Dual immunosuppression enhances vasomotor injury: interactive effect between endothelin-1 and nitric oxide bioavailability.
OBJECTIVE
Cyclosporine A and corticosteroids are associated with many side effects, such as endothelial dysfunction and transplant vasculopathy. We examined the effects of cyclosporine A and hydrocortisone exposure on endothelial function of the rat thoracic aorta.


METHODS
Lewis rats were injected with cyclosporine A, hydrocortisone, cyclosporine A + hydrocortisone, or intraperitoneal saline daily for 2 weeks. Endothelial-dependent and independent vascular relaxation were assessed in isolated segments of thoracic aorta, as well as endothelin-1-induced vasoreactivity. Protein expression of endothelial nitric oxide synthase, endothelin(A), and endothelin(B) receptors were also determined in the thoracic aorta.


RESULTS
Exposure to cyclosporine A and cyclosporine A + hydrocortisone resulted in a reduction in endothelial-dependent vasorelaxation compared with control and hydrocortisone (P = .001). Cyclosporine A and hydrocortisone-treated rats demonstrated increased vasoreactivity to endothelin-1 compared with control, whereas cyclosporine A + hydrocortisone treatment resulted in a synergistic increase (P = .04). All treatment groups displayed a significant reduction in endothelial nitric oxide synthase expression compared with control (P = .001). Endothelin(A) receptor expression was increased in all treatment groups with a synergistic effect seen after cyclosporine A + hydrocortisone treatment. No differences were seen in endothelin(B) receptor expression.


CONCLUSIONS
Cyclosporine A and hydrocortisone induce vasomotor dysfunction with a synergistic impairment observed after concomitant exposure. Our findings suggest that the resultant vasomotor dysfunction is the result of alterations in both nitric oxide and endothelin-1 regulation.
Ramzy
Danny
D
Heart Transplant Program, Peter Munk Cardiac Center, Toronto General Hospital, Toronto, Ontario, Canada.
Tumiati
Laura C
LC
Tepperman
Elissa
E
Sheshgiri
Rohit
R
Jackman
Jessica
J
Badiwala
Mitesh
M
Rao
Vivek
V
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D019332:Endothelin-1 / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D016572:Cyclosporine; D006854:Hydrocortisone