Short-term treatment with a beta-blocker with vasodilative capacities improves intrarenal endothelial function in experimental renal failure.
OBJECTIVE
In patients with renal disease the cardiovascular risk is greatly increased, and endothelial dysfunction is assumed to play a pivotal role in this process. Therefore we compared treatment effects of a beta-blocker with additional vasodilatory capacities (nebivolol) and a beta-blocker lacking these actions (metoprolol) on intrarenal and coronary vascular function in a rat model of renal failure with hypertension.


METHODS
Renal failure was induced by 5/6-nephrectomy (Nx) and analyzed after 4 weeks in Wistar rats. Untreated Nx, Nx/nebivolol 6 mg/d (Nx-Nebi); Nx/metoprolol 60 mg/d (Nx-Meto) and sham-operated (Sham) animals were studied. Isolated small renal and coronary arteries were investigated for endothelium-dependent relaxation to acetylcholine (ACh) and for the contribution of the endothelial mediators NO and endothelium-derived hyperpolarizing factor (EDHF).


RESULTS
Systolic blood pressure (SBP) was significantly increased in Nx, Nx-Nebi, and Nx-Meto (168+/-5, 153+/-3, and 162+/-6 mmHg) compared to Sham (138+/-3 mmHg, p<0.05, respectively). The increase in albuminuria of Nx (120-fold vs. Sham, p<0.0001) was almost (-85%) normalized by nebivolol compared to Sham (p<0.05), whereas metoprolol induced no significant effect. Renal arteries showed significantly increased Ach-relaxation in Nx and Nx-Nebi (Emax 86+/-4% and 76+/-7%, p<0.05) due to an increase in EDHF-mediated dilation (Emax_EDHF 78+/-7% and 73+/-6%) compared to Sham (Emax 54+/-4% and Emax_EDHF 44+/-6%) and Nx-Meto (Emax 42+/-12% and Emax_EDHF 18+/-5%). ACh-relaxation in coronary arteries was similar between groups but the contribution of NO (relative to EDHF) was strongly increased by nebivolol.


CONCLUSIONS
The present findings offer an explanation of the nephroprotective effect of intrarenal endothelial function in renal failure.
Gschwend
Simone
S
Institut für Klinische Pharmakologie und Toxikologie, Charité Centrum für Therapieforschung, Germany.
Haug
Marcel Bernhard
MB
Nierhaus
Marc
M
Schulz
Angela
A
Vetter
Roland
R
Kossmehl
Peter
P
Orzechowski
Hans-Dieter
HD
Scholze
Jürgen
J
Rothermund
Lars
L
Kreutz
Reinhold
R
D000109:Acetylcholine / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000503:physiopathology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000419:Albuminuria / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D001685:Biological Factors / Q000502:physiology; D003404:Creatinine / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D000068577:Nebivolol; D009392:Nephrectomy; D009569:Nitric Oxide / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D001685:Biological Factors; D004983:Ethanolamines; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D000068577:Nebivolol; D009599:Nitroprusside; D009569:Nitric Oxide; D003404:Creatinine; D000109:Acetylcholine