Acute renal effects of neutral endopeptidase inhibition in humans.
The acute renal effects of neutral endopeptidase 24.11 (E-24.11) inhibition induced by a single oral dose of sinorphan (100 mg) were investigated in 10 healthy normotensive subjects on normal sodium diet. Sinorphan inhibited 90% of E-24.11 activity and increased plasma atrial natriuretic peptide (ANP) and urinary guanosine 3',5'-cyclic monophosphate (cGMP) by 70 and 100%, respectively. Sinorphan increased urinary sodium output by 50% (P < 0.001) and decreased fractional distal reabsorption by 4% (P < 0.01). Sinorphan increased glomerular filtration rate (GFR) and filtration fraction by 10% 1 h after administration and decreased renal plasma flow by 10%. Mean arterial pressure, renal vascular resistance, plasma aldosterone concentration, and renin activity were unmodified. Sinorphan decreased fractional clearance of neutral dextrans over the 34- to 52-A radius range. Applying the changes along with a hydrodynamic isopore with shunt model, sinorphan significantly increased capillary pressure gradient (delta P; 39 +/- 1 vs. 34 +/- 1 mmHg; P < 0.01), whereas ultrafiltration coefficient was unchanged. In conclusion, endopeptidase inhibition increased endogenous plasma ANP and cGMP generation and induced natriuresis through both an increase in filtered load and a decrease in distal tubular reabsorption of sodium. Sinorphan increases GFR, filtration fraction, and delta P, probably through an increase in efferent over afferent arteriolar resistance ratio.
Schmitt
F
F
Institut National de la Santé et de la Recherche Médicale, Unité 90, Paris, France.
Martinez
F
F
Ikeni
A
A
Savoiu
C
C
Natov
S
S
Laborde
K
K
Lacour
B
B
Grünfeld
J P
JP
Hannedouche
T
T
D001794:Blood Pressure / Q000187:drug effects; D003911:Dextrans / Q000493:pharmacokinetics; D004573:Electrolytes / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006728:Hormones / Q000097:blood; D006801:Humans; D007668:Kidney / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D012079:Renal Circulation / Q000187:drug effects; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D003911:Dextrans; D004573:Electrolytes; D006728:Hormones; C049331:racecadotril; D015244:Thiorphan; D015260:Neprilysin