Endogenous asymmetrical dimethylarginine and hypertension associated with puromycin nephrosis in the rat.
1. The present experiments were designed to investigate the role of asymmetrical NG,NG-dimethyl-L-arginine (ADMA) in causing hypertension associated with the focal and segmental glomerulosclerosis (FSGS) produced by a single bolus of puromycin aminonucleoside (PAN) and successive injection of protamine for 7 days in rats which had undergone unilateral nephrectomy. 2. After the unilateral nephrectomy, and administering PAN and protamine, histological examinations of the kidney revealed a typical FSGS, that is, evident abnormalities including segmental mesangial proliferation, obliteration of glomerular capillary lumens and adhesions between the glomerulus and Bowman's capsule could be observed. Changes in the glomerular epithelial cells consisted of the swelling with bleb formation. 3. In the FSGS rats, urine volume and urinary protein were significantly (P<0.05 and P<0.005) increased throughout 4-week experimental period, while the creatinine clearance was significantly (P<0.005) and transiently decreased, and recovered 4 weeks later. These changes were associated with the sustained elevation of the systolic blood pressure. 4. ADMA levels in aortic endothelial cells, plasma and urine were significantly (P<0.05 and P<0.005) increased in the FSGS rats, but the level in the kidney remained unchanged. 5. The basal level and net production of cyclic GMP in the aortic vessel wall with endothelium when stimulated by norepinephrine and acetylcholine were significantly (P<0.05 and P<0.01) attenuated in the FSGS rats. 6. There were significant and positive correlations between systolic blood pressure (y) and ADMA levels (x) in endothelial cells (y=4.43x+122.2, r=0.979, P<0.0001), plasma (y=0.10x+71.9, r=0.921, P<0.001) and urine (y=0.48x+126.9, r =0.699, P<0.005), but not significant in the kidney (y=0.06x+102.7, r=0.252, NS). 7. These findings suggest that ADMA as an endogenous inhibitor of NO synthesis may play an important role for the pathogenesis in the hypertension associated with the experimental FSGS in the rat.
Sato
J
J
Department of Medicinal Chemistry, Institute for Medical and Dental Engineering, Faculty of Medicine, Tokyo Medical and Dental University, Japan.
Masuda
H
H
Tamaoki
S
S
Hamasaki
H
H
Ishizaka
K
K
Matsubara
O
O
Azuma
H
H
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D006152:Cyclic GMP / Q000096:biosynthesis; D004727:Endothelium / Q000737:chemistry; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced*; D006973:Hypertension / Q000139:chemically induced*; D007668:Kidney / Q000737:chemistry; D008297:Male; D009609:Nitrous Oxide / Q000378:metabolism; D011692:Puromycin Aminonucleoside; D051381:Rats; D017207:Rats, Sprague-Dawley
D011692:Puromycin Aminonucleoside; C018524:N,N-dimethylarginine; D001120:Arginine; D006152:Cyclic GMP; D009609:Nitrous Oxide