Intravascular and intraparenchymatous hepatic segmentary sclerosis.

PURPOSE: To evaluate the morphological effects of injected sclerosing agents into the liver. METHODS: This study was performed on twenty dogs, distributed into five groups: Group 1 (n = 5) - control, Group 2 (n = 5) - injection of 50% glucose solution inside hepatic parenchyma and animals followed during seven days, Group 3 (n = 10) - injection of ethanol inside hepatic parenchyma and animals distribution into two subgroups Subgroup 3A (n = 5) - followed during 24 hours and subgroup 3B (n = 5) - followed during seven days (group 3B), Group 4 (n = 5) - ethanol injection inside left portal vein branch and followed during 24 hours. Livers were macroscopically evaluated, submitted to hepatic arteriography and portography, then histology. RESULTS: All animals in Group 4 died within 23 hours due to diffuse hepatic necrosis. The animals of groups 2 and 3 had a satisfactory evolution. Fibrosis formed in the segment reached by the sclerosant solution and interruption of the contrast flow injected into the portal system. CONCLUSION: Intrahepatic parenchymal ethanol injection is well tolerated and causes sclerosis restricted to a specific segment; however, intraportal ethanol injection causes massive hepatic necrosis and can lead to death.

Intravascular and intraparenchymatous hepatic segmentary sclerosis

Abstract Purpose: To evaluate the morphological effects of injected sclerosing agents into the liver. Methods: This study was performed on twenty dogs, distributed into five groups: Group 1 (n = 5) - control, Group 2 (n = 5) - injection of 50% glucose solution inside hepatic parenchyma and animals followed during seven days, Group 3 (n = 10) - injection of ethanol inside hepatic parenchyma and animals distribution into two subgroups Subgroup 3A (n = 5) - followed during 24 hours and subgroup 3B (n = 5) - followed during seven days (group 3B), Group 4 (n = 5) - ethanol injection inside left portal vein branch and followed during 24 hours. Livers were macroscopically evaluated, submitted to hepatic arteriography and portography, then histology. Results: All animals in Group 4 died within 23 hours due to diffuse hepatic necrosis. The animals of groups 2 and 3 had a satisfactory evolution. Fibrosis formed in the segment reached by the sclerosant solution and interruption of the contrast flow injected into the portal system. Conclusion: Intrahepatic parenchymal ethanol injection is well tolerated and causes sclerosis restricted to a specific segment; however, intraportal ethanol injection causes massive hepatic necrosis and can lead to death.

Venous endothelium reactivity to Angiotensin II: A study in primary endothelial cultures of rat vena cava and portal vein.

The role of the vascular endothelium in modulating the arterial system has been widely investigated, but poorly explored at the venous site. In the present work, primary cultures of venous endothelium from rat Vena Cava (VC) and Portal Vein (PV) were established, characterized and analyzed according to their growth pattern and ability to produce nitric oxide (NO) and prostanoids (PGF2 α and PGI2), at basal state and after stimulation with Angiotensin II (Ang II, 1µmol/L). Basal NO was detected in all examined cells in culture. Pre-incubation with Ang II increased NO production in cells from VC (but not in PV cultures), through activation of both AT1 and AT2 receptors. Both cultures exhibited detectable levels of PGF2 α at resting conditions, which were similarly enhanced by Ang II. Basal PGI2 levels were higher in PV, but increased after Ang II treatment in VC, with no further effect on PV cells. We conclude that endothelial cells from VC and PV exhibit important properties and react to Ang II, probably influencing the whole circulatory system. This experimental cell model gives support to further studies concerning intracellular pathways of the venous endothelium, analyzed in separate from the vascular smooth muscle wall.

Hepatoportal sclerosis related to the use of herbals and nutritional supplements. Causality or coincidence?

 Introduction and aim. Non-cirrhotic idiopathic portal hypertension (NCIPH), also known as hepatoportal sclerosis (HPS) is a disease of uncertain etiology. However, various pathophysiological mechanisms has been postulated, including chronic or recurrent infections and exposure to drugs or toxins. In this context, it appears to be of multifactorial etiology or resulting from a portal vascular endothelium aggression. It is important to consider whether the use of dietary supplements and herbs can trigger or contribute to the occurance of HPS. We report a possible association of HPS with the consumption of herbals and / or dietary supplements. MATERIAL AND METHODS: We describe two cases of HPS in patients without known etiology causes associated with this disease. RESULTS: Both patients were females who were diagnosed with HPS following the consumption of Herbalife® products and putative anorexigenic agents in the form herbals infusions. Image-based analysis and the assessment of the histopathological alterations found in the livers confirmed the diagnosis. The histopatological analysis of liver samples from both patients showed portal tracts enlarged by fibrosis with disappearance or reduction in the diameter of the portal vein branches. In many portal tracts, portal veins branches were replaced by aberrant thin-walled fendiforme vessels. The bile ducts and branches of the hepatic artery show normal aspects. CONCLUSION: After the exclusion of other etiologic factors and a comprehensive analysis of clinical history, consumption of Herbalife® products and anorexigenic agents was pointed-out as a puttative predisposing factor for the development of the disease.

A comparative study of two clerodane diterpenes from Baccharis trimera (Less.) DC. on the influx and mobilization of intracellular calcium in rat cardiomyocytes.

Baccharis trimera (Less.) D.C. (Asteraceae) is a medicinal species native to South America and used in Brazilian folk medicine to treat gastrointestinal and liver diseases, kidney disorders and diabetes. The aqueous extract (AE) of the aerial parts of this species presented two mainly constituents: the ent-clerodane diterpene (Fig. 1) and the neo-clerodane diterpene (Fig. 2). The objective of this work was to study their activities on the blockade of Ca(2+)-induced contractions in KCL-depolarized rat portal vein preparations, and on the influx and mobilization of cytosolic calcium in rat cardiomyocytes by fluorescence measurements. The results showed that both the neo- and the ent-clerodane diterpenes reduced the maximal contractions induced by CaCl2, in KCl depolarized rat portal vein preparations, without modifying the EC50. The data on the concentration of cytosolic calcium ([Ca(2+)]c) showed that, while the neo-clerodane diterpene stimulates the mobilization of [Ca(2+)]c in rat cardiomyocytes, this effect was not observed with the ent-clerodane diterpene. On the other hand, the influx of calcium was not altered by the neo-clerodane diterpene, but was reduced in the presence of the ent-clerodane diterpene, indicating that this compound induces a blockade of the voltage-dependent calcium channels.

Changes in CNS cells in hyperammonemic portal hypertensive rats.

Rats with pre-hepatic portal hypertension because of partial portal vein ligation develop minimal hepatic encephalopathy (MHE) with hyperammonemia, impaired blood-brain barrier, mild brain edema, and severe mitochondrial changes in the hippocampus. The aim of this study was to evaluate changes of different neural cells in the cerebral cortex and the hippocampus. Animals were divided into two groups, MHE and sham. Astrocytes were studied by immunostaining with glial fibrillary acidic protein and S100ß protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1α (HIF-1α) and its downstream proteins, P-glycoprotein (P-gp) and erythropoietin receptor (Epo-R), were also evaluated. Astrocytes were increased in area and number only in the hippocampus, while S100ß increased in both brain areas in MHE animals. Microtubule associated protein-2 and NF-200 immunoreactivities (-ir) were significantly reduced in both areas. Hippocampal Nestin-ir was increased in MHE animals. These cellular changes were similar to those described in ischemic conditions, thus HIF-1α, P-gp, and Epo-R were also evaluated. A high expression of HIF-1α in cortical neurons was observed in the MHE group. It is likely that this hypoxia-like state is triggered via ammonia occupying the binding domain of HIF-1α and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.

Endothelium dependent expression and underlying mechanisms of des-Arg9-bradykinin-induced B1R-mediated vasoconstriction in rat portal vein.

Endothelial dysfunction has been implicated in portal vein obstruction, a condition responsible for major complications in chronic portal hypertension. Increased vascular tone due to disruption of endothelial function has been associated with an imbalance in the equilibrium between endothelium-derived relaxing and contracting factors. Herein, we assessed underlying mechanisms by which expression of bradykinin B(1) receptor (B(1)R) is induced in the endothelium and how its stimulation triggers vasoconstriction in the rat portal vein. Prolonged in vitro incubation of portal vein resulted in time- and endothelium-dependent expression of B(1)R and cyclooxygenase-2 (COX-2). Inhibition of protein kinase C (PKC) or phosphatidylinositol 3-kinase (PI3K) significantly reduced expression of B(1)R through the regulation of transcription factors, activator protein-1 (AP-1) and cAMP response element-binding protein (CREB). Moreover, pharmacological studies showed that B(1)R-mediated portal vein contraction was reduced by COX-2, but not COX-1, inhibitors. Notably, activation of endothelial B(1)R increased phospholipase A(2)/COX-2-derived thromboxane A(2) (TXA(2)) levels, which in turn mediated portal vein contraction through binding to TXA(2) receptors expressed in vascular smooth muscle cells. These results provide novel molecular mechanisms involved in the regulation of B(1)R expression and identify a critical role for the endothelial B(1)R in the modulation of portal vein vascular tone. Our study suggests a potential role for B(1)R antagonists as therapeutic tools for diseases where portal hypertension may be involved.

Vascular mechanisms involved in angiotensin II-induced venoconstriction in hypertensive rats.

To investigate the venoconstrictor effect of angiotensin II (Ang II) in spontaneously hypertensive rats (SHR), we used preparations of mesenteric venular beds and the circular muscle of the portal veins. Vessels were tested with Ang II in the presence or absence of losartan, PD 123319, HOE 140, L-NAME, indomethacin, or celecoxib. In the mesenteric venular bed of SHR, the effect of Ang II (0.1 nmol) was nearly abolished by losartan and enhanced by HOE 140, indomethacin, and celecoxib, while PD123319 and L-NAME had no effect. In portal vein preparations, cumulative-concentration response curves (CCRC) to Ang II (0.1-100 nmol/L) exhibited a lower maximal response (E(max)) in SHR compared to Wistar rats. AT(1) receptor expression was similar in the two strains, while AT(2) receptor levels were lower in SHR portal veins when compared to Wistar. In SHR portal veins, losartan shifted the CCRC to Ang II to the right, while indomethacin and HOE 140 increased the E(max) to Ang II. PD 123319, celecoxib, and L-NAME had no effect. Taken together, our results suggest that Ang II-induced venoconstriction in SHR is mediated by activation of AT(1) receptors and this effect may be counterbalanced by kinin B(2) receptor and COX metabolites. Furthermore, our data indicate that there are different cellular and molecular mechanisms involved in the regulation of venous tonus of normotensive and hypertensive rats. These differences probably reflect distinct factors that influence arterial and venous bed in hypertension.

Liver transplantation using University of Wisconsin or Celsior preserving solutions in the portal vein and Euro-Collins in the aorta.

INTRODUCTION: Orthotopic liver transplantation (OLT) is today the gold standard treatment of the end-stage liver disease. Different solutions are used for graft preservation. Our objective was to compare the results of cadaveric donor OLT, preserved with the University of Wisconsin (UW) or Celsior solutions in the portal vein and Euro-Collins in the aorta. METHODS: We evaluated retrospectively 72 OLT recipients, including 36 with UW solution (group UW) and 36 with Celsior (group CS). Donors were perfused in situ with 1000 mL UW or Celsior in the portal vein of and 3000 mL of Euro-Collins in the aortia and on the back table managed with 500 mL UW or Celsior in the portal vein, 250 mL in the hepatic artery, and 250 mL in the biliary duct. We evaluated the following variables: donor characteristics, recipient features, intraoperative details, reperfusion injury, and steatosis via a biopsy after reperfusion. We noted grafts with primary nonfunction (PNF), initial poor function (IPF), rejection episodes, biliary duct complications, hepatic artery complications, re-OLT, and recipient death in the first year after OLT. RESULTS: The average age was 33.6 years in the UW group versus 41 years in the CS group (P = .048). There was a longer duration of surgery in the UW group (P = .001). The other recipient characteristics, ischemia-reperfusion injury, steatosis, PNF, IPF, rejection, re-OLT, and recipient survival were not different. Stenosis of the biliary duct occured in 3 (8.3%) cases in the UW group and 8 (22.2%) in the CS (P = .19) with hepatic artery thrombosis in 4 (11.1%) CS versus none in the UW group (P = .11). CONCLUSION: Cadaveric donor OLT showed similar results with organs preserved with UW or Celsior in the portal vein and Euro-Collins in the aorta.

Exercise increases the angiotensin II effects in isolated portal vein of trained rats.

Training in rats adapts the portal vein to respond vigorously to sympathetic stimuli even when the animal is re-exposed to exercise. Moreover, changes in the exercise-induced effects of angiotensin II, a potent venoconstrictor agonist, in venous beds remain to be investigated. Therefore, the present study aimed to assess the effects of angiotensin II in the portal vein and vena cava from sedentary and trained rats at rest or submitted to an exercise session immediately before organ bath experiments. We found that training or exposure of sedentary animals to a single bout of running exercise does not significantly change the responses of the rat portal vein to angiotensin II. However, the exposure of trained animals to a single bout of running exercise enhanced the response of the rat portal vein to angiotensin II. This enhancement appeared to be territory-specific because it was not observed in the vena cava. Moreover, it was not observed in endothelium-disrupted preparations and in preparations treated with N(omega)-nitro-l-arginine methyl ester hydrochloride, indomethacin, BQ-123 or BQ-788. These data indicate that training causes adaptations in the rat portal vein that respond vigorously to angiotensin II even upon re-exposure to exercise. This increased response to angiotensin II requires an enhancement of the vasocontractile influence of endothelin beyond the influence of nitric oxide and vasodilator prostanoids.

Orchidectomy enhances the effects of phenylephrine in rat isolated portal vein.

1. Orchidectomy results in long-term testosterone deprivation similar to that observed in male clinical pathologies, such as hypogonadism and age-related reductions in plasma testosterone concentrations. Although the vascular effects of these sorts of hormone deprivations are known in arteries, they have not been studied to the same extent in veins. 2. The aim of the present study was to determine the effect of orchidectomy, with or without subsequent testosterone replacement (started 23 days after orchidectomy; 10 mg/kg, i.m., testosterone propionate once every 5 days for 3 weeks), on responses of rat isolated portal veins and vena cavae to exogenous phenylephrine (PE). Isolated vessels were mounted in an organ bath and concentration-response curves constructed to PE (10(-10)-10(-4) mol/L), endothelin (ET; 10(-10)-10(-5) mol/L) and KCl (10(-2)-1.2 x 10(-1) mol/L; as a control). 3. Orchidectomy had no effect on contractile responses of either the portal vein or vena cava to KCl. However, orchidectomy enhanced the maximum response (R(max)) of the portal vein, but not the vena cava, to PE. Testosterone replacement had no effect on these responses. The effects of orchidectomy on the R(max) to PE in portal veins were not altered by the nitric oxide synthase inhibitor N(G)-nitro-l-arginine methyl ester (10(-4) mol/L) alone or combined with 10(-5) mol/L indomethacin (a non-selective cyclo-oxygenase inhibitor), but they were abolished following treatment of isolated vessels with the ET(A) and ET(B) receptor antagonists BQ-123 and BQ-788 (both at 10(-6) mol/L). Orchidectomy did not alter portal vein responses to the application of exogenous ET. 4. The results of the present study indicate that orchidectomy-induced decreases in plasma testosterone can increase the venoconstrictor effects of PE on the portal vein and that this effect involves activation of both ET(A) and ET(B) receptors by locally produced ET.

Exercise increases the phenylephrine effects in isolated portal vein of trained rats.

Physical exercise evokes an extensive circulatory redistribution. However, the influence of exercise upon the effects of sympathomimetic agonists in veins was not well studied. Thus, the present study aimed to determine whether a single bout of exercise modifies the effects of sympathomimetic agonists in veins and whether this exercise-induced modification may be altered by exercise training. The results have shown that the training did not change the responsiveness of the rat portal vein, but exposure of trained animals to a single bout of exercise enhanced the phenylephrine Rmax in these preparations. Such exercise-induced modifications of vascular response were territory-specific since similar modifications of response to phenylephrine were not observed in vena cava. Moreover, this exercise-induced augmentation of phenylephrine Rmax in the portal vein of trained rats was prevented by endothelium removal or in the presence of N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), indomethacin, BQ-123 or BQ-788. In conclusion, these data indicate that the training adapted the rat portal vein to respond vigorously to sympathetic stimuli even when the animal is exposed to this exercise. This increased response to sympathetic stimuli appears to involve an enhancement of the vasocontractile influence of endothelin that supplants the modulation exerted by nitric oxide (NO) and vasodilator prostanoids.

The possible involvement of hyperpolarizing mechanisms in histamine-induced relaxation of the rat portal vein.

The present study evaluated the effects of histamine 10(-2) M on longitudinal preparations of rat portal vein. It was observed that histamine 10(-2) M induced relaxation of rat portal vein preparations pre-contracted with phenylephrine 10(-4) M. On the other hand, no pharmacological effects were observed in preparations not pre-contracted. The observed histamine-induced relaxing effect was absent in preparations pre-contracted with KCl (120 mM) or in the presence of depolarizing nutritive solution. However, the histamine-induced relaxation was still present in the endothelium-removed preparations. The histamine-induced relaxation also was not prevented by astemizole (10(-6) M, 10(-5) M and 10(-4) M), cimetidine (10(-5) M, 10(-4) M and 10(-3) M) or thioperamide (10(-6) M, 10(-5) M and 10(-4) M), selective antagonists H(1), H(2) and H(3), respectively. The presence of L-NAME 10(-4) M or L-NAME 10(-4) M plus indomethacin 10(-5) M also did not prevent the histamine-induced relaxation observed in rat portal vein. Thus, the histamine-induced relaxation observed in rat portal vein appears to involve a non-endothelial hyperpolarizing mechanism independent of H(1), H(2) and H(3) receptors.

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis.

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg(-1) min(-1) for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

Systemic and regional hemodynamic effects of enalaprilat infusion in experimental normotensive sepsis

Angiotensin-converting enzyme inhibitors have been shown to improve splanchnic perfusion in distinct shock states. We hypothesized that enalaprilat potentiates the benefits of early fluid resuscitation in severe experimental sepsis, particularly in the splanchnic region. Anesthetized and mechanically ventilated mongrel dogs received an intravenous infusion of live Escherichia coli over a period of 30 min. Thereafter, two interventions were performed: fluid infusion (normal saline, 32 mL/kg over 30 min) and enalaprilat infusion (0.02 mg kg-1 min-1 for 60 min) in randomized groups. The following groups were studied: controls (fluid infusion, N = 4), E1 (enalaprilat infusion followed by fluid infusion, N = 5) and E2 (fluid infusion followed by enalaprilat infusion, N = 5). All animals were observed for a 120 min after bacterial infusion. Mean arterial pressure, cardiac output (CO), portal vein blood flow (PVBF), systemic and regional oxygen-derived variables, and lactate levels were measured. Rapid and progressive reductions in CO and PVBF were induced by the infusion of live bacteria, while minor changes were observed in mean arterial pressure. Systemic and regional territories showed a significant increase in oxygen extraction and lactate levels. Widening venous-arterial and portal-arterial pCO2 gradients were also detected. Fluid replacement promoted transient benefits in CO and PVBF. Enalaprilat after fluid resuscitation did not affect systemic or regional hemodynamic variables. We conclude that in this model of normotensive sepsis inhibition of angiotensin-converting enzyme did not interfere with the course of systemic or regional hemodynamic and oxygen-derived variables.

A simple and effective method to improve intrasplenic rat hepatocyte transplantation.

Transplanted hepatocytes integrate, survive, and express their specific functions in the liver parenchyma. The aim of this study was to determine whether a large number of hepatocytes could move from the spleen to the liver when the cells are injected together with sodium nitroprusside, and if the improved hepatocyte migration may be related with portal vein dilatation. Wistar rats were transplanted in the spleen with fluorescent-labeled hepatocytes alone or together with sodium nitroprusside. At 1, 3, 6, and 24 h after the transplant, the liver from recipient animals was removed and morphometric analyses were performed. Portal and arterial pressures were also measured immediately after intrasplenic injection of a solution of sodium nitroprusside, hepatocytes alone, or hepatocytes plus sodium nitroprusside. Intrasplenically injected sodium nitroprusside produced a transient drop in arterial pressure and a sustained reduction in portal pressure. During hepatocyte transplantation it increased the number of transplanted cells migrating to the liver after 3 h. Sodium nitroprusside simultaneously injected with hepatocytes in the spleen allowed more cells to migrate into the liver of the host animal without risk in animal survival.

Changes in distribution spaces and cell permeability caused by ATP in the rat liver.

AIMS/BACKGROUND: Cellular and extracellular volume changes caused by ATP were investigated in the liver as well as the possible formation of diffusion barriers, which could be responsible for some of its metabolic effects. METHODS: The experimental system was the bivascularly perfused rat liver. [(14)C]Sucrose and [(3)H]water were simultaneously injected into either the portal vein or the hepatic artery. Mean transit times, distribution spaces, variances and linear superimpositions were calculated. RESULTS: In the portal system, ATP reduced the transit time in the great vessels, had little or no effect on sinusoidal and cellular spaces, but impaired the flow-limited distribution of both [(14)C]sucrose and [(3)H]water. In the arterial bed ATP infused into either the portal vein or the hepatic artery produced vasodilation and increased the aqueous extra-sucrose space. These effects were inhibited by Nomega-nitro-L-arginine methyl ester infused into the hepatic artery. CONCLUSIONS: Sucrose and extra-sucrose space changes caused in the arterial bed by portally infused ATP are most probably analogous to the transhepatic vasodilation effect already described for the rabbit liver. Impairment of flow-limited distribution of tracers in the sinusoidal bed indicates that ATP induces the formation of permeability barriers, which could be responsible for some of its metabolic effects.

Molecular and pharmacological evidence for modulation of kinin B(1) receptor expression by endogenous glucocorticoids hormones in rats.

1. The effect of endogenous glucocorticoid hormones on the expression of rat B(1) receptors was examined by means of molecular and pharmacological functional approaches. 2. Rats were adrenalectomized (ADX), and 7 days after this procedure the intradermal injection of B(1) receptor agonist des-Arg(9)-BK produced a significant increase in the paw volume, while only a weak effect was observed in sham-operated animals. A similar increase in the contractile responses mediated by B(1) agonist des-Arg(9)-BK was also observed in the rat portal vein in vitro. 3. Chemical ADX performed with mitotane (a drug that reduces corticosteroid synthesis) produced essentially the same up-regulation of B(1) receptors as that observed in ADX rats. 4. The modulation of B(1) receptor expression was evaluated by ribonuclease protection assay, employing mRNA obtained from the lungs and paw of ADX rats. 5. Additionally, both paw oedema and contraction of portal vein mediated by B(1) agonist des-Arg(9)-BK in ADX rats, were markedly inhibited by treatment with dexamethasone, or COX-2 inhibitor meloxican, or with the NF-kappaB inhibitor PDTC. Interestingly, the same degree of inhibition was achieved when the animals were treated with a combination of submaximal doses of dexamethasone and PDTC. 6. The involvement of NF-kappaB pathway was further confirmed by mobility shift assay using nuclear extracts from lung, paw and heart of ADX rats. It was also confirmed that the treatment of ADX rats with dexamethasone, PDTC or dexamethasone plus PDTC completely inhibit NF-kappaB activation caused by absence of endogenous glucucorticoid. 7. Together, the results of the present study provide, for the first time, molecular and pharmacological evidence showing that B(1) kinin receptor expression can be regulated through endogenous glucocorticoids by a mechanism dependent on NF-kappaB pathway. Clinical significance of the present findings stem from evidence showing the importance of B(1) kinin receptors in the mediation of inflammatory and pain related responses.

Action of polygodial on agonist-induced contractions of the rat portal vein in vitro.

This study investigated the vasorelaxant action of the sesquiterpene polygodial, isolated from the bark of Drymis winteri, on rat portal vein in vitro, contracted by various agonists. Polygodial (21-342 microM) preincubated 20 min before, produced graded antagonism of the contractile responses caused by bradykinin, endothelin-1, noradrenaline, the stable analogue of thromboxane A2 U46619, substance P, neurokinin B, and senktide (an NK3-selective agonist). Polygodial, at the same concentration, also produced graded inhibition of the contractile response induced by potassium chloride and by phorbol ester. At the median inhibitory concentration (IC50) level, polygodial was approximately 114- to 177-fold more active in inhibiting mediated contractions to senktide and phorbol ester. When assessed in the tonic contraction induced by endothelin-1 (0.5 nM) or by phorbol (3 microM), polygodial (0.1-100 microM) produced concentration-dependent relaxation, with maximal inhibition (E(max)) of 62 +/- 2% and 100%, respectively. Finally, polygodial (0.1-100 microM) inhibited the rhythmic spontaneous contractions of the rat portal vein (E(max) of 75 +/- 2%). Taken together, these results suggest that the vasorelaxant actions caused by polygodial in rat portal vein are, at least in part, associated with inhibition of calcium influx through voltage-sensitive channels and interaction with protein kinase C-dependent mechanisms. In addition, these data confirm and extend our previous suggestion that polygodial preferentially antagonizes tachykinin-mediated contraction, especially the NK3-mediated responses.

Increased reactivity to 5-hydroxytryptamine of portal veins from mice infected with Schistosoma mansoni.

In chronic severe infection with Schistosoma mansoni, portal hypertension accompanied by anatomical changes of the portal vasculature can develop as a consequence of granulomatous response to eggs. Mice infected unisexually with male worms were used in the present study in order to investigate a direct effect of worms on the reactivity of their host portal vein. A higher reactivity in the presence of 5-hydroxytryptamine (5-HT), but not in the presence of KCl 100 mM solution, was observed in portal vein from infected mice compared to healthy mice. It was characterized by an increase in the maximal contraction and sensitivity to 5-HT. Blockade of NO-synthase with N omega-nitro-L-arginine methyl ester (L-NAME) induced a small increase in 5-HT potency in the portal vein from non-infected mice, but did not change the amplitude of the contractions. In portal veins from infected mice, preincubation with L-NAME did not affect the reactivity to 5-HT. Histological analysis indicated endothelial damage, subendothelial fibrous plaques, and focal areas of inflammatory infiltrates in the adventitial layer. As a conclusion, these results show that unisexual infection of mice with male S. mansoni increased the reactivity of the portal vein to 5-HT which seems to be only partially related to an alteration in the endothelial production of nitric oxide.