Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites. Am J Physiol Heart Circ Physiol 2016 Jun 01;310(11):H1695-701
Date
04/24/2016Pubmed ID
27106038Pubmed Central ID
PMC4935507DOI
10.1152/ajpheart.00023.2016Scopus ID
2-s2.0-84983739117 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
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.
Author List
Imig JD, Hye Khan MA, Sharma A, Fish BL, Mandel NS, Cohen EPMESH terms used to index this publication - Major topics in bold
AcetylcholineAnimals
Arterioles
Blood Pressure
Cyclooxygenase Inhibitors
Endothelium, Vascular
Indomethacin
Male
NG-Nitroarginine Methyl Ester
Nitric Oxide Synthase
Prostaglandin-Endoperoxide Synthases
Rats
Vasodilation
Whole-Body Irradiation
