¹Département de Physiologie et Pharmacologie Clinique, Faculté de Pharmacie, Université Claude Bernard Lyon 1, Lyon, France.

Correspondence: Gaëlle Naelten, Faculté de Pharmacie, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France E-mail: gaelle.naelten@univ-lyon1.fr

^*Support was provided through a scholarship from the Ministère de l'Education Nationale, de la Recherche et de la Technologie (to GN).

Received 23 July 2004; Revised 2 November 2004; Accepted 22 November 2004.

Abstract

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.