Pharmacological treatment of portal hypertension: present and future

Lebrec, Didier

doi:10.1016/s0168-8278(98)80241-9

Cited by 42 publications

(29 citation statements)

References 86 publications

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“…Phosphor-ylation is associated with increased activity of these calcium pumps with a consequent increase in the velocity of cytosolic calcium resetting to prestimulatory values after calcium transient. 67 The results of the present study suggest that, in addition to this mechanism, pretreatment with SNAP may influence PDGF-induced [Ca 2ϩ ] i increase through a dose-dependent inhibition of PDGFinduced PLC␥ phosphorylation, and possibly its activation with reduced synthesis of downstream effectors, such as IP 3 , is able to affect [Ca 2ϩ ] i dynamics. This observation is similar to previous findings in fibroblasts where inhibition of PLC␥ phosphorylation was shown to be a possible molecular target for the action of NO.…”

Section: Discussionmentioning

confidence: 64%

“…[1][2][3] Accordingly, these compounds, particularly isosorbide-5-mononitrate, have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers, 4,5 although their use may be contraindicated in patients with cirrhosis with ascites. 6 The direct action of organic nitrates on the intrahepatic circulation, although well conceivable according to the constitutive vasodilatory properties of these compounds, has not been substantiated in cellular and molecular terms.…”

Section: E Xperimental and Clinical Studies Have Indicated Thatmentioning

confidence: 99%

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Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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Background & Aims:Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods & Results: Both NTG and SNAP induced a dosedependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca 2؉ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3 ,5 -cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the ␣ 1 ␤ 1 ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10 -20-fold increase in prostaglandin E 2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3 ,5 -cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen. Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

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Section: Discussionmentioning

confidence: 64%

Section: E Xperimental and Clinical Studies Have Indicated Thatmentioning

confidence: 99%

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Failli¹,

et al. 2000

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confidence: 99%

“…It has been reported that the portal pressure gradient is an important risk factor for esophageal variceal hemorrhage, a major complication of portal hypertension (2,3). The pharmacological treatment of portal hypertension aims to treat acute bleeding episodes or prevent variceal bleeding (2,3). There are mainly two types of drugs to reduce portal hypertension, either by reducing portal tributory blood flow (PTBF) (e.g., terlipressin [triglycyl-lysine-vasopressin, a synthetic vasopressin analogue with long-lasting effects], octreotide [a synthetic 8-amino-acid analogue of somatostatin with prolonged action], and propranolol) or by reducing intrahepatic and porto-systemic collateral vascular resistances (e.g., nitrovasodilators) (1 -3).…”

mentioning

confidence: 99%

“…Terlipressin and somatostatin (an inhibitor of gut-derived secretion of vasodilatory peptides such as glucagon, vasoactive intestinal peptide, etc.) are two widely used vasoconstrictors in the treatment of acute variceal bleeding, while propranolol is used as a prophylactic drug for prevention of variceal rebleeding (2,3). However, side effects of severe systemic vasoconstriction and cardiodepresssion are still a significant clinical concern for use of terlipressin (4), while about one third of cirrhotic patients are non-responders to propranolol (2,3).…”

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confidence: 99%

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Hemodynamic Effects of Synephrine Treatment in Portal Hypertensive Rats

Huang¹,

Chang³

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Synephrine, a sympathomimetic a1-adrenoceptor agonist, has been shown to induce dosedependent portal hypotensive effects after acute intravenous infusion. The present study was undertaken to investigate the hemodynamic effects of 8-day administration of synephrine in portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL) or bile duct ligation (BDL). Portal hypertensive rats were allocated into one of two groups: vehicle group (0.1 N HCl, 0.5 ml/ 12 h) or synephrine group (1 mg/kg per 12 h), with 7 rats in each group. Synephrine or vehicle was administered by gavage into PVL and BDL rats for 8 consecutive days. Systemic as well as splanchnic hemodynamic parameters were measured thereafter. Synephrine significantly ameliorated the hyperdynamic state in both PVL and BDL rats. The portal venous pressure in PVL and BDL rats (-13.5% and -10.1%, respectively), portal tributary blood flow (-19.5% and -20.4%) and cardiac index (-12.1% and -18.8%) were significantly reduced, while mean arterial pressure (10.4% and 23.4%) and systemic (26.3% and 51.0%) as well as portal territory (47.1% and 67.7%) vascular resistance were enhanced by treatment of synephrine as compared with vehicle treatment. Our results showed that eight-day administration of synephrine exerted beneficial hemodynamic effects in two models of portal hypertensive rats.

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Organic nitrates for prevention of oesophageal varices bleeding and re-bleeding

Suo

Zhang

et al. 2000

Cochrane Database of Systematic Reviews

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Pharmacological treatment of portal hypertension: present and future

Cited by 42 publications

References 86 publications

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Nitrovasodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells

Hemodynamic Effects of Synephrine Treatment in Portal Hypertensive Rats

Organic nitrates for prevention of oesophageal varices bleeding and re-bleeding

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