Enhanced vasoconstrictor response of the isolated perfused cirrhotic rat liver to humoral vasoconstrictor substances found in portal venous blood

Grossman, Howard; Grossman, Virginia L; Bhathal, Prithi S.

doi:10.1111/j.1440-1746.1992.tb00981.x

Cited by 20 publications

(14 citation statements)

References 12 publications

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“…In another set of experiments, the a1-adrenergic receptor agonist phenylephrine (PE) was used as the positive control, since adrenergic nerve endings (12) and catecholamine-mediated constriction are localized to the portal venules in the rat (13). The whole organ vascular resistance in the liver was estimated as the ratio of the pressure gradient between the portal and hepatic veins versus flow volume according to the previous method (14). In some experiments, heterogeneity of the lobular perfusion was macroscopically evaluated to check the difference in the vasoconstrictive mechanism between the ZnPP-and the PE-treated livers.…”

Section: Methodsmentioning

confidence: 99%

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

et al. 1995

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Heme oxygenase is a heme-oxidizing enzyme which generates biliverdin and carbon monoxide (CO). The present study was designed to elucidate whether CO endogenously produced by this enzyme serves as an active vasorelaxant in the hepatic microcirculation. Microvasculature of the isolated perfused rat liver was visualized by dual-color digital microfluorography to alternately monitor sinusoidal lining and fat-storing Ito cells. In the control liver, the CO flux in the venous effluent ranged at 0.7 nmol/min per gram of liver. Administration of a heme oxygenase inhibitor zinc protoporphyrin IX (1 ,uM) eliminated the baseline CO generation, and the vascular resistance exhibited a 30% elevation concurrent with discrete patterns of constriction in sinusoids and reduction of the sinusoidal perfusion velocity.The major sites of the constriction corresponded to local sinusoidal segments colocalized with Ito cells which were identified by imaging their vitamin A autofluorescence. The increase in the vascular resistance and sinusoidal constriction were attenuated significantly by adding CO (1 ,uM) or a cGMP analogue 8-bromo-cGMP (1 ,uM) in the perfusate. From these findings, we propose that CO can function as an endogenous modulator of hepatic sinusoidal perfusion through a relaxing mechanism involving Ito cells. (J. Clin. Invest. 1995. 96:2431-2437

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Section: Methodsmentioning

confidence: 99%

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

et al. 1995

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“…2 This dynamic component of hepatic vascular resistance is believed to be the consequence of an imbalance between the vasodilator/vasoconstrictor forces that regulate hepatic vascular tone. 1 In addition, the hepatic vascular resistance of cirrhotic livers exhibits a hyperresponse to several vasoconstrictors, such as endothelin 1, 3 norepinephrine, 4 or leukotriene D 4 . 5 Nitric oxide blunts the response of the hepatic vascular bed to several vasoconstrictors, 6 and its production is decreased in the cirrhotic liver.…”

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confidence: 99%

“…20 COX-2 expression has also been recently described in hepatocytes of cirrhotic human livers. 21 In addition, the isolated Kupffer cells from livers with steatonecrosis and CCl 4 cirrhosis present an imbalance in COX metabolites with an overproduction of TXA 2 and a decrease of PGE 2 . 22 It is therefore possible that the binding of different vasoconstrictors to G-protein-coupled receptors increases the release of arachidonic acid and results in an increased production of vasoconstrictive prostanoids, contracting the hepatic vascular bed and contributing to the observed increase in hepatic vascular resistance of cirrhotic livers.…”

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confidence: 99%

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Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

et al. 2003

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In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the I n cirrhotic livers, increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension. 1 This increased resistance is determined in part by the architectural distortion of the hepatic structure caused by cirrhosis. However, substantial evidence shows that a dynamic component, caused by the active contraction of vascular and extravascular contractile cells, plays a major role in further increasing intrahepatic resistance. 2 This dynamic component of hepatic vascular resistance is believed to be the consequence of an imbalance between the vasodilator/vasoconstrictor forces that regulate hepatic vascular tone. 1 In addition, the hepatic vascular resistance of cirrhotic livers exhibits a hyperresponse to several vasoconstrictors, such as endothelin 1, 3 norepinephrine, 4 or leukotriene D 4 . 5 Nitric oxide blunts the response of the hepatic vascular bed to several vasoconstrictors, 6 and its production is decreased in the cirrhotic liver. It is therefore possible that an insufficient availability of NO 7 could account for the hyperresponse to vasoconstrictors observed in cirrhotic livers.In addition, it has been shown that the activation of G protein-coupled receptors, such as those for ␣ 1 -adrenergic agonists, vasopressin, or endothelin 1, stimulates release of arachidonic acid, leading to the formation of its vasoactive-derived metabolites, including prostaglandins (PGs), thromboxanes (TXs), and leukotrienes. [8][9][10] Cyclooxygenase (COX)

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“…[1][2][3] Apart from structural changes (i.e., fibrosis, capillarization of sinusoids, regeneratory nodules), increased vascular tone of the intrahepatic vasculature (mainly perisinusoidal hepatic stellate cells [HSC] and presinusoidal venules) is functionally responsible for this increased resistance. 4,5 Increased sensitivity of the intrahepatic microcirculation to vasoconstrictors [4][5][6][7] and decreased levels of the vasodilator nitric oxide (NO) and its downstream signaling cyclic guanosine 3Ј,5Ј-monophosphate (cGMP)/protein kinase G (PKG) are responsible for this elevated contractile state. 4,8,9 We previously showed that increased RhoA/ Rho-kinase signaling essentially contributes to increased intrahepatic resistance as well as increased sensitivity to vasoconstrictors in rats with secondary biliary cirrhosis.…”

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confidence: 99%

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

Trebicka

Hennenberg

Laleman³

et al. 2007

Hepatology

279

338

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In cirrhosis, increased RhoA/Rho-kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho-kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT-PCR and immunoblots. Three-dimensional stress-relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ-perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3-dimensional stress-relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho-kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho-kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho-eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG). Conclusion: In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rhokinase signaling and activates the NO/PKG-pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis. (HEPATOLOGY 2007;46:242-253.)

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Enhanced vasoconstrictor response of the isolated perfused cirrhotic rat liver to humoral vasoconstrictor substances found in portal venous blood

Cited by 20 publications

References 12 publications

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

Carbon monoxide: an endogenous modulator of sinusoidal tone in the perfused rat liver.

Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

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