A nitric oxide-generating beta-blocking agent prevents renal injury in the rat remnant kidney model. Comparative study of two beta-blocking drugs, nipradilol and propranolol.
BACKGROUND
The L-arginine-nitric oxide (NO) pathway plays an important role in the modulation of glomerular disease. We investigated whether beta-blocking agents, with and without an NO-generating function, had renoprotective effects in the 5/6 nephrectomized rats (Nx), an animal model of glomerulosclerosis.


METHODS
Nipradilol, a beta-blocker with an ONO(2) group (5, 10 or 15 mg/kg/day) and propranolol, a beta-blocker without this group (50 mg/kg/day) were administered for 12 weeks to Nx together with and without nitro-L-arginine methyl ester (L-NAME). We evaluated the effects of both drugs on proteinuria, hypertension, renal function, glomerulosclerosis and urinary excretion of NO metabolites (U(NOx)) and cyclic GMP (U(cGMP)).


RESULTS
Both drugs similarly attenuated the elevated blood pressure in Nx. However, nipradilol, at doses of 10 and 15 mg/kg/day, significantly decreased proteinuria and glomerulosclerosis, while propranolol did not. Nx showed reduced U(NOx) in comparison with the sham-operated rats. Nipradilol increased U(NOx) and U(cGMP) significantly and in a dose- dependent manner, whereas propranolol reduced them to levels lower than those in Nx. Nx receiving L-NAME reduced U(NOx). The addition of nipradilol increased U(NOx) and decreased urinary protein excretion and glomerulosclerosis, suggesting that the NO released from the drug contributed to its renoprotective effect.


CONCLUSIONS
These findings indicate that nipradilol exerts its renoprotective effect through NO generation, and not by lowering blood pressure. The beta-adrenergic blocking action per se does not seem to be related to the renoprotective effect of these agents.
Takamitsu
Yoshihiro
Y
Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. y-tkmt@hyo-med.ac.jp
Nakanishi
Takeshi
T
Nishihara
Futoshi
F
Hasuike
Yukiko
Y
Izumi
Masaaki
M
Inoue
Toru
T
Hiraoka
Keisuke
K
Itahana
Reiko
R
Miyagawa
Koji
K
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D006152:Cyclic GMP / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000517:prevention & control; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control* / Q000652:urine; D007678:Kidney Glomerulus / Q000473:pathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009392:Nephrectomy; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000652:urine; D011412:Propanolamines / Q000627:therapeutic use*; D011433:Propranolol / Q000627:therapeutic use*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011916:Rats, Inbred F344; D012083:Renin / Q000097:blood
D000319:Adrenergic beta-Antagonists; D004791:Enzyme Inhibitors; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D011412:Propanolamines; D009569:Nitric Oxide; D011433:Propranolol; D019001:Nitric Oxide Synthase; D012083:Renin; C036089:nipradilol; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester