Persistent effects on blood pressure and renal function of perindopril alone or combined with losartan in Lyon hypertensive rats.
BACKGROUND
In Lyon genetically hypertensive (LH) rats, an early and long-term angiotensin-converting enzyme (ACE) inhibition with perindopril prevents their hypertension and renal alterations. The present work aimed to determine whether: 1) these effects persist after treatment withdrawal; 2) a short-term additional angiotensin II type 1 (AT1) receptor blockade with losartan potentiates these effects; and 3) an early combination of low doses of perindopril and losartan produces the same prolonged effects as monotherapy with a higher dose of perindopril.


METHODS
Perindopril (0.4 or 3 mg/kg/day orally) was given from 3 to 12 weeks of age to male LH rats. In other perindopril-treated LH rats, losartan (10 mg/kg/day orally) was added 1 week before perindopril withdrawal and during a 3-week period. In another group of LH rats, perindopril (0.1 mg/kg/day) and losartan (2.5 mg/kg/day) were given together from 3 to 12 weeks. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were monitored using radio-telemetry and renal function studied in anesthetized rats.


RESULTS
Eight weeks after perindopril withdrawal, a significant reduction (P < .05) in SBP and DBP was observed with the both doses (SBP: 135 +/- 3, 139 +/- 5 v 157 +/- 4; DBP: 89 +/- 4, 93 +/- 5 v 111 +/- 3 mm Hg for 0.4 and 3 mg/kg/day v untreated LH rats). This was accompanied by a persistent decrease in urinary protein excretion and a long-lasting improvement in pressure natriuresis. The persistent antihypertensive effect was not improved by short-term addition of losartan. Interestingly, the early combination of perindopril with losartan at fourfold lower doses produced similar persistent antihypertensive and renoprotective effects.


CONCLUSIONS
The blood pressure reduction produced by an early ACE inhibition in LH rats persists long after treatment withdrawal and is associated with an improvement in renal function. The combination of low doses of perindopril and losartan reveals a long-term effect similar to that of a monotherapy with a higher dose of perindopril.
Naelten
Gaëlle
G
Département de Physiologie et Pharmacologie Clinique, Faculté de Pharmacie, Université Claude Bernard Lyon 1, Lyon, France. gaelle.naelten@univ-lyon1.fr
Liu
Kiao-Ling
KL
Chapuis
Bruno
B
Lo
Ming
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D020913:Perindopril / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D019808:Losartan; D020913:Perindopril