Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites.
Chronic kidney disease is a known complication of hematopoietic stem cell transplant (HSCT) and can be caused by irradiation at the time of the HSCT. In our rat model there is a 6- to 8-wk latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension. The current study tested the hypothesis that decreased endothelial-derived factors contribute to impaired afferent arteriolar function in rats exposed to total body irradiation (TBI). WAG/RijCmcr rats underwent 11 Gy TBI, and afferent arteriolar responses to acetylcholine were determined at 1, 3, and 6 wk. Blood pressure and blood urea nitrogen were not different between control and irradiated rats. Afferent arteriolar diameters were not altered in irradiated rats. Impaired endothelial-dependent responses to acetylcholine were evident at 3 and 6 wk following TBI. Nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) contribution to acetylcholine dilator responses were evaluated. NOS inhibition with N(G)-nitro-l-arginine methyl ester (l-NAME) reduced acetylcholine responses by 50% in controls and 90% in 3-wk TBI rats. COX inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of l-NAME. EPOX inhibition with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide significantly decreased acetylcholine responses (35%) in controls but did not significantly alter acetylcholine responses (4%) in TBI rats. Biochemical analysis revealed decreased urinary EPOX metabolites but no change in COX, NOS, or reactive oxygen species at 3 wk TBI. Taken together, these results indicate that afferent arteriolar endothelial dysfunction involves a decrease in EPOX metabolites that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; jdimig@mcw.edu.
John D
JD
Imig
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Md Abdul
MA
Hye Khan
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Amit
A
Sharma
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin;
Brian L
BL
Fish
Clement J. Zablocki Veterans Affairs Medical Center and Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
Neil S
NS
Mandel
Baltimore Veterans Affairs Medical Center and University of Maryland School of Medicine, Baltimore, Maryland.
Eric P
EP
Cohen
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D001794:Blood Pressure / Q000187:drug effects / Q000528:radiation effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D014664:Vasodilation / Q000187:drug effects / Q000528:radiation effects*; D014916:Whole-Body Irradiation
D016861:Cyclooxygenase Inhibitors; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
endothelium; epoxyeicosatrienoic acids; kidney; nitric oxide