SHORT-TERM AND LONG-TERM CARDIOVASCULAR ACTIONS OF DIFFERENT DOSES OFPERINDOPRIL IN THE RABBIT

Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demons trate if short-term results can predict chronic outcomes. In short-ter m treatment, five doses of perindopril were examined in random order s eparated by a one week recovery period in each of six rabbits. Two dos es of perindopril which resulted in a moderate hypotensive effect (-14 mmHg) and no hypotensive effect, respectively, were then selected for long-term treatment. Each rabbit in the short-term study received per indopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg(-1) day(-1) fo r a week at a time. Rabbits on long-term treatment received either 0.3 or 0.01 mg kg(-1) day(-1) perindopril for six weeks. All rabbits had their mean arterial blood pressure (MAP) and heart rate recorded throu ghout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotens in converting enzyme (ACE) inhibition were also assayed. Perindopril t reatment for one week produced a dose-dependent hypotensive effect wit h the threshold dose, 0.06 mg kg(-1) day(-1), producing a 6.5+/-1.8 mm Hg fall in MAP. The highest dose (10.0 mg kg(-1) day(-1)) produced a l arge fall in blood pressure of -29.6+/-4.2 mmHg. The 0.01 and 0.06 mg kg(-1) day(-1) doses of perindopril produced an average 2.65 fold incr ease in plasma AngI levels compared to the initial control. The three higher doses (0.32-10.0 mg kg(-1) day(-1)) of perindopril produced an equivalent 5.7 fold increase in plasma AngI levels compared to the ini tial controls. However, over six weeks 0.01 mg kg(-1) day(-1) perindop ril induced a similar decrease in MAP as the 30 fold higher dose (-9.3 mmHg compared to -11.7 mmHg,). This was in spite of a 3 fold differen ce in plasma perindoprilat concentrations between the high and low dos e perindopril groups. Plasma ACE inhibition was >80% with both doses o f perindopril. The results indicate that while perindopril decreases M AP in a dose-dependent manner in short-term (one week) periods, over l onger treatment times (six weeks) low concentrations of perindopril, n on-hypotensive with shortterm treatment, may be as anti-hypertensive a s considerably higher doses. (C) 1996 The Italian Pharmacological Soci ety.