Role of endothelin-1 and nitric oxide bioavailability in transplant-related vascular injury: comparative effects of rapamycin and cyclosporine.
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.


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.
Ramzy
Danny
D
Heart Transplant Program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Rao
Vivek
V
Tumiati
Laura C
LC
Xu
Ning
N
Miriuka
Santiago
S
Delgado
Diego
D
Ross
Heather J
HJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D016572:Cyclosporine / Q000494:pharmacology* / Q000633:toxicity; D015237:Dinoprost / Q000031:analogs & derivatives / Q000032:analysis; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D023421:Models, Animal; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D016377:Organ Transplantation; D018384:Oxidative Stress; D011183:Postoperative Complications; D051381:Rats; D011917:Rats, Inbred Lew; D044022:Receptor, Endothelin A / Q000096:biosynthesis / Q000235:genetics; D044023:Receptor, Endothelin B / Q000096:biosynthesis / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology* / Q000633:toxicity; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects
D019332:Endothelin-1; D007166:Immunosuppressive Agents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D009599:Nitroprusside; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D016572:Cyclosporine; D015237:Dinoprost; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine; D020123:Sirolimus