The renal and systemic hemodynamic effects of a nitric oxide-synthase inhibitor are reversed by a selective endothelin(a) receptor antagonist in men.
There is evidence for an interaction between nitric oxide (NO) and endothelin (ET) at the level of the renal vasculature. We hypothesized that acute renal effects of systemic NO synthase inhibition (NG-monomethyl-l-arginine, L-NMMA) may be blunted by coadministration of a specific ET(A) receptor antagonist (BQ-123) in healthy humans. Fifteen healthy young male subjects participated in this randomized, double-blind, placebo-controlled 3-way crossover study. These sodium-repleted volunteers received L-NMMA alone, or BQ-123 alone, or L-NMMA with a subsequent coinfusion of BQ-123. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined with the PAH and inulin clearance method, respectively. Mean arterial pressure (MAP) and pulse rate were measured noninvasively at baseline and every 15 min after the start of the study period. L-NMMA alone reduced RPF (-22%, P < 0.001) and GFR (-8%, P < 0.009) and increased MAP (+10%, P < 0.001). BQ-123 alone did not affect these parameters. However, coinfusion of BQ-123 blunted the effects of L-NMMA on RPF (P < 0.001), GFR (P < 0.001), and MAP (P = 0.006). Peripheral and renal hemodynamic effects of acute systemic NO synthase inhibition are at least partially reversed by ET(A) receptor blockade with BQ-123. This indicates a functional antagonism between specific ET(A) receptor antagonist and NO synthase inhibitors at the level of the renal vasculature.
Schmidt
A
A
Department of Clinical Pharmacology, University of Vienna, Vienna, Austria.
Bayerle-Eder
M
M
Pleiner
H
H
Zeisner
C
C
Wolzt
M
M
Mayer
G
G
Schmetterer
L
L
D000328:Adult; D001783:Blood Flow Velocity / Q000502:physiology; D004336:Drug Antagonism; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007260:Infusion Pumps; D007668:Kidney / Q000098:blood supply; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; C072247:cyclo(Trp-Asp-Pro-Val-Leu)