alpha2-Adrenergic agonists protect against radiocontrast-induced nephropathy in mice.
Radiocontrast nephropathy (RCN) is a common clinical problem for which there is no effective therapy. Utilizing a murine model, we tested the hypothesis that alpha(2)-adrenergic receptor agonists (clonidine and dexmedetomidine) protect against RCN induced with iohexol (a nonionic low-osmolar radiocontrast). C57BL/6 mice were pretreated with saline, clonidine, or dexmedetomidine before induction of RCN. Some mice were pretreated with yohimbine (a selective alpha(2)-receptor antagonist) before saline, clonidine, or dexmedetomidine administration. alpha(2)-Agonist-treated mice had reduced plasma creatinine, renal tubular necrosis, renal apoptosis, and renal cortical proximal tubule vacuolization 24 h after iohexol injection. Yohimbine reversed the protective effects of clonidine and dexmedetomidine pretreatment. Injection of iohexol resulted in a rapid ( approximately 90 min) fall of renal outer medullary blood flow. Clonidine and dexmedetomidine pretreatment significantly attenuated this perfusion decrease without changing systemic blood pressure. To determine whether proximal tubular alpha(2)-adrenergic receptors mediate the cytoprotective effects, we treated cultured human proximal tubule (HK-2) cells and rat pulmonary microvascular endothelial cells with iohexol after vehicle, clonidine, or dexmedetomidine pretreatment. Iohexol caused a direct dose-dependent reduction of HK-2 and rat pulmonary microvascular endothelial cell viability, but alpha(2)-agonists failed to preserve the viability of both cell types. We conclude that alpha(2)-adrenergic receptor agonists protect mice against RCN by preserving outer medullary renal blood flow. As alpha(2)-agonists are widely utilized during the perioperative period, our findings may have significant clinical relevance to improving outcomes following radiocontrast exposure.
Billings
F T
FT
Department of Anesthesiology, Anesthesiology Research Laboratories, Columbia University, 630 West 168th St., New York, NY 10032-3784, USA.
Chen
Sean W C
SW
Kim
Mihwa
M
Park
Sang Won
SW
Song
Joseph H
JH
Wang
Shuang
S
Herman
Joseph
J
D'Agati
Vivette
V
Lee
H Thomas
HT
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002460:Cell Line; D003000:Clonidine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D003287:Contrast Media / Q000506:poisoning*; D020927:Dexmedetomidine / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use; D007472:Iohexol / Q000506:poisoning*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control; D007679:Kidney Medulla / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012079:Renal Circulation / Q000187:drug effects*
D000316:Adrenergic alpha-Agonists; D003287:Contrast Media; D007472:Iohexol; D020927:Dexmedetomidine; D003000:Clonidine