvious in bleeding patients as compared with stable patients (4 +/- 3 vs. 9 +/- 2 mm Hg, p less than 0.0001). A significant reduction of hepatic venous pressure gradient after vasopressin infusion was found in five bleeding patients without shock (from a median of 16 mm Hg [range = 12 to 26] to 11 mm Hg [range = 6 to 18], p less than 0.05), but not in four bleeding patients with shock (from 28 [range = 15 to 36] to 25 [range = 18 to 33] mm Hg, p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Snake skin pattern gastropathy in cirrhotic patients.

Gastric mucosal lesions are common in patients with cirrhosis. Among them, snake skin pattern gastropathy (SSPG) is the most distinguishing one. A prospective study was conducted to investigate the incidence of SSPG in cirrhotic patients, the relationship between the degree of portal pressure and SSPG, and the possible association of SSPG with serum levels of gastrin and pepsinogen I. SSPG was found to be significantly more common in 100 cirrhotic patients than in 100 age- and sex-matched healthy controls (41% vs 0%, P less than 0.0001). Hepatic venous pressure gradient and serum gastrin and pepsinogen I levels were measured in 21 cirrhotic patients with SSPG and 25 cirrhotics without SSPG. There was no significant difference in hepatic venous pressure gradient (16.1 +/- 4.4 mmHg vs 16.1 +/- 4.9 mmHg, P greater than 0.05), serum gastrin level (78.0 +/- 26.7 pg/mL vs 80.1 +/- 32.5 pg/mL, P greater than 0.05) and serum pepsinogen I level (69.5 +/- 26.6 ng/mL vs 65.2 +/- 26.1 ng/mL, P greater than 0.05) in cirrhotic patients with or without SSPG. In conclusion, SSPG is common in cirrhotic patients. Portal pressure per se may not be the only factor causing SSPG--other aggressive factors may be needed together to cause the gastropathy. There is no evidence of correlation between serum gastrin or pepsinogen I level and SSPG.

Comparison of ultraviolet irradiation-induced mutagenesis of the lacI gene in Escherichia coli and in human 293 cells.

We report the sequence changes in the Escherichia coli lacI gene in 133 mutants detected after passage of an ultraviolet-irradiated shuttle vector human 293 cells. The results are compared with our previous studies of the lacI gene after ultraviolet light treatment in E. coli. In human cells, base substitutions predominate, and frameshifts are found much less frequently than in bacteria. The most frequent base change is the G.C to A.T transition. Overall, 110 to 112 transitions were G.C to A.T. Some of the hotspots seen in lacI in bacteria are prominent also in human 293 cells, suggesting that the same lesions are targeting mutations in both systems. Transitions are found almost exclusively at sequences at which pyrimidine-pyrimidine photoproducts can form. The data are consistent with the notion that a significant fraction of ultraviolet irradiation-induced mutagenesis in mammalian systems occurs by adding an A across from a photolesion. Double mutations are significantly more frequent in human cells than in bacteria. Reasons for this difference are discussed.