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(Circulation. 2006;114:I-214 – I-219.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Role Of Endothelin-1 and Nitric Oxide Bioavailability in Transplant-Related Vascular Injury

Comparative Effects of Rapamycin and Cyclosporine

Danny Ramzy, MD; Vivek Rao, MD, PhD; Laura C. Tumiati, BSc; Ning Xu, MSc; Santiago Miriuka, MD; Diego Delgado, MD; Heather J. Ross, MD, MSc

From Heart Transplant Program, Toronto General Hospital, University Health Network; Division of Cardiac Surgery (D.R., V.R., L.C.T., N.X.), University of Toronto; Division of Cardiology (S.M., D.D., H.J.R.), University of Toronto, Toronto, Ontario, Canada.

Correspondence to Vivek Rao, Alfredo and Teresa DeGasperis Chair in Heart Failure Surgery, EN4N-464, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4. E-mail: vivek.rao{at}uhn.on.ca

Background— Cyclosporine (CyA) is associated with many side effects, including endothelial dysfunction and transplant vasculopathy (TxV). We previously demonstrated that CyA results in impairment of nitric oxide bioavailability and enhanced sensitivity to endothelin-1 (ET-1). In this study, we evaluated rapamycin (SRL) for its effects on the endothelium.

Methods and Results— Lewis rats (n =8) were injected with SRL (1.5 mg/kg), CyA (5 mg/Kg), or saline (Con) intraperitoneally daily for 2-weeks. Thoracic aortic segments were assessed for endothelial-dependent (Edep) and independent (Eind) relaxation after exposure to acetylcholine and sodium nitroprusside by deriving the percent maximum relaxation (Emax). ET-1 plasma levels were also measured. Thoracic aortic expression of endothelial nitric oxide synthase (eNOS), ET_A and ET_B receptors (Rc), were determined. Oxidative injury was assessed by changes in 8-isoprostane levels. CyA exposure resulted in lower Edep vasorelaxation compared with control and SRL (Emax: SRL, 58±4%; CyA, 24±7%; Con, 52±8%; P=0.001). No differences in Eind vasorelaxation were seen. CyA exposure also increased sensitivity to ET-1 (% maximum contraction [Cmax]: Con, 211±8%; SRL, 230±5%; CyA, 259±3%; P=0.04). Only SRL treatment reduced ET-1 plasma levels. CyA reduced eNOS expression by 30% and increased ETA Rc expression by 34% compared with both Con and SRL (P=0.02). CyA resulted in higher 8-isoprostane levels (CyA, 50±2%; SRL, 3±3%; Con, 2±5%; P=0.02).

Conclusions— CyA results in vascular dysfunction characterized by impairment of Edep vasorelaxation and enhanced sensitivity to vasospasm. SRL did not impair Edep vasorelaxation or increase sensitivity to vasospasm while lowering ET-1 levels and preserving eNOS protein expression. We conclude that SRL is less deleterious to the vasculature than CyA and may prevent TxV by these mechanisms.

Key Words: cyclosporine • endothelial function • nitric oxide • rapamycin