Resistance to renal damage by chronic nitric oxide synthase inhibition in the Wistar-Furth rat.
Chronic nitric oxide synthase inhibition (NOSI) causes chronic kidney disease (CKD) in the Sprague Dawley (SD) rat. We previously showed that the Wistar-Furth (WF) rats are resistant to several models of CKD and maintain renal nitric oxide (NO) production compared with SD rats, whereas low-dose NOSI caused progression of CKD in WF rats. Here, we evaluate the impact of high-dose chronic NOSI in WF and SD rats, as well as intrarenal responses to an acute pressor dose of NOSI in the normal WF. Rats were given N(G)-nitro-l-arginine methyl ester (l-NAME) (150 and 300 mg/l for 6-10 wk) in the drinking water after an initial bolus tail vein injection. Both strains showed significant reductions in total NO production with chronic l-NAME. SD given 150 mg/l l-NAME for 6 wk developed proteinuria and renal injury, whereas WF rats receiving 150 mg/l l-NAME for 6-10 wk or 300 mg/l for 6 wk developed no proteinuria and minimal renal injury. Blood pressure was significantly elevated with chronic NOSI in both strains but was higher in the SD rat. There was little impact on renal nitric oxide synthase expression with l-NAME, except that cortical endothelial nitric oxide synthase abundance increased in WF after 6 wk (150 mg/l). Micropuncture experiments with acute pressor NOSI resulted in similar increases in systemic blood pressure in SD and WF rats, whereas WF rats showed a much smaller increment in glomerular blood pressure compared with SD rats. In conclusion, WF rats do not develop renal injury after chronic NOSI at, or above, a dose that causes significant injury in the SD rat. This protection may be associated with protection from glomerular hypertension.
Erdely
Aaron
A
Department of Physiology and Functional Genomics, 1600 SW Archer Rd., P. O. Box 100274, University of Florida, Gainesville, FL 32610-0274, USA.
Freshour
Gary
G
Baylis
Chris
C
D000818:Animals; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000201:enzymology* / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009585:Nitrogen Dioxide / Q000652:urine; D011691:Puromycin / Q000633:toxicity; D051381:Rats; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019323:omega-N-Methylarginine; D011691:Puromycin; D019001:Nitric Oxide Synthase; D009585:Nitrogen Dioxide; D019331:NG-Nitroarginine Methyl Ester