Renal effects of angiotensin I-receptor blockade and angiotensin convertase inhibition in man.
1. The objective was to compare two means of inhibition of the renin-angiotensin system [angiotensin-converting enzyme inhibition and selective antagonism of angiotensin II subtype 1 (AT1) receptor] on renal function in 10 healthy normotensive volunteers on a normal sodium diet. Since mechanisms of action may differ between both drugs, a synergistic action was further studied by combining the two drugs. 2. The design was a double-blind randomized acute administration of either placebo or a single oral dose of enalapril, 20 mg, followed in each case by administration of the AT1 selective antagonist losartan potassium, 50 mg orally. 3. The methods included measurements of hormones (plasma renin activity, plasma aldosterone), blood pressure and renal function from 45 to 135 min after administration of placebo or enalapril, and from 45 to 135 min after losartan and placebo or losartan and enalapril. Renal function was studied using clearance of sodium, lithium, uric acid, inulin and para-aminohippuric acid. To examine further the determinants of glomerular filtration at the microcirculation level, fractional clearance of neutral dextran was determined and sieving curves were applied on a hydrodynamic model of ultrafiltration. 4. Losartan did not change plasma renin activity, blood pressure or glomerular filtration rate, but increased significantly renal plasma flow and urinary excretion of sodium and uric acid. Enalapril increased plasma renin activity and renal plasma flow, and decreased blood pressure without natriuretic, lithiuretic or uricosuric effects. The renal vasodilatation was potentiated when losartan and enalapril were combined, despite a further rise in plasma renin. In contrast to enalapril, losartan either alone or in combination with enalapril significantly depressed fractional clearances of dextran of small radii (34-42 A). These changes in fractional clearances of dextran were presumably related to the rise in glomerular plasma flow since the other major determinants of filtration, i.e. transcapillary glomerular pressure gradient, ultrafiltration coefficient and membrane property, were computed as unchanged by either losartan, enalapril or a combination of both. 5. In conclusion, these findings suggest that in normal sodium-repleted man the renal, hormonal and blood pressure effects of AT1 antagonism and angiotensin-converting enzyme inhibition are not strictly similar and could be synergistic.
Schmitt
F
F
INSERM 90, Paris, France.
Natov
S
S
Martinez
F
F
Lacour
B
B
Hannedouche
T P
TP
D000328:Adult; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004357:Drug Synergism; D004656:Enalapril / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D019808:Losartan; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D012039:Regional Blood Flow / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D004656:Enalapril; D007703:Peptidyl-Dipeptidase A; D012083:Renin; D019808:Losartan