Nebivolol does not protect against 5/6 ablation/infarction induced chronic kidney disease in rats - comparison with angiotensin II receptor blockade.
OBJECTIVE
Nitric oxide (NO) deficiency contributes to chronic kidney disease progression. Nebivolol, a beta adrenergic receptor antagonist, may enhance endogenous NO. Here, we investigated whether Nebivolol attenuates hypertension and renal injury after 5/6 ablation/infarction (A/I). Efficacy was compared to the AT1 receptor antagonist Olmesartan.


METHODS
Kidney disease and hypertension were induced by right kidney ablation and ~2/3 infarction of the left kidney. Rats were treated orally with vehicle (placebo), Nebivolol (5mg/kg b.i.d.), or Olmesartan (2.5mg/kg/day) for 6 weeks after A/I.


RESULTS
With placebo, glomerular sclerosis and tubulointersititial fibrosis developed with increased blood pressure and proteinuria, and a fall in NO(x) excretion. Olmesartan prevented these changes, but Nebivolol had no effect on these measures but lowered heart rate. Neither treatment reduced systemic oxidative stress (urinary hydrogen peroxide and TBARS). Compared to controls, renal cortex abundance of nNOSα decreased and nNOSβ increased in rats after 5/6 A/I, with no changes in eNOS. Neither treatment restored nNOSα; however, both reduced nNOSβ. Activity of DDAH was decreased by 5/6 A/I but restored by both treatments despite no increase in DDAH protein abundance. Kidney cortex abundance of manganese SOD fell after 5/6 A/I and was restored by treatment with Olmesartan but not Nebivolol. Extracellular and copper/zinc SOD abundances were not changed.


CONCLUSIONS
In conclusion, Nebivolol showed no benefit after 6 weeks in rapidly progressing, ANG II-dependent 5/6 A/I model of chronic kidney disease. This contrasts to the protection seen with 6 month treatment of Nebivolol in the slowly progressing 5/6 ablation model.
Departments of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA. jsasser@umc.edu
Jennifer M
JM
Sasser
Natasha C
NC
Moningka
Tatsiana
T
Tsarova
Chris
C
Baylis
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007238:Infarction / Q000150:complications* / Q000517:prevention & control*; D007672:Kidney Cortex / Q000187:drug effects* / Q000648:ultrastructure; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control; D008297:Male; D000068577:Nebivolol; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001578:Benzopyrans; D004983:Ethanolamines; D007093:Imidazoles; D013777:Tetrazoles; D000068577:Nebivolol; C437965:olmesartan