New approach in the therapy of chronic rejection? ACE- and AT1-blocker reduce the development of chronic rejection after cardiac transplantation in arat model

Background: Angiotensin II is one of the most potent mitogens of smooth mus cle cell proliferation and plays a central role in the development of accel erated coronary artery disease (ACAD), which remains a serious consequence after heart transplantation and limits long-term survival. We investigated the effect of an angiotensin-II blocker, Losartan (angiotensin II Type 1 [A T(1)]-blocker), and an angiotensin-converting enzyme (ACE) inhibitor, Enala pril, on experimental ACAD in a rat cardiac transplant model (Fisher to Lew is). Methods: After grafting, recipients were treated with 10 mg/kg/day per os L osartan or 40 mg/kg/day per os Enalapril. Two groups of animals received ad ditional pre-treatment with Losartan or Enalapril 7 days before transplanta tion. All study groups, including the control group, received immunosuppres sion with cyclosporine (3 mg/kg/day subcutaneously). We assessed the extent of ACAD of large and small arteries 80 days after grafting using digitizin g morphometry. Results: We observed significant reduction of neointimal proliferation in s mall arteries in Losartan pre- and post-treated and in Enalapril pre-treate d recipients compared with the cyclosporine-treated group (p < 0.05). In ep icardial arteries, Enalapril pre- and post-treatment as well as Losartan po st-treatment significantly reduced neointimal formation compared with the c ontrol group. Reduction of neointima by Enalapril post treatment in small a rteries and Losartan pre-treatment in large arteries trended toward but fai led statistical significance. Conclusions: Our results suggest the important role of the renin-angiotensi n system in neointimal proliferation, which can be reduced equally with ACE inhibitors or the angiotensin-II blocker. Therefore AT(1) blockade with Lo sartan is a useful therapeutic strategy for inhibition of ACAD after cardia c transplantation.