Combination treatment with an ETA-receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant vasculopathy in different aorta allotransplantation rat models

Background. The effect of the specific endothelin (A) (ETA)-receptor antagonist LU 302146 (LU) was assessed in a normotensive model of chronic transplant vasculopathy, i.e. orthotopic allotransplantation of the infrarenal abdominal aorta from spontaneously hypertensive-to-Wistar-Kyoto (SHR-to-WKY) rats. A second experimental setting was used to confirm the results in a different model, which to some extent may also address the issue of blood pressure (BP) in transplant vasculopathy, i.e. orthotopic allotransplantation of infrarenal abdominal aorta from WKY-to-SHR rats. Untreated sham-operated and isografted WKY and SHR served as controls. Allotransplanted animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril served as positive treatment controls. Methods. Rats were randomized to receive standard diet or a diet designed to deliver either 30 mg LU/kg bw/day, 0.3 mg/kg bw/day trandolapril or a combination of both. The duration of either experiment was 8 weeks. BP was measured by tail plethysmography. Results. Treatment with LU did not affect systolic BP in either experimental setting. In contrast, trandolapril and combination treatment significantly reduced systolic BP in SHRs. The increase in aortic wall thickness (given in mm) was abrogated to a similar extent in the three treatment groups as compared with untreated allotransplanted animals in either experimental setting (e.g. WKY sham-operated 0.084 +/- 0.013, P < 0.05 vs treatment groups; WKY isotransplanted 0.100 +/- 0.010, P < 0.05 vs treatment groups; WKY allotransplanted 0.289 +/- 0.077, P < 0.05 vs all groups; WKY allotransplanted + trandolapril 0.185 +/- 0.025; WKY allotransplanted + LU 301246 0.192 +/- 0.049; WKY allotransplanted + LU 301246 + trandolapril 0.190 +/- 0.041). This was due to an attenuation of the increase of intima and media thickness. Treatment with LU and trandolapril were similarly effective in attenuating the increase of the number of proliferating cell nuclear antigen (PCNA)-positive cells in the intima. Again, combination treatment did not confer additional benefit. In contrast, trandolapril was more effective than LU in attenuating the increase in the number of PCNA-positive cells in the media. Trandolapril or combination treatment, but not LU, attenuated transforming growth factor-beta expression in aortic allografts. Conclusions. The ETA-receptor blockade abrogates allograft vasculopathy in two different aorta allotransplantation models to a similar extent as ACE inhibition even in the absence of concomitant immunosuppression. At least in SHRs the effect of ETA-receptor blockade is independent of BP. This finding is consistent with the notion that ETA-receptor mediated events play a partly BP-independent role in the genesis of chronic transplant vasculopathy.