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

Background: Angiotensin II is one of the most potent mitogens of smooth muscle cell proliferation and plays a central role in the development of accelerated 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 [AT(1)]-blocker), and an angiotensin-converting enzyme (ACE) inhibitor, Enalapril, on experimental ACAD in a rat cardiac transplant model (Fisher to Lewis). Methods: After grafting, recipients were treated with 10 mg/kg/day per os Losartan or 40 mg/kg/day per os Enalapril. Two groups of animals received additional pre-treatment with Losartan or Enalapril 7 days before transplantation. All study groups, including the control group, received immunosuppression with cyclosporine (3 mg/kg/day subcutaneously). We assessed the extent of ACAD of large and small arteries 80 days after grafting using digitizing morphometry. Results: We observed significant reduction of neointimal proliferation in small arteries in Losartan pre- and post-treated and in Enalapril pre-treated recipients compared with the cyclosporine-treated group (p < 0.05). In epicardial arteries, Enalapril pre- and post-treatment as well as Losartan post-treatment significantly reduced neointimal formation compared with the control group. Reduction of neointima by Enalapril post treatment in small arteries and Losartan pre-treatment in large arteries trended toward but failed statistical significance. Conclusions: Our results suggest the important role of the renin-angiotensin system in neointimal proliferation, which can be reduced equally with ACE inhibitors or the angiotensin-II blocker. Therefore AT(1) blockade with Losartan is a useful therapeutic strategy for inhibition of ACAD after cardiac transplantation.