Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells.

Bunchman, Timothy E.; Brookshire, C A

doi:10.1172/jci115293

Cited by 243 publications

(85 citation statements)

References 35 publications

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“…3,4 This phenomenon had been attributed to CsA treatment, as had been reported by other investigators of CsA-treated solid organ transplant recipients. 24 CsA enhances endothelin release from vascular endothelial cells, 25 smooth muscle cells, 26 and renal epithelial cells, 27 as well as upregulation of endothelin receptors. 28,29 These actions of endothelins contribute to its ability to induce renal vasoconstriction, hypoperfusion, and decreased glomerular filtration, 7 which may in turn be reversed by endothelin inhibitors and antagonists.…”

Section: Discussionmentioning

confidence: 99%

Plasma endothelin-1 levels after stem cell transplantation

Tomás

Sanz-Rodrı́guez

Soria

et al. 2000

Bone Marrow Transplant

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Summary:Acute renal failure and veno-occlusive disease of the liver are serious complications following stem cell transplantation (SCT) and contribute to the non-relapse mortality associated with this procedure. Endothelins, a family of vasoconstrictor peptides, may be involved in the pathogenesis of a variety of renal and hepatic diseases, including CsA-associated hypertension and the hepatorenal syndrome. In order to study the relevance of endothelins to SCT-related liver and kidney dysfunction, we determined endothelin-1 (ET-1) levels in plasma samples obtained from 65 patients (38 autologous, 27 allogeneic) 7 days before and 7, 14 and 28 days after SCT. A steady increase in plasma ET-1 was observed after SCT (5.36 pg/ml, 95% CI 4.30-6.43 on day +28 vs 3.82 pg/ml, 95% CI 3.21-4.43 on day −7; P = 0.020). No differences in ET-1 levels existed between autologous and allogeneic SCT recipients at any of the time points studied (P = 0.561). In addition, no significant differences were observed among patients with renal dysfunction vs those without (P = 0.187), nor in patient groups with or without hepatic dysfunction (P = 0.075). In conclusion, even though plasma ET-1 levels showed a steady increase following SCT, no correlation could be found with development of SCT-related kidney or liver dysfunction. Bone Marrow Transplantation (2000) 26, 1199-1204. Keywords: endothelin; endothelin-1; stem cell transplantation; acute renal failure; veno-occlusive disease; graftversus-host disease Transplant-related morbidity and mortality continue to be the greatest obstacles to improving clinical results in stem cell transplantation (SCT). There are fewer and less serious non-hematopoietic complications after autologous SCT than after allogeneic SCT. This is reflected by a higher incidence of both acute renal failure 1 and liver toxicity, including graft-versus-host disease (GVHD) and veno-occlusive disease (VOD) of the liver after allogeneic SCT. 2 It has been hypothesized that administration of CsA, immunological dysfunction during SCT, and increased release of specific cytokines, are associated with the greater rate of com-

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Section: Discussionmentioning

confidence: 99%

Plasma endothelin-1 levels after stem cell transplantation

Tomás

Sanz-Rodrı́guez

Soria

et al. 2000

Bone Marrow Transplant

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“…[8][9][10][11][19][20][21][22][23][24][25][26][27][28][29][30][31][32] These agents cause systemic and afferent arteriolar vasoconstriction by increasing the production of endothelin and thromboxane A 2 and interfering with nitric oxide-mediated vasodilation. [19][20][21][22][23] The afferent arteriolar vasoconstriction results in significant reductions in glomerular filtration rate and renal blood flow. [23][24][25][26] Chronic nephropathy also contributes to the renal insufficiency and is characterized by arteriolar hyalinosis, global glomerulosclerosis, proximal tubule damage, and tubulointerstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Maternal hemodynamics and pregnancy outcome in women with prior orthotopic liver transplantation

Carr¹,

Larson

Schmucker³

et al. 2000

Liver Transpl

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The aim of this study is to evaluate the hemodynamics and pregnancy outcome of women with prior orthotopic liver transplantation. Hemodynamic measurements by Doppler technique were performed on pregnant subjects with prior orthotopic liver transplantation. Maternal characteristics, renal function, pregnancy complications, delivery indications, delivery mode, and neonatal outcomes were evaluated. Six pregnancies occurred in 5 women after orthotopic liver transplantation at the University of Washington Medical Center (Seattle, WA) between 1991 and 1999. Four of the 6 pregnancies were complicated by chronic hypertension, fetal growth restriction, and preterm delivery. Two pregnancies had worsening hypertension characterized by vasoconstriction in the second trimester despite antihypertensive therapy. These 2 subjects were administered cyclosporine for maintenance immunosuppression and had greater mean arterial pressures preconception and in the first trimester than the other subjects. One of these pregnancies resulted in fetal demise at 25 weeks' gestation. The other subject was delivered at 28 weeks' gestation for nonreassuring fetal status and superimposed preeclampsia. All pregnancies were complicated by renal insufficiency; however, the 2 subjects with poor obstetric outcome had preconception serum creatinine levels greater than 1.5 mg/dL and creatinine clearances less than 40 mL/min. Pregnancies complicated by second-trimester vasoconstriction and moderate renal insufficiency are at risk for preeclamspia, fetal growth restriction, and fetal demise. Good obstetric outcome can occur in women with mild renal insufficiency and well-controlled chronic hypertension. Improved hypertensive control preconception may decrease the risk for preeclampsia and poor obstetric outcome. Copyright 2000 by the American Association for the Study of Liver DiseasesP regnancies in women with prior orthotopic liver transplantation are complicated by fetal growth restriction (9% to 20%), preterm delivery (40% to 86%), cesarean delivery (45% to 71%), and preeclampsia (20% to 71%). 1-5 Significant preeclampsia rates of 27% to 71% have been reported by several investigators who evaluated smaller series of patients. 1,3 However, larger studies 2,5 and registry data 4 report preeclampsia rates in the range of 13.6% to 21%. Most of the women included in these reports were administered cyclosporine, prednisone, and azathioprine as maintenance immunosuppression. Recently, pregnancy outcomes were published for women administered tacrolimus (FK506) for maintenance immunosuppression. These women had lower rates of preeclampsia (0% to 4%), severe chronic hypertension (0% to 11%), and fetal growth restriction (0% to 4%) and similar rates of cesarean delivery (44%) and preterm delivery (48%) as patients administered cyclosporine. 6,7 The increased rate of pregnancy complications is not surprising because both cyclosporine and FK506 are known to cause renal insufficiency and hypertension. [8][9][10][11] Our institution has previously described pregna...

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“…All these observations favor the view that cyclosporin may increase the renal endothelin production. In fact, in cultured endothelial cells and renal tubular epithelial cells, cyclosporin has been demonstrated to increase endothelin-1 synthesis and secretion (194).…”

Section: V-3 Acute Renal Failurementioning

confidence: 99%

Molecular Pharmacology and Pathophysiological Significance of Endothelin

Goto

Hama

Kasuya

1996

Japanese Journal of Pharmacology

159

108

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ABSTRACT-Since the discovery of the most potent vasoconstrictor peptide, endothelin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological features of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene expression, intracellular processing, specific endothelia converting enzyme (ECE), receptor subtypes (ETA and ETB), intracellular signal transduction following receptor activation, etc. ECE was recently cloned, and its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal that contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has been shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonists have been developed. They, as well as current peptide antagonists, markedly accelerated the pace of investigations into the true pathophysiological roles of endogenous endothelin-1 in mature animals; e.g., hypertension, pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference with the endothelin pathway by either ECE-inhibition or receptor blockade may

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Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells.

Cited by 243 publications

References 35 publications

Plasma endothelin-1 levels after stem cell transplantation

Plasma endothelin-1 levels after stem cell transplantation

Maternal hemodynamics and pregnancy outcome in women with prior orthotopic liver transplantation

Molecular Pharmacology and Pathophysiological Significance of Endothelin

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