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J Thorac Cardiovasc Surg 2008;135:938-944
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability

Danny Ramzy, MD, Laura C. Tumiati, BSc, Elissa Tepperman, BSc, Rohit Sheshgiri, BSc, Jessica Jackman, BSc, Mitesh Badiwala, MD, Vivek Rao, MD, PhD*

Heart Transplant Program, Peter Munk Cardiac Center, Toronto General Hospital; Division of Cardiac Surgery, University of Toronto; and Division of Cardiology, University of Toronto, Toronto, Ontario, Canada

Received for publication May 14, 2007; revisions received August 18, 2007; accepted for publication September 6, 2007.

* Address for reprints: Vivek Rao, MD, PhD, Toronto General Hospital, Division of Cardiovascular Surgery, 4N-464, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4. (Email: vivek.rao{at}uhn.on.ca).

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, endothelinA, and endothelinB 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). EndothelinA receptor expression was increased in all treatment groups with a synergistic effect seen after cyclosporine A + hydrocortisone treatment. No differences were seen in endothelinB receptor expression.

Conclusion: 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.

Abbreviations and Acronyms CyA = cyclosporine A; eNOS = endothelial nitric oxide synthase; ET = endothelin; Hcort = hydrocortisone; LV = left ventricular; NO = nitric oxide; Rc = receptor; SNP = sodium nitroprusside; TAo = thoracic aorta






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