Do vascular compartments differ in the development of chronic rejection? AT(1) blocker candesartan versus Ace blocker enalapril in an experimental heart transplant model.
BACKGROUND
Accelerated coronary artery disease (ACAD), a serious consequence after heart transplantation, is characterized by diffuse, concentric myointimal proliferation in the arteries. Increasing evidence supports the existence of a local renin-angiotensin system and the role of angiotensin-II in smooth muscle cell proliferation. We investigated the effect of angiotensin-II blocker candesartan and angiotensin-converting enzyme (ACE) inhibitor enalapril on experimental ACAD in a rat model.


METHODS
After heterotopic cardiac transplantation (Fisher to Lewis), recipients received 20 mg/kg/day candesartan or 40 mg/kg/day enalapril per os. Two groups of animals received additional pre-treatment with candesartan or enalapril 7 days before transplantation, and treatment was continued after grafting. All study groups including the controls received 3 mg/kg/day of sub-cutaneous cyclosporine for immunosuppression. A syngeneic group (Lewis to Lewis), serving as extra control, did not receive any treatment. Eighty days after grafting, we assessed the extent of ACAD in large and small arteries, using digitizing morphometry and expressed as mean vascular occlusion (MVO).


RESULTS
In enalapril and candesartan pre- and post-treated animals, we observed significant reduction of MVO of intramyocardial arteries compared with the cyclosporine group (p < 0.005), to levels similar to the syngeneic transplants. MVO of epicardial arteries in enalapril and candesartan pre- or posttreated animals did not significantly differ from cyclosporine controls (p > 0.05).


CONCLUSIONS
Our results support the hypothesis of 2 proliferative compartments in the development of ACAD, with differing receptor or enzyme distribution: the compartment of small, intramyocardial arteries in which ACAD can be reduced by ACE or AT(1) blockade, and that of large, epicardial arteries in which inhibition fails.
Richter
M
M
Heart Center, University of Leipzig, Leipzig, Germany. drrichter@gmx.de
Richter
H
H
Skupin
M
M
Mohr
F W
FW
Olbrich
H G
HG
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D016572:Cyclosporine / Q000627:therapeutic use; D004656:Enalapril / Q000627:therapeutic use*; D006084:Graft Rejection / Q000188:drug therapy*; D016027:Heart Transplantation / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D023421:Models, Animal; D011300:Preoperative Care / Q000379:methods; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007166:Immunosuppressive Agents; D013777:Tetrazoles; D004656:Enalapril; D016572:Cyclosporine; C081643:candesartan