Combining lisinopril and l-arginine slows disease progression and reduces endothelin-1 in passive Heymann nephritis.
BACKGROUND
Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease.


METHODS
Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control.


RESULTS
Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy.


CONCLUSIONS
Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.
Zoja
Carla
C
Mario Negri Institute for Pharmacological Research, Bergamo, Italy. zoja@marionegri.it
Benigni
Ariela
A
Camozzi
Davide
D
Corna
Daniela
D
Longaretti
Lorena
L
Todeschini
Marta
M
Remuzzi
Giuseppe
G
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D001794:Blood Pressure; D006152:Cyclic GMP / Q000652:urine; D018450:Disease Progression; D004338:Drug Combinations; D019332:Endothelin-1 / Q000097:blood* / Q000652:urine; D005921:Glomerulonephritis / Q000097:blood / Q000473:pathology* / Q000503:physiopathology* / Q000652:urine; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D017706:Lisinopril / Q000494:pharmacology*; D008297:Male; D011507:Proteinuria; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole
D000806:Angiotensin-Converting Enzyme Inhibitors; D004338:Drug Combinations; D019332:Endothelin-1; D001120:Arginine; D017706:Lisinopril; D006152:Cyclic GMP