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

Abstract

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. 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. 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. 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.