Effects of combined administration of ACE inhibitor and angiotensin II receptor antagonist are prevented by a high NaCl intake

Background To prevent the action of angiotensin II by blockade with either an angiotensin converting enzyme inhibitor (ACE1) or an angiotensin recepto r antagonist (ARA) is difficult due to the physiological compensations. Com bined therapy with both drugs may enable complete blockade, and in rats in high doses this has produced a syndrome that results in death. Objective To determine the effect of combined blockade using losartan (10 m g/kg per day) and perindopril (6 mg/kg per day) on blood pressure, cardiac growth, renal function and behaviour, and to determine how this is influenc ed by different salt intakes in normotensive Sprague Dawley rats. Methods Rats were fed an 0.2 or 4% NaCl diet and received the above drugs i ntraperitoneally. Blood pressure was measured by telemetry. Cardiac weight was measured after 10 days of therapy. Renal function was assessed by plasm a creatinine and electrolytes, plasma renin and angiotensinogen concentrati ons were measured. Results On 0.2% NaCl intake, combined blockade lowered blood pressure progr essively; at day 7, rats on 0.2% NaCl developed a syndrome of listlessness and failure to eat which led to loss of weight and death. Cardiac size was dramatically reduced. Plasma creatinine was elevated to 50% above normal. T here was a polyuria. The syndrome was reversed by adding NaCl to the drinki ng water or prevented in rats on a 4% NaCl intake. In rats on 0.2% NaCl pla sma renin rose dramatically with medication and angiotensinogen became depl eted. Haematocrit in all groups of rats did not differ. Conclusion Combined blockade of the renin-angiotensin system can cause deat h in rats on a reduced NaCl intake. This was prevented by a high salt intak e. The syndrome may result from depletion of angiotensinogen and the failur e to synthesize sufficient angiotensin II that may be critical for normal c ardiac growth and function and critical for survival. (C) 2001 Lippincott W illiams & Wilkins.