K. Schmerbach, Philipp. Kalk, Christina Wengenmayer, K. Lucht, T. Unger, Berthold Hocher, C. Thoene-Reineke

• Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreatedBackground: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options. Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.…