Pharmacological demonstration of the additive effects of angiotensin-converting enzyme inhibition and angiotensin II antagonism in sodium depleted healthy subjects.
A blockade of the hemodynamic and tissue effects of angiotensin II (Ang II) more complete than that presently achieved with usual daily doses of angiotensin coverting enzyme (ACE) inhibitors or type 1 Ang II receptor antagonists has potential advantages and risks. Therefore, it is worthwhile to investigate the biological and the hemodynamic effects of the simultaneous blockade of the renin-angiotensin system (RAS) at the two sites where it can be currently achieved, ACE and type 1 Ang II receptors. To investigate this issue, 2 double-blind randomized crossover studies were performed in a model of mild sodium depletion in normotensive volunteers. They ingested single oral doses of captopril 50 mg, losartan 50 mg, their combination or matched placebos, and in a second study, single oral doses of enalapril 10 mg, enalapril 20 mg and the combination of losartan 50 mg with enalapril 10 mg. The combination of captopril 50 mg and losartan 50 mg had additive effects on blood pressure fall and renin release in sodium-depleted normotensive subjects. When compared to enalapril 10 mg and the doubling of its dose, the combination of losartan 50 mg and enalapril 10 mg significantly increased both the area under the time curve of mean blood pressure fall and plasma active renin levels. It did not further decrease plasma aldosterone levels. The conclusion is that a more complete blockade of the RAS can be achieved by concomitant administration of a type 1 Ang II receptor antagonist and an ACE inhibitor.
Azizi
M
M
Broussais Hospital Clinical Investigation Center, INSERM U367, Paris, France.
Guyene
T T
TT
Chatellier
G
G
Ménard
J
J
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D001713:Biphenyl Compounds / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000008:administration & dosage; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted; D004311:Double-Blind Method; D004357:Drug Synergism; D004792:Enzyme Precursors / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D019808:Losartan; D008297:Male; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D012964:Sodium / Q000172:deficiency; D013777:Tetrazoles / Q000008:administration & dosage
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004792:Enzyme Precursors; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D002216:Captopril; D012964:Sodium; D012083:Renin; D019808:Losartan