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‐β 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 vasculopath

Combination treatment with an ETA‐receptor blocker and an ACE inhibitor is not superior to the respective monotherapies in attenuating chronic transplant nephropathy in a ‘Fisher‐to‐Lewis' rat model

Background. Specific endothelin A (ETA)‐receptor blockade and ACE inhibition attenuate chronic transplant nephropathy (CTN) in the ‘Fisher‐to‐Lewis' rat model. It is unknown (i) which of both pharmacological interventions attenuates CTN more effectively and (ii) whether combination therapy exerts additive nephroprotection. Methods. We compared (i) the effects of specific ETA‐receptor blockade with LU 302146 (30 mg/kg bw/day) and ACE inhibition with trandolapril (0.3 mg/kg bw/day) and (ii) the effect of a combination therapy of both drugs on the development of CTN. Kidneys of Fisher rats were orthotopically grafted to Lewis rats. Untreated ‘Fisher‐to‐Lewis' allografts served as controls (TX). All animals received low‐dose cyclosporin A (1.5 mg/kg body weight) for 10 days post‐transplant to inhibit early acute rejection episodes. The duration of the experiment was 36 weeks. Blood pressure (BP) was measured every other week by tail plethysmography. Indices of glomerulosclerosis (GS), tubulointerstitial and vascular damage, number of glomeruli, total glomerular volume and mean glomerular volume were measured using morphometric and stereological techniques, respectively. Albuminuria, blood chemistry and haematology were measured at the end of the experiment. Results. LU 302146 did not affect systolic BP. In contrast, trandolapril and combination treatment significantly reduced systolic BP. Histological signs of CTN were almost completely prevented by LU 302146 and trandolapril as compared to TX, e.g. GS=0.8±0.08 and 0.9±0.20 vs 1.8±0.21* (arbitrary unit; *P<0.001 vs treated groups). Allograft weight was significantly lower in treated vs TX animals. Trandolapril and combination therapy, but not LU 302146 alone, abrogated glomerular hypertrophy, i.e. mean glomerular volume: TX 2.22±0.43, trandolapril 1.61±0.38**, LU 302146 2.22±0.11, trandolapril+LU 302146 1.78±0.28* (μm3; *P<0.05 vs control and LU 302146, **P<0.01 vs control and LU 302146). Albuminuria was lower in treated compared to TX animals. Combination therapy did not confer additional benefit compared to the respective monotherapies. Conclusions. We conclude that ETA‐receptor blockade abrogates GS, tubulointerstitial and vascular damage in the ‘Fisher‐to‐Lewis' model of CTN to a similar extent as ACE inhibition. However, only ACE inhibition inhibits glomerular hypertrophy. In contrast to ACE inhibition, 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 CTN. Combination therapy exerts no additive nephroprotectio