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 (ACE I) or an angiotensin receptor antagonist (ARA) is difficult due to the physiological compensations. Combined 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 mg/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 influenced 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 intraperitoneally. Blood pressure was measured by telemetry. Cardiac weight was measured after 10 days of therapy. Renal function was assessed by plasma creatinine and electrolytes, plasma renin and angiotensinogen concentrations were measured.


RESULTS
On 0.2% NaCl intake, combined blockade lowered blood pressure progressively; 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. There was a polyuria. The syndrome was reversed by adding NaCl to the drinking water or prevented in rats on a 4% NaCl intake. In rats on 0.2% NaCl plasma renin rose dramatically with medication and angiotensinogen became depleted. Haematocrit in all groups of rats did not differ.


CONCLUSIONS
Combined blockade of the renin-angiotensin system can cause death in rats on a reduced NaCl intake. This was prevented by a high salt intake. The syndrome may result from depletion of angiotensinogen and the failure to synthesize sufficient angiotensin II that may be critical for normal cardiac growth and function and critical for survival.
Griffiths
C D
CD
Department of Physiology, University of Melbourne, Victoria, Australia.
Morgan
T O
TO
Delbridge
L M
LM
D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001769:Blood / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight; D004039:Diet, Sodium-Restricted; D004357:Drug Synergism; D004435:Eating; D006321:Heart / Q000033:anatomy & histology; D019808:Losartan / Q000494:pharmacology*; D009929:Organ Size; D020913:Perindopril / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D000803:Angiotensin I; D019808:Losartan; D020913:Perindopril