Nebivolol (N) Prevents Chronic Nitric Oxide Synthase Inhibition (CNOSI) Induced Chronic Kidney Disease (CKD) and Hypertension

Nitric oxide (NO) deficiency contributes to CKD progression and hypertension. The β‐blocker, N, also enhances NO production and we studied whether N attenuates CKD and hypertension caused by CNOSI (L‐NAME, 150 mg/L drinking water). Rats on 6 wks of CNOSI received placebo (P), N (10 mg/kg/d) or Olmesartan (O, 2.5 mg/kg/d). BP, protein and NOx were monitored throughout and at sacrifice kidney cortex (KC) was harvested for renal pathology, markers of oxidative stress and NOS. BP increased > 50mmHg in P by weeks 4–6, whereas no change in BP occurred in N or O. P rats developed proteinuria and glomerular sclerosis (GS) while Ccr was ~30% of normal. In both N and O all values remained normal. In KC of P, p22phox was higher and extracellular superoxide dismutase (ECSOD) was lower compared to normal kidneys. N and O normalized p22phox and ECSOD and elevated the abundance of Mn SOD. N and O prevented CNOSI–induced hypertension, proteinuria, and GS. N (but not O) prevented a fall in total NO production as well as an increase in nNOSβ seen in P. Also, both O and N enhanced antioxidants and reduced the abundance of NADPH oxidase subunit, creating an anti‐oxidant state. We suggest that the major benefit derived from both N and O is reduction in KC oxidative stress, which allows renal NO production to be maintained. We view increased nNOSβ in P as part of the pathology, since in the presence of oxidants, the nNOS will “switch” to become a superoxide generator.