Prevention of salt induced hypertension and fibrosis by angiotensin converting enzyme inhibitors in Dahl S rats

Abstract

Background and purpose: In Dahl S rats, high salt increases activity of the tissue renin-angiotensin-aldosterone system (RAAS) in the CNS, heart and kidneys. Here, we assessed the effects of chronic angiotensin converting enzyme (ACE) inhibition on salt-induced hypertension and cardiovascular and renal hypertrophy and fibrosis, relative to the extent of ACE blockade.

Experimental approach: From 4.5 weeks of age, Dahl S rats received either the lipophilic ACE inhibitor trandolapril (1 or 5 mg kg(-1) day(-1)) or the hydrophilic ACE inhibitor lisinopril (10 or 50 mg kg(-1) day(-1)) and a high salt diet was started 0.5 week later. Treatments ended at 9 weeks of age.

Key results: High salt diet markedly increased blood pressure (BP), decreased plasma angiotensin II and increased ACE binding densities in brain, heart, aorta and kidneys. Trandolapril and lisinopril prevented 50% of the increase in BP in light and dark period of the day. After the last doses, trandolapril decreased ACE densities by approximately 80% in brain nuclei and heart and lisinopril by approximately 60% in the brain and by approximately 70% in the heart. The two ACE inhibitors prevented right ventricular hypertrophy and attenuated left ventricular hypertrophy but did not affect renal hypertrophy caused by high salt. Both drugs prevented high salt-induced fibrosis in heart, kidney and aorta.

Conclusion and implication: As the ACE inhibitors could completely prevent tissue fibrosis and partially prevent tissue hypertrophy and hypertension, the tissue RAAS may play a critical role in salt-induced fibrosis, but a lesser role in the hypertrophy.

Figure 1

MAP (mean arterial blood pressure) in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril from days 31 to 33 of high salt diet. The arrow indicates the time of vehicle or ACE inhibitor injection. Values are expressed as mean±s.e.mean; n=6 rats per group. ^*P<0.001 vs other groups, a P<0.001 vs regular and high salt+vehicle.

Figure 2

Plasma angiotensin II levels at 4 and 24 h after the last dose in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril at two dose levels for 5 weeks. Values are expressed as mean±s.e.m.; n=6 rats per group. ^*P<0.05 vs regular salt diet.

Figure 3

Left (LV) and right (RV) ventricular and kidney changes in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril. In (a) LV weight and in (b) RV weight in the protocol II study are shown. In (c), the left kidney weight and in (d) the glomerular size (d) in protocol I studies are shown. Values are expressed as mean±s.e.mean, n=6 rats per group. ^*P<0.05 vs regular salt diet, ^†P<0.05 vs high salt diet+vehicle.

Figure 4

Representative images of cardiac and aorta fibrosis in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril. % refers to % of total area. LA: left atrium; LV: left ventricle.

Figure 5

Cardiac interstitial fibrosis (upper two panel) and perivascular fibrosis (bottom panel) in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril at two dose levels. Values are expressed as mean±s.e.mean, n=6 rats per group. ^*P<0.05 vs regular salt diet, ^†P<0.05 vs high salt diet+vehicle.

Figure 6

Aorta tunica media and tunica adventitia fibrosis and kidney tubular fibrosis in Dahl S rats on regular salt intake or on high salt intake treated with vehicle, lisinopril or trandolapril at two dose levels. Values are expressed as mean±s.e.mean, n=6 rats per group. ^*P<0.05 vs regular salt diet, ^†P<0.05 vs high salt diet+vehicle.