Circulation In Portal Hypertensive Rats Research Articles

Central neural activation of hyperdynamic circulation in portal hypertensive rats depends on vagal afferent nerves

Background:Hyperdynamic circulation in portal hypertensive rats depends on central neural c-fos gene expression, but how the portal hypertensive signal activates central c-fos expression remains obscure.Aim:To elucidate the afferent pathway from...

Chronic administration of propylthiouracil ameliorates hyperdynamic circulation in portal hypertensive rats

Objective To evaluate the effect of a hypothyroid state, induced by chronic propylthiouracil administration, on splanchnic and systemic hemodynamic parameters in rats with portal hypertension due to portal vein ligation. Methods Portal hypertension was induced by surgical stenosis of the portal vein. Cardiac index and portal blood flow were measured using radioactive microspheres. Measurements were performed after treatment with propylthiouracil (1 mg/ml in drinking water) for 5 days. Results Propylthiouracil-treated portal hypertensive rats had a lower portal pressure (12.4 ± 1.9 versus 16.3 ± 0.7 mmHg; p < 0.05) and portal blood flow (11.6 ± 0.7 versus 13.2 ± 1.3 ml/min/100 g; p < 0.05) than non-treated animals. Splanchnic vasoconstriction in treated animals was associated with a higher peripheral vascular resistance (2.3 ± 0.4 versus 1.8 ± 0.3mmHg/ml/min/100 g; p < 0.05) than controls. Conclusion These results suggest that portal pressure can be lowered by inducing a hypothyroid state by chronic administration of propylthiouracil.

154 Oxidative stress contributes to the hyperdynamic circulation in portal hypertensive rats

154 Oxidative stress contributes to the hyperdynamic circulation in portal hypertensive rats

Heat shock protein 90 is responsible for hyperdynamic circulation in portal hypertensive rats.

To examine the participation of HSP90 in portal hypertensive rat mesentery in vitro. Immunohistochemistry and Western-blot were used to examine the expression of HSP90 in mesenteric vasculature. HSP90 mRNA was detected by RT-PCR, and the role of HSP90 in hyperdynamic circulation was examined by in vitro mesenteric perfusion studies. HSP90 was overexpressed in endothelium of mesentery vasculature in animals with experimental portal hypertension induced by partial portal vein ligation (PVL) compared with normal animals. Geldanamycin (GA), a special inhibitor of HSP90 signaling, attenuated ACh-dependent vasodilation but did not affect vasodilation in response to sodium nitroprusside in normal rats. In PVL animals, the perfused mesentery was hyporesponsive to vasoconstrictor methoxamine. GA significantly potentiated methoxamine-induced vasoconstrictor after PVL. HSP90 plays a key role in NO-dependent hyperdynamic circulation in portal hypertension and provides a novel method for future treatment of portal hypertension.

Hyperdynamic circulation in portal hypertensive rats is dependent on intact vagal innervation

Hyperdynamic circulation in portal hypertensive rats is dependent on intact vagal innervation

Hyperdynamic circulation in portal-hypertensive rats is dependent on central c-fos gene expression

Portal hypertension is associated with hyperdynamic circulation, but the pathogenesis remains unclear. To clarify the role of central cardiovascular regulatory mechanisms, several protocols were conducted in rats with portal hypertension due to portal vein stenosis (PVS). Neuronal activation was quantified by immunohistochemical staining for Fos, the protein product of the c-fos gene. Fos expression in several brain nuclei with cardiovascular-regulatory roles was examined at 1, 3, 5, and 10 days following PVS surgery. This was correlated with development of cardiovascular changes measured at the same time points. Finally, Fos expression in the nucleus tractus solitarius (NTS) was blocked by local microinjection of c-fos antisense oligonucleotides twice daily for 5 days following PVS. The results showed that Fos-positive neurons were significantly increased in the paraventricular nucleus of hypothalamus, supraoptic nucleus, ventrolateral medulla, and NTS, detectable at day 1 and persistently increased at every day examined in the PVS rats. However, the hyperdynamic circulation developed between days 3 to 5. Administration of c-fos antisense oligonucleotides eliminated the hyperdynamic circulation in PVS rats, but had no effect on sham-operated controls. We conclude that the activation of central cardiovascular-regulatory nuclei, through a c-fos–dependent pathway, is necessary for development of hyperdynamic circulation in portal-hypertensive rats. (H EPATOLOGY 2002;35:159-166.)

Effects of vasopressin on portal-systemic collaterals in portal hypertensive rats: role of nitric oxide and prostaglandin.

This study investigated the effect of vasopressin on portal-systemic collaterals in portal hypertensive rats and the influence of nitric oxide (NO) and prostaglandin on the responsiveness of collateral vessels to vasopressin. The vascular responsiveness to graded concentrations of vasopressin was tested with or without the incubation of n(omega)-nitro-L-arginine (NNA) (100 micromol/L) and/or indomethacin (10 micromol/L) in perfused collateral vascular beds of rats with portal hypertension induced by partial portal vein ligation. In addition, concentration-response curves to vasopressin with incubation of a vasopressin V(1) receptor antagonist d(CH(2))(5)Tyr(Me) arginine vasopressin and concentration-response curves to a V(2) receptor agonist 1-desamino-8-D-arginine vasopressin were performed. Vasopressin significantly increased the perfusion pressure of collaterals, and this effect was suppressed by the addition of the V(1) receptor antagonist. Perfusion with the V(2) receptor agonist had no effect on the collaterals. Incubation with NNA, indomethacin, or both significantly potentiated the response of collaterals to vasopressin. In addition, the pressor response to vasopressin in the combination group was significantly higher than that in the NNA-alone group. The results show that vasopressin produces a direct vasoconstrictive effect on the portal-systemic collaterals of portal hypertensive rats. This effect is mediated by the vasopressin V(1,) but not V(2), receptors. The attenuation of the response to vasopressin by NO and prostaglandin suggest a function role of both mediators in the regulation of the portal-systemic collateral circulation in portal hypertensive rats.

NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats.

Chronic high blood flow and the hyperdynamic circulatory syndrome in portal hypertension are associated with endothelial constitutive nitric oxide (NO) synthase (eNOS) upregulation and increased NO release. In portal vein-ligated (PVL) rats the splanchnic circulation is not yet hyperdynamic on day 3 postoperatively. In vitro perfused superior mesenteric arteries (SMAs) of day 3 PVL and sham rats were challenged with increasing flow rates or the alpha-adrenoreceptor agonist methoxamine (30 and 100 microM) before and after incubation with the NO inhibitor, Nomega-nitro-L-arginine (L-NNA, 10(-4) M). Perfusate NO metabolite (NOx) concentrations were measured by chemiluminescence. PVL rats expressed a significant hyporesponsiveness to increases in flow rate or methoxamine that was overcome by incubation with L-NNA. The PVL vasculature showed significantly higher slopes of NOx production vs. flow-induced shear stress, higher increases in perfusate NOx concentration in response to methoxamine, and higher eNOS protein levels (Western blot) compared with sham rats. In conclusion, eNOS-upregulation and increased NO release by the SMA endothelium occur before the development of the hyperdynamic splanchnic circulation, suggesting a primary role of NO in the pathogenesis of arterial vasodilatation.

The Effects of Nitric Oxide Inhibitor on Hyperdynamic Circulation in Portal Hypertensive Rats

Background: Nitric oxide, a vasodilator synthesized from L-arginine by vascular endothelial cells, accounts for the biological activity of endothelium derived relaxing factor. Previous studies demonstrated that nitric oxide inhibitor, -Nitro-L-Arginine(NNA) diminished the hyperdynamic splanchnic and systemic circulation in portal hypertensive rats The present study was done to determine the role of nitric oxide in the development of hyperdynamic circulations in the prehepatic portal hypertensive rat model produced by partial portal vein ligation. Methods: The portal hypertensive rats were divided into water ingestion group and NNA ingestion group. After partial portal vein ligation, NNA ingestion group and water ingestion group received NNA 1mg/kg/day and plain water through the mouth for 14 days, respectively. Cardiac output, mean arterial pressure, organ blood flow and porto-systemic shunting were measured by radioisotope labeled microsphere methods. Vascular resistances were calculated by standard equation. Results: There were significant decreases in mean arterial pressure, increases in cardiac output and cardiac index, and decreases in total systemic and splanchnic vascular resistance in portal hypertensive rats compared to normal control group (p

Splenorenal shunt blood flow by transit-time ultrasound as an index of collateral circulation in portal hypertensive rats

The aim of this study was to develop a technique that could serve as an index of portosystemic shunt (PSS) blood flow in portal hypertensive rats whose main shunt is the splenorenal shunt (SRS). The main hemodynamic measurements performed were: SRS blood flow by the transit-time ultrasound (TTU) method, percentage of PSS, and regional blood flows by the microsphere method. We determined the accuracy and reproducibility of SRS blood flow measurements under baseline and pharmacological (octreotide) conditions. SRS blood flow was compared with other hemodynamic characteristics. Two models of portal hypertension were used: secondary biliary and dimethylnitrosamine cirrhosis. The SRS blood flow was correlated with mesenteric (r = .76; P < .001) and splenic (r = .67; P < .01) PSS percentages. The intra- and interobserver agreements for SRS blood flow were excellent: ric = .99 and ric = .98, respectively. SRS blood flow was six times higher in portal hypertensive rats (0.6 +/- 0.7 mL . min-1 . 100 g-1) than in sham rats (0.1 +/- 0.1 mL . min-1 . 100 g-1 [P < .01]). Octreotide significantly decreased SRS blood flow but not mesenteric or splenic PSS percentages. SRS is the main PSS in rats. The measurement of SRS blood flow by TTU is accurate and reproducible. This method can be used to identify new mechanisms in hemodynamic studies that differ from those identified by the measurement of the percentage of PSS by the microsphere method, especially in pharmacological studies.

Tumor necrosis factor alpha regulates nitric oxide synthase expression in portal hypertensive gastric mucosa of rats.

Anti-tumor necrosis factor alpha (TNF-alpha) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-alpha is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-alpha treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-alpha and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-alpha-neutralizing antibody treatment. The TNF-alpha protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-alpha antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-alpha may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-alpha treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa.

Neonatal capsaicin treatment does not prevent splanchnic vasodilatation in portal-hypertensive rats.

It has been suggested that the peripheral sensory neurons are involved in the splanchnic hemodynamic changes of portal hypertension. Therefore the influence of permanent ablation of sensory neurons by neonatal capsaicin pretreatment (50 mg/kg, subcutaneously) on the development of the hyperdynamic splanchnic circulation in portal-hypertensive rats was studied. In adulthood, portal hypertension was induced with partial portal vein ligation. In study 1, systemic and splanchnic hemodynamics were measured by means of a radiolabeled-microsphere technique in portal-hypertensive rats, under ketamine anesthesia, pretreated with capsaicin or vehicle. Mean arterial pressure, heart rate, cardiac index, systemic and splanchnic vascular resistance, portal pressure, portal venous inflow, portal-collateral resistance and portal-systemic shunting were not significantly different between capsaicin-pretreated and vehicle-pretreated rats. In study 2, gastric mucosal blood flow, measured by means of hydrogen gas clearance, and the hemoglobin and oxygen content of the gastric mucosa, as assessed with reflectance spectrophotometry, were not significantly different in the two groups of anesthetized portal-hypertensive rats pretreated with capsaicin or vehicle. In study 3, we confirmed the effectiveness of neonatal capsaicin pretreatment by measuring calcitonin gene-related peptide content of the gastric corpus wall. Capsaicin pretreatment caused a depletion of calcitonin gene-related peptide by at least 98% compared with that in vehicle-pretreated rats. These results do not support a role of capsaicin-sensitive sensory neurons that innervate the gastrointestinal tract in the development of the splanchnic vasodilatation characteristically observed in chronic portal hypertension.

Pharmacology of portal-systemic collaterals in portal hypertensive rats: role of endothelium.

The portal-systemic collateral circulation of portal hypertensive rats was studied. The collaterals were perfused through the mesenteric vein with Krebs solution, which was allowed to escape through the jugular veins. The portal-collateral resistance can be quantitated from slopes of the pressure-flow relationships. In collaterals perfused at constant flow, both norepinephrine (NE) and 5-hydroxytryptamine (5-HT) increased the perfusion pressure. Phentolamine caused surmountable antagonism of the constrictor effects of NE, suggesting an involvement of alpha-adrenoceptors. The effects of 5-HT were competitively blocked by the 5-HT2 receptor-selective antagonist ICI 169,369. Isoproterenol dilated NE-preconstricted collaterals. The effect of isoproterenol was blocked by propranolol, demonstrating that the effect was mediated by beta-adrenoceptors. Acetylcholine (ACh) dilated NE-preconstricted collaterals. The dilatation effect of ACh was absent in collaterals in which the endothelium was removed. The competitive inhibitor of the nitric oxide synthase, N omega-nitro-L-arginine (L-NNA), increased collateral resistance and prevented the ACh-induced dilatation of the collaterals. The constrictor response to L-NNA and the blockade of the ACh-induced relaxation by both L-NNA and removal of endothelium are consistent with an involvement of nitric oxide. This experimental model can thus be used to explore the pathophysiological and the pharmacological properties of the collateral venous bed in portal hypertensive states.

Blockade of ATP-sensitive K + channels by glibenclamide reduces portal pressure and hyperkinetic circulation in portal hypertensive rats

Certain results of in vitro studies raise the possibility that blockade of ATP-sensitive K+ channels by glibenclamide may induce vasoconstriction. Therefore, this substance might decrease portal pressure and hyperkinetic circulation in animals with portal hypertension. Thus, systemic and regional hemodynamics (radioactive microspheres) were measured before and 20 min after a bolus intravenous injection of glibenclamide (20 mg/kg) in conscious rats with portal vein stenosis. Blood pressure decreased significantly from 14.5 +/- 1.5 to 12.2 +/- 1.2 (mean +/- SE). Cardiac index significantly decreased by 24%, portal tributary blood flow by 31%, and hepatic artery blood flow by 35%. Systemic vascular resistance significantly increased by 38%, portal territory vascular resistance and hepatic artery vascular resistance by 61%, each, and renal vascular resistance by 17%. Arterial pressure, heart rate, and renal blood flow were unchanged. Moreover, glibenclamide blunted the vasodilating action of diazoxide (an ATP-sensitive K+ channel opener). These results show that in rats with extrahepatic portal hypertension the blockade of ATP-sensitive K+ channels by glibenclamide reduces portal pressure and hyperkinetic circulation.

Bile acids do not mediate the hyperdynamic circulation in portal hypertensive rats

Portal hypertension is accompanied by hyperdynamic systemic and splanchnic circulation. Serum bile acids (BAs), which are elevated in portal hypertension and have vasodilatory properties, have been proposed as mediators of this hyperdynamic circulation. In this study, portal hypertensive rats [accomplished by partial portal vein ligation (PVL)] were gavaged with cholestyramine (PVL-CH) to decrease circulating BA levels. A control group of rats was gavaged with an inert suspension of Metamucil (PVL-ME). The following hyperdynamic parameters were found to be similar in PVL-CH and PVL-ME: mean arterial pressure (119 +/- 6 vs. 124 +/- 5 mmHg), portal pressure (13.2 +/- 0.6 vs. 14.5 +/- 0.5 mmHg), cardiac index (0.33 +/- 0.04 vs. 0.34 +/- 0.03 ml.min-1.g body wt-1), splanchnic blood flow (1.4 +/- 0.13 vs. 1.6 +/- 0.1 ml.min-1.g body wt-1), portosystemic shunting (82 +/- 8 vs. 92 +/- 3%), peripheral arteriolar resistances (344 +/- 74 vs. 387 +/- 29 mmHg.min.ml-1.g body wt), and splanchnic arteriolar resistances (75 +/- 14 vs. 72 +/- 6 mmHg.min.ml-1.g splanchnic wt; 1,471 +/- 150 vs. 1,325 +/- 120 mmHg.min.ml-1.g body wt). BA in PVL-ME (84 +/- 9 microM/l) were similar to those previously observed in untreated PVL and significantly greater than those measured in PVL-CH (25 +/- 4 microM/l; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between portosystemic shunts and the hyperdynamic circulation in portal hypertensive rats and in rats with end-to-side porta-caval shunts

Correlation between portosystemic shunts and the hyperdynamic circulation in portal hypertensive rats and in rats with end-to-side porta-caval shunts