Vasoactive effect of cyclosporine on the rat peribiliary capillary plexus: relationship with cholestasis and hyperbilirubinemia

Nakache, Richard; Фёдоров, Д. В.; Almogy, N; Weinbroum, Avi A.

doi:10.1016/s0041-1345(97)00548-4

Cited by 5 publications

(5 citation statements)

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“…Our data support the hypothesis that an increase of eNOS expression is associated with vasoconstriction because this effect was observed only in renal cortex and liver, the tissues in which CsA has been reported to induce vasoconstriction. 1,17 In agreement with our findings, a preliminary report shows that CsA did not change the transcription activity of the human eNOS promoter transfected in rat pulmonary endothelial cells when the eNOS promoter was studied with a reporter gene strategy. 18 Because eNOS is a Ca 2ϩ /calmodulin-dependent enzyme, an increase in Ca 2ϩ enhances NO production, thus CsA administration may increase NO through its stimulatory effect on intracellular calcium.…”

Section: Sánchez-lozada Et Al Nos Mrna Expression In Csa Toxicity 645supporting

confidence: 90%

“…3 Bile flow and secretion of bile acid, cholesterol, and phospholipids are reduced during CsA treatment. 4,17 In the liver, most of the blood flow enters through the portal vein, and the resistance changes are thought to occur in the microvascular anastomosis of the portal and hepatic veins, known as hepatic sinusoids. Shah et al 19 have recently reported that in rat liver, eNOS is abundantly expressed in the sinusoidal endothelial cells and that these cells respond to shear stress by increasing NO release.…”

Section: Sánchez-lozada Et Al Nos Mrna Expression In Csa Toxicity 645mentioning

confidence: 99%

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Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine

Sánchez‐Lozada

Gamba²,

Bolio³

et al. 2000

Hypertension

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Abstract-Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipineϩcyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects. (Hypertension. 2000;36:642-647.)Key Words: nitric oxide Ⅲ liver Ⅲ hypertension Ⅲ cyclosporine C yclosporine (CsA) is an immunosuppressor drug. Despite its beneficial effects, however, long-term use is frequently associated with hypertension, nephrotoxicity, and hepatotoxicity.Nephrotoxicity is the most common complication associated with CsA therapy. 1 It is characterized by renal vasoconstriction that induces a decrease in renal plasma flow and glomerular filtration rate. This side effect is usually reversible when CsA dose is reduced. However, even with normal blood levels or during long-term dosage, CsA can produce chronic hypertension and can be the cause of irreversible impairment of renal function. 2 The mechanism by which CsA induces hypertension remains unknown.Hepatotoxicity is a less common side effect, which is characterized by cholestasis and metabolic disturbances. 3,4 In isolated perfused rat liver, CsA administration produced a dose-dependent reduction of bile flow, increased the release of cytosolic and mitochondrial enzymes, and decreased oxygen consumption. 3 High blood levels of CsA in human allograft recipients have been associated with an increase in ␥-glutamyl transpeptidase, a liver enzyme that correlates with hepatotoxicity. 5 In one study, hepatic abnormalities developed in up to 32% of patients with endogenous uveitis treated with CsA. 6 CsA toxicity has been attributed to an imbalance of vasoactive substance release. 1 Recent studies have shown that nitric oxide (NO) is increased during CsA administration by a mechanism th...

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Section: Sánchez-lozada Et Al Nos Mrna Expression In Csa Toxicity 645supporting

confidence: 90%

Section: Sánchez-lozada Et Al Nos Mrna Expression In Csa Toxicity 645mentioning

confidence: 99%

Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine

Sánchez‐Lozada

Gamba²,

Bolio³

et al. 2000

Hypertension

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“…Following the protocol of our previously described dually perfused isolated rat liver model [25], all the animals were anesthetized with an intraperitoneal injection of phenobarbital sodium 50 mg/kg. They underwent a tracheotomy and were ventilated with 95% air-5% CO 2 , using a piston-type rodent ventilator set to deliver 1 mL/100 g body weight tidal volume at a rate of 40 breaths/min.…”

Section: Isolated Dually Perfused Liver Preparationmentioning

confidence: 99%

“…In the event of failed cannulation or deviation of the stabilization hepatic indices from the known ranges [25], the experiment on that liver was terminated and the data were discarded.…”

Section: Perfusion Protocolmentioning

confidence: 99%