RGD Reference Report - Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine-induced vasomotor impairment. - Rat Genome Database

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Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine-induced vasomotor impairment.

Authors: Ramzy, D  Wallen, J  Badiwala, MV  Tumiati, LC  Tepperman, E  Ross, HJ  Delgado, DH  Rao, V 
Citation: Ramzy D, etal., J Heart Lung Transplant. 2010 Sep 17.
RGD ID: 4144133
Pubmed: PMID:20851640   (View Abstract at PubMed)
DOI: DOI:10.1016/j.healun.2010.08.001   (Journal Full-text)

BACKGROUND:: We previously demonstrated that cyclosporine (CyA) impairs endothelial function as a result of alterations in nitric oxide (NO) and endothelin-1 (ET-1) regulation. Bosentan (BOS), an ET-1 antagonist, and tetrahydrobiopterin (BH(4)), an eNOS cofactor, may reduce endothelial dysfunction by improving ET-1/NO homeostasis. METHODS:: Lewis rats received intraperitoneal injections of CyA with BOS or with BOS+BH(4) daily for 2 weeks. Control (Con) animals received saline injections. Thoracic aortic segments were assessed for endothelial-dependent (E(dep)) and -independent (E(ind)) relaxation (E(max%)) after exposure to acetylcholine and sodium nitroprusside. Vessel sensitivity to ET-1-induced vasospasm was evaluated. RESULTS:: CyA use resulted in impaired E(dep) vasorelaxation when compared with Con, whereas BOS and BH(4) treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH(4) therapy attenuated CyA-induced effects. Compared with Con, CyA and BH(4) exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH(4)-induced sensitivity to vasospasm. CyA treatment resulted in higher 8-isoprostane levels compared with Con. CyA-mediated vascular dysfunction is characterized by impaired NO and ET-1 homeostasis. CONCLUSIONS:: Our study suggests potential therapeutic strategies to prevent endothelial dysfunction as combined therapy with ET-1 antagonism and NO augmentation completely abrogated CyA-induced vascular injury.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to xenobiotic stimulus  IEP 4144133bosentanRGD 

Objects Annotated

Genes (Rattus norvegicus)
Edn1  (endothelin 1)


Additional Information