Renal endothelial function and blood flow predict the individual susceptibility to adriamycin-induced renal damage.
BACKGROUND
Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in vitro and renal perfusion in vivo predict the severity of renal damage in a model of adriamycin-induced nephropathy.


METHODS
In three separate studies, the following baseline parameters were measured in healthy male Wistar rats: (1) acetylcholine (ACh)-induced relaxation in small renal arteries in vitro (n = 16) and the contribution of prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarizing factor (EDHF) to the relaxation; (2) glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in spontaneously voiding rats in vivo (n = 16) and (3) the acute effect of the NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME, n = 12) on renal blood flow (RBF) as compared to vehicle infusion (n = 9). Following these measurements, adriamycin (1.75 mg/kg i.v.) was injected and subsequent renal damage after 6 weeks was related to the baseline parameters.


RESULTS
Total ACh-induced (r = 0.51, P < 0.05) and EDHF-mediated relaxation (r = 0.68, P < 0.05), as well as ERPF (r = 0.66, P < 0.01), positively correlated with the severity of proteinuria 6 weeks after injection. In contrast, pronounced baseline NO-mediated dilation was associated with lower proteinuria (r = 0.71, P < 0.01). Nevertheless, an acute L-NAME infusion, strongly reducing RBF by 22 +/- 8%, during adriamycin administration provided protection against the development of proteinuria.


CONCLUSIONS
Individual animals with pronounced baseline endothelial dilatory ability measured in vitro and high ERPF in vivo are vulnerable to renal damage after the adriamycin injection. Acute inhibition of NO during adriamycin administration, resulting in a decrease of RBF, protects against renal injury, probably by limiting the delivery of the drug to the kidney. Therefore, interindividual variability in renal haemodynamics might be crucially involved in susceptibility to nephrotoxic renal damage.
Ochodnicky
Peter
P
Department of Clinical Pharmacology, University Medical Center Groningen (UMCG) and Graduate School for Drug Exploration (GUIDE), University of Groningen, The Netherlands. ochodnicky@fpharm.uniba.sk
Henning
Robert H
RH
Buikema
Hendrik
H
Kluppel
Alex C A
AC
van Wattum
Marjolein
M
de Zeeuw
Dick
D
van Dokkum
Richard P E
RP
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D004198:Disease Susceptibility; D004317:Doxorubicin / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects* / Q000293:injuries; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D019323:omega-N-Methylarginine / Q000494:pharmacology
D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D004317:Doxorubicin; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester