Contraction of human hepatic stellate cells activated in culture: A role for voltage-operated calcium channels

Bataller, Ramón; Nicolás, Josep M.; Ginès, Pere; Görbis, M.Nives; García-Ramallo, Eva; Lario, Sergio; Tobías, Ester; Pinzani, Massimo; Thomas, Andrew P.; Arroyo, Vicente; Rodés, Juan

doi:10.1016/s0168-8278(98)80057-3

Cited by 53 publications

(42 citation statements)

References 33 publications

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“…As to the possible mechanisms of the effects of tetrandrine on rat hepatic stellate cells, tetrandrine administration has been shown to block the calcium channels in various cell types (Weinberg et al 1994;Liu et al 1995;Chen et al 1999). Recent investigation found that voltage-operated calcium channel (VOCC) plays an important role in the regulation of hepatic stellate cells contractility which is the marked phenotype of activated hepatic stellate cells (Berlin 1995;Bataller et al 1998). Moreover, activated hepatic stellate cells have receptors for a number of vasoconstrictor substances such as endotheline, angiotensin II, vasopressin, thrombin and thromboxan A2 (Pinzani et al 1992;Sakamoto et al 1993;Kawada et al 1993;Bataller et al 1997;Rockey 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Tetrandrine also showed a blocking action of calcium channels (Weinberg et al 1994;Liu et al 1995). It has been shown that calcium channels play an important role in the regulation of hepatic stellate cells contractility that is the marked phenotype of activated hepatic stellate cells (Berlin 1995;Bataller et al 1998).To investigate wheter tetrandrine has an antifibrotic effect on hepatic fibrosis induced by bile duct ligation and scission in rats, we examined the effects of tetrandrine on fibrogenesis-induced by bile duct ligation and scission in rats, and on proliferation and smooth muscle-a-actin expression of rat cultured hepatic stellate cells. …”

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Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

Park

Nan

Park

et al. 2000

Pharmacology & Toxicology

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Tetrandrine, an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to elicit antifibrotic effects in various cell types. In the present study, the effect of tetrandrine on liver fibrosis was investigated by using bile duct ligation and scission in rats as a model of hepatic fibrosis. Treatment with tetrandrine in fibrotic rats reduced serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels to 72%, 52% and 51% that of controls at 10 mg/kg/day, respectively. Liver hydroxyproline contents in tetrandrine-treated rats with bile duct ligation and scission were also reduced to 65% of that of control rats with bile duct ligation and scission at 10 mg/kg/day. The morphological characteristics of fibrotic liver, which appeared in control bile duct ligation and scission group, were improved in tetrandrine-treated bile duct ligation and scission group. We also examined the effect of tetrandrine on cultured rat hepatic stellate cells, which plays an important role in the pathogenesis of hepatic fibrosis, activation to investigate whether it could act mainly by direct action on rat hepatic fibroblastic cells. In cultured rat hepatic stellate cells, tetrandrine reduced DNA synthesis to 57% of control hepatic stellate cells at 10 mg/ml without affecting cell viability. Smooth muscle-a-actin expression, the phenotypic marker of activated hepatic stellate cells, was also decreased. We conclude that tetrandrine has an antifibrotic effect on liver fibrosis in rats induced by bile duct ligation and scission, indicating that it might exert a direct effect on rat hepatic stellate cells.Hepatic fibrosis is a consequence of severe liver damage that occurs in many patients with chronic liver disease. Regardless of many different causes, hepatic fibrosis is characterized by increased and altered deposition of newly formed extracellular matrix components such as collagens, proteoglycans, fibronectin and hyaluronic acid (Friedman 1993), leading to the complication of portal hypertension and hepatic failure.In the injured liver, these extracellular matrix components are produced in hepatic stellate cells in the space of Disse, which function in intact liver lobules as the primary storage area for retinoids (Hendrisks et al. 1985). During the course of ongoing liver fibrogenesis, hepatic stellate cells acquire myofibroblastic features, proliferate (Friedman et al. 1989;Hautekeete & Geerts 1997), synthesize increased amounts of extracellular matrix components (Shiratori et al. 1987) and express smooth muscle-a-actin . The transformation of hepatic stellate cells into myofibroblast-like cells is recognized as a critical step in hepatic fibrosis. Therefore, this cell type is an important target for antifibrotic therapy.Tetrandrine is a bis-benzyl isoquinoline alkaloid derived from Stephania tetrandra (Moore). This compound has been characterized pharmacologically to exhibit hypotensive, immunosuppressive properties (Sutter & Wang 1993), and inhibition of lipid perox...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

Park

Nan

Park

et al. 2000

Pharmacology & Toxicology

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“…Changes in cytosolic-free [Ca 2ϩ ] i were measured in individual cultured human HSCs loaded with fura-2 acetoxymethyl ester (5 µmol/L) (Calbiochem, San Diego, CA) using an inverted epifluorescence microscope as described elsewhere. 15,26 Briefly, cells were plated on 25-mm diameter glass coverslips (VWR Scientific Inc., Philadelphia, PA) and maintained in culture for 48 hours. Coverslips were mounted on the stage of the microscope (40ϫ fluor immersion objective) and maintained at 37°C for the duration of the experiment.…”

Section: Determination Of Intracellular Cyclic Guanosine Monophosphatmentioning

confidence: 99%

“…In fact, we have previously shown that cell contraction is extremely uncommon in cells showing an increase in [Ca 2ϩ ] i below this threshold. 26 Measurement of HSC Contraction. Contraction of cultured human HSCs was estimated by measuring changes in cell area using a morphometric method described in detail previously.…”

Section: Determination Of Intracellular Cyclic Guanosine Monophosphatmentioning

confidence: 99%

Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells

et al. 1999

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Several lines of evidence indicate that hepatic stellate cells (HSCs), besides their crucial role in the increased synthesis of extracellular matrix components that occurs in chronic liver diseases, may participate in the regulation of sinusoidal blood flow. [1][2][3] Morphological studies have shown that HSCs have numerous cell processes that surround the sinusoids and contain cytosolic proteins characteristic of contractile cells. [4][5][6][7][8][9][10] Moreover, HSCs have receptors for a large number of vasoconstrictor substances, including endothelin-1, arginine vasopressin, thrombin, thromboxanes, and angiotensin II. 6,8,[11][12][13][14][15] Finally, the stimulation of HSCs in culture with these vasoconstrictor substances is associated with a marked increase in intracellular calcium concentration ([Ca 2ϩ ] i ) and cell contraction, 6,[8][9][10][11][12][13][14][15] suggesting that the contractile function of HSCs may be regulated by the action of vasoconstrictors.In contractile cells, the effects of vasoconstrictor agonists may be attenuated by the action of vasodilators. In fact, the state of contraction/relaxation of contractile cells is dependent on the interaction between vasoconstrictor and vasodilator factors. 16 In clear contrast with the large amount of information available on the effects of vasoconstrictor factors on HSCs, little is known about the effects of vasodilating substances on these cells. It has been shown that prostaglandins and nitric oxide produce relaxation of HSCs in culture and reduce the effects of vasoconstrictor agents, which suggests that these vasodilator factors may act as paracrine or autocrine regulators of HSCs' contractility. 10,12 However, it is not known whether the contractile function of HSCs may also be regulated by circulating vasodilator substances. One of the most important circulating vasodilators is atrial natriuretic peptide (ANP), a peptide synthesized in atrial myocytes, which besides its potent natriuretic action has important effects in the circulation by antagonizing the effects of vasoconstrictors. 17,18 Therefore, the aims of the current study were to determine (1) whether human HSCs have receptors for ANP, and (2) whether the stimulation of human HSCs with ANP in vitro reduces the effects elicited by contractile agonists on these cells. MATERIALS AND METHODSIsolation and Culture of Human and Rat Hepatic Stellate Cells. Human HSCs were isolated from fragments of normal human livers obtained from resections of liver metastases as described in detail elsewhere. 15,19 Briefly, after a combined digestion of liver tissue with

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Hepatic Stellate Cells

Rojkind

Reyes‐Gordillo

2009

The Liver

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Contraction of human hepatic stellate cells activated in culture: A role for voltage-operated calcium channels

Cited by 53 publications

References 33 publications

Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

Effect of Tetrandrine on Experimental Hepatic Fibrosis Induced by Bile Duct Ligation and Scission in Rats

Atrial natriuretic peptide antagonizes endothelin-induced calcium increase and cell contraction in cultured human hepatic stellate cells

Hepatic Stellate Cells

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