Altered calcium regulation in freshly isolated aortic smooth muscle cells from bile duct-ligated rats: role of nitric oxide

Atucha, Noemı́ M.; Iyú, David; Rycker, Manu De; Soler, A; Garcı́a-Estañ, Joaquı́n

doi:10.1016/s0143-4160(02)00206-3

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…This difference in NOS induction was further illustrated by the higher ratio of inducible to total NOS activity in the lung (70%) compared to the aorta (30%). The accumulation of pulmonary intravascular macrophages most probably explains the greater inducibility of NOS in the lung, as compared to systemic vessels, where the major source of iNOS is smooth muscle cells [30]. Similar observations have been made for the heart of cirrhotic rats [31].…”

Section: Discussionsupporting

confidence: 71%

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Sztrymf¹,

Rabiller²,

Nunès³

et al. 2004

Eur Respir J

120

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Inhibition of tumour necrosis factor-alpha (TNF-alpha), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary over-production of NO by macrophages accumulated in lung vessels. Since TNF-alpha is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF-alpha inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF-alpha was inhibited by 5 weeks of pentoxifylline (10 mg x kg body weigh(-1) x day(-1)) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium-99m-labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF-alpha concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor-alpha on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor-alpha in the genesis of hepatopulmonary syndrome.

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Section: Discussionsupporting

confidence: 71%

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Sztrymf¹,

Rabiller²,

Nunès³

et al. 2004

Eur Respir J

120

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“…It has been suggested that nitric oxide inhibits CCE in human platelets by activating the refilling of the stores [33]. Whether an excess of nitric oxide present in this rat model of liver cirrhosis and cholestasis [11][12][13] is involved in the alterations shown in the present study is not known at the present time.…”

Section: Discussionmentioning

confidence: 57%

“…200 g were subjected to bileduct ligation and excision or sham operation, as described previously [11][12][13]. Normal rat chow and tap water were offered ad libitum.…”

Section: Experimental Groupsmentioning

confidence: 99%

Altered calcium signalling in platelets from bile-duct-ligated rats

et al. 2007

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In the present study, we have analysed the mechanisms of Ca(2+) entry and release in platelets obtained from BDL (bile-duct-ligated) rats, 11-13 days and 4 weeks after surgery. Platelets were washed and loaded with fura-2, and [Ca(2+)](i) (cytosolic Ca(2+) concentration) was determined in cell suspensions by means of fluorescence spectroscopy. Basal [Ca(2+)](i) was similar in platelets from BDL rats compared with those from their respective controls, both in the absence and presence of extracellular Ca(2+). Platelet stimulation with thrombin in the absence and presence of extracellular Ca(2+) induced a rapid rise in [Ca(2+)](i) that was of greater magnitude in platelets from BDL rats than in controls. Ca(2+) storage was significantly elevated in platelets from BDL rats, as well as the activity of SERCA (sarcoplasmic/endoplasmic-reticulum Ca(2+)-ATPase). Capacitative Ca(2+) entry, as evaluated by inhibition of SERCA with thapsigargin, was also altered in platelets from BDL rats, having lower rates of Ca(2+) entry. In conclusion, chronic BDL alters intracellular Ca(2+) homoeostasis in platelets, such that an enhanced Ca(2+) release is evoked by thrombin, which may be due to an increased amount of Ca(2+) stored in the intracellular organelles and secondary to an enhanced activity of SERCA. These alterations are already evident before cirrhosis has completely developed and occurs during the cholestasis phase.

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“…Atucha and colleagues found increased Ca 2+ mobilization following thrombin stimulation. In contrast, defective calcium entry and mobilization after bile duct ligation in rats was shown before [44-46]. Calcium signaling is an important key mechanism in platelet function essential for integrin activation, degranulation and cytoskeletal reorganization of platelets [47].…”

Section: Discussionmentioning

confidence: 99%

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

Gowert

Klier

Reich

et al. 2017

Cell Physiol Biochem

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Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin α_IIbβ₃ on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

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Altered calcium regulation in freshly isolated aortic smooth muscle cells from bile duct-ligated rats: role of nitric oxide

Cited by 15 publications

References 24 publications

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Altered calcium signalling in platelets from bile-duct-ligated rats

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice

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