Abstract 016: Combined AT 2 Receptor Stimulation/ AT 1 Receptor Blockade Does Not Cause Renal Dysfunction

Combined ACE inhibition and angiotensin type 1 receptor (AT 1 R) blockade (dual RAS) blockade) causes renal failure which limits their combined use. Angiotensin type 2 receptor (AT 2 R) stimulation evokes renoprotective effects but potential adverse renal effects in drug combination are not known. We examined the effects of the AT 2 R agonist compound 21 (C21) combined with either candesartan cilexetil or perindopril on renal function in a preclinical model that is predictive of clinical outcome. Adult (~25 week-old) male SHR were placed on a normal salt (0.35%, n=8) or a low salt (LS; 0.05%) diet for 17 days with rats on a LS diet randomised to receive one of the following treatments for the final 10 days: untreated (n=8); C21 (0.3mg/kg/d s.c., n=5); candesartan (2 mg/kg/d, n=6); perindopril (0.5mg/kg/d, n=5); C21+candesartan (n=8); C21+perindopril (n=5); or candesartan+perindopril (dual RAS blockade, n=7). Systolic arterial pressure (SBP) was measured via tail cuff at days 0, 7 and 17. At the end of the treatment, renal function was assessed by measuring plasma creatinine, urea, K+ and glomerular filtration rate (GFR) in conscious rats via transdermal assessment of elimination half-life kinetics of FITC-sinistrin (3-5mg/100g i.v.). Candesartan (-43±10 mmHg) or perindopril (-49±12 mmHg) reduced SBP to a similar extent alone or combined with C21, whereas dual RAS blockade markedly reduced SBP (-115±14 mmHg; P<0.01 versus all groups). Plasma creatinine (424 ±65 μmol/L), urea (>50 mmol/L cut-off) and K+ (5.94 ±0.82 mmol/L) levels were all significantly elevated by dual RAS blockade compared with untreated SHR on normal diet (creatinine 39 ±2 μmol/L; urea 7.08±0.22 mmol/L; K+ 4.23±0.13 mmol/L; all P<0.01) or LS diet (creatinine 29 ±2 μmol/L; urea 5.2±0.57 mmol/L; K+ 4.29±0.17 mmol/L; all P<0.01), whereas plasma measurements for C21+candesartan and C21+perindopril were similar to control groups. Estimated GFR in LS group (1.18±0.06 ml/min/100g BW) was similar to other groups except during dual RAS blockade where GFR was markedly impaired (0.32±0.10 ml/min/100g BW; P<0.01 versus LS). Collectively, these data suggest that, unlike dual RAS blockade, an AT 2 R agonist combined with either ACE inhibition or AT 1 R blockade is not likely to cause renal dysfunction.