Effect of nebivolol, a novel beta(1)-selective adrenoceptor antagonist with vasodilating properties, on kidney function

Nebivolol (CAS 99200-09-6) is a novel beta (1)-selective adrenoceptor antag onist which possesses vasodilating properties and lowers systemic vascular resistance in dogs and humans, presumably by a nitric oxide-related mechani sm. In the present study, clearance techniques were applied to anaesthetize d male Sprague Dawley rats, and the effects of nebivolol on renal hemodynam ics (glomerular filtration rate and renal plasma flow), on urinary excretio n of sodium, chloride and potassium, on renal NO-excretion, and on plasma r enin activity were studied. Nebivolol doses ranging from 0.1 to 2 mg/kg i.v . were tested. The results revealed that nebivolol dose-dependently increas ed glomerular filtration rate, urine flow and urinary excretion of sodium a nd chloride. Potassium excretion was only inconsistently increased and show ed no dose dependency. At a dose of 1 mg/kg, the drug also significantly in creased renal plasma flow measured as H-3-PAH (p-aminohippurate) clearance. The effect of nebivolol on the glomerular filtration rate could be abolish ed by L-NMMA (N-6-monomethyl-L-arginine) (1 mg/kg), a non-selective inhibit or of NO-synthase and by iminoethyllysine (1 mg/kg), a relatively selective inhibitor of the inducible NO-synthase, but not by 7-nitroindazole (1 mg/k g), a relatively selective inhibitor of the neuronal NO-synthase isoform. T he saluretic effect of nebivolol was diminished by all of the three NO-synt hase inhibitors, but could not be completely reversed. At a dose of 2 mg/kg , nebivolol increased renal NO-excretion by 70.7 %. This effect could be co mpletely abolished by L-NMMA (1 mg/kg). Plasma renin activity was lowered b y nebivolol (2 mg/kg) from 14.6 +/- 1.49 to 6.5 +/- 1.66 ng angiotensin I/m l/h (p < 0.01). The results demonstrate that, in anaesthetized rats, nebivo lol exerts significant renal vasodilating effects and increases urinary exc retion of fluid and solutes. The actions of nebivolol on renal hemodynamics are assumed to be mediated by a stimulation of the NO-synthase, probably t he inducible isoform. Since none of the NO-synthase inhibitors could comple tely abolish the saluretic effect of nebivolol, an additional mechanism, no t related to NO, may be involved in the tubular action of this drug.