Short-term and long-term cardiovascular actions of different doses of perindopril in the rabbit.
Short-term (one week) and chronic (six week) cardiovascular effects of orally administered perindopril were examined in the rabbit to demonstrate if short-term results can predict chronic outcomes. In short-term treatment, five doses of perindopril were examined in random order separated by a one week recovery period in each of six rabbits. Two doses 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 perindopril in doses of 0.01, 0.06, 0.32, 1.8 and 10 mg kg-1 day-1 for 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 throughout treatment. Plasma angiotensin I (AngI), perindoprilat, angiotensin converting enzyme (ACE) inhibition were also assayed. Perindopril treatment for one week produced a dose-dependent hypotensive effect with the threshold dose, 0.06 mg kg-1 day-1, producing a 6.5 +/- 1.8 mmHg fall in MAP. The highest dose (10.0 mg kg-1 day-1) produced a large 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 increase 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 initial controls. However, over six weeks 0.01 mg kg-1 day-1 perindopril 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 difference in plasma perindoprilat concentrations between the high and low dose perindopril groups. Plasma ACE inhibition was > 80% with both doses of perindopril. The results indicate that while perindopril decreases MAP in a dose-dependent manner in short-term (one week) periods, over longer treatment times (six weeks) low concentrations of perindopril, non-hypotensive with short-term treatment, may be as anti-hypertensive as considerably higher doses.
Fennessy
P A
PA
Department of Anatomical Sciences, University of Queensland, Brisbane, Australia.
Godwin
S
S
Head
G A
GA
Campbell
J H
JH
Campbell
G R
GR
D000803:Angiotensin I / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020913:Perindopril; D011817:Rabbits; D013686:Telemetry; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; D000803:Angiotensin I; D020913:Perindopril