Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine.
Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion of L-arginine on renal hemodynamic function in subjects segregated by the presence or absence of the T allele. If this polymorphism represented a functional variant, subjects with the GT/TT form should exhibit a blunted renal hemodynamic response to L-arginine compared to those with a GG allele. All subjects were given a diet controlled for sodium and protein intake. GG subjects had lower mean arterial pressure and an augmented glomerular filtration rate at baseline. In response to a graded L-arginine infusion, this group had significant changes in effective renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance, and renal blood flow. The renal response to L-arginine in GT/TT subjects was blunted. Circulating cGMP levels and endothelial NOS mRNA expression, measured in skin biopsies by real-time PCR, did not differ between the groups. Our study shows that the G894T allele of endothelial NOS is associated with a blunted response to L-arginine, suggesting this polymorphism may be a functional variant in humans.
Cherney
David Z I
DZ
Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Scholey
James W
JW
Zhou
Joyce
J
Zimpelmann
Joseph
J
Kennedy
Christopher
C
Burns
Kevin D
KD
Lai
Vesta
V
Miller
Judith A
JA
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001120:Arginine / Q000494:pharmacology*; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D011110:Polymorphism, Genetic; D012079:Renal Circulation / Q000187:drug effects*; D055815:Young Adult
D009569:Nitric Oxide; D001120:Arginine; D052250:Nitric Oxide Synthase Type III