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From Département de Pharmacologie (C.R., J.-F.G.), Faculté
de Médecine Paris-Sud, Le Kremlin-Bicêtre, France, INSERM U430
(P.B.), Paris, France, and INSERM U367 (J.M.), Paris, France.
Correspondence to Jean-François Giudicelli, Département de Pharmacologie, Faculté de Médecine Paris-Sud, 63 Rue Gabriel Péri, Le Kremlin-Bicêtre 94276, France. E-mail jean.francois.giudicelli{at}kb.u-psud.fr
Abstract—Blockade of
angiotensin II AT1 receptors combined with
angiotensin I–converting enzyme inhibition might amplify
the potency of the renin-angiotensin system blockade. We
studied whether chronic and simultaneous administration of
enalapril and losartan would result in additive or synergistic
effects in the (mREN-2)27 transgenic rat (TGR), the investigated
targets being blood pressure, cardiac hypertrophy,
renin-angiotensin system blockade achieved, and plasma
active renin concentration. In addition, the origin (renal or
extrarenal, rat or mouse) of the induced renin release was determined.
Adult TGRs were treated orally and daily for 5 to 7 weeks with 1 mg/kg
(E1) or 3 mg/kg (E3) enalapril or 1 mg/kg (L1) or 3 mg/kg (L3)
losartan, or their combinations (E1L1 and E3L3). At the end of
the treatment period, enalapril and losartan exerted
dose-dependent and, when combined, additive effects in terms of blood
pressure fall and cardiac hypertrophy limitation, and
synergistic effects in terms of plasma active renin stimulation and
blockade of exogenous angiotensin I pressor effects, with
E3L3>E3>L3, E1L1>E1
© 1998 American Heart Association, Inc.
Scientific Contributions
Additive Effects of Enalapril and Losartan in (mREN-2)27 Transgenic Rats
L1, and E1L1=E3>L3). This indicates that in
the TGR, (1) the greater the renin-angiotensin system
blockade achieved, the greater are the reduction in blood pressure, the
limitation of cardiac hypertrophy, and the reactive rise in
plasma renin concentration elicited, and (2) the
enalapril-losartan combinations are more potent at achieving
these goals than any of their constituents individually. In contrast,
there was no interaction between the two drugs regarding aldosteronuria
reduction. Measurement of plasma renin concentration and renal renin at
pH 6.5 and 8.5, ie, the optimal pH values for rat and mouse renin
activities, respectively, indicates that in TGRs the counterregulatory
process for renin release elicited by enalapril, losartan, or
their combination involves primarily rat renin of renal origin, a
finding supported further by the observed increase in the rat renal
renin hybridization index.
Key Words: enalapril • losartan • renin-angiotensin system • rats, TGR(mREN2)27
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