Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine-induced vasomotor impairment.
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 (BH₄), 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+BH₄ 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 BH₄ treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH₄ therapy attenuated CyA-induced effects. Compared with Con, CyA and BH₄ exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH₄-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.
Ramzy
Danny
D
Heart Transplant Program, Toronto General Hospital, University Health Network, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
Wallen
Jack
J
Badiwala
Mitesh V
MV
Tumiati
Laura C
LC
Tepperman
Elissa
E
Ross
Heather J
HJ
Delgado
Diego H
DH
Rao
Vivek
V
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077300:Bosentan; D016572:Cyclosporine / Q000009:adverse effects / Q000494:pharmacology; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000097:blood*; D006706:Homeostasis; D008297:Male; D009569:Nitric Oxide / Q000097:blood*; D018384:Oxidative Stress; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species; D013449:Sulfonamides / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D016572:Cyclosporine; C003402:sapropterin; D000077300:Bosentan