title: Predisposition of spontaneously hypertensive rats to develop renal injury during nitric oxide synthase inhibition.
abstract: Chronic nitric oxide (NO) synthase (NOS) inhibition results in renal injury. Hypertension is an important risk factor for renal injury. We studied the influence of preexistent hypertension on the sensitivity for renal injury induced by chronic NOS inhibition in rats. Spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with 3, 10, 30 and 100 mg/l Nomega-nitro-L-arginine (L-NNA) until death. Systolic blood pressure and proteinuria were measured regularly and compared with time-control measurements in untreated SHR and WKY. In WKY, 3 and 10 mg/l L-NNA did not affect systolic blood pressure, while 30 and 100 mg/l L-NNA resulted in an increase in systolic blood pressure after 12 and 4 weeks, respectively. In contrast in SHR, every dose of L-NNA resulted in an increase in systolic blood pressure after 2 weeks. In WKY, 3 and 10 mg/l L-NNA did not affect proteinuria or survival, while 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30 and 9 weeks, and a median survival of 36 and 12 weeks, respectively. In SHR, 3, 10, 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30, 12, 3 and 3 weeks, and a median survival of 41, 20, 5 and 3 weeks, respectively. Thus, at every dose of the inhibitor, chronic NOS inhibition resulted in far earlier increases in systolic blood pressure and proteinuria and a marked increase in mortality in SHR as compared to WKY. Indeed, a very low dosage of L-NNA that caused no harm in WKY was followed by marked increases in proteinuria and blood pressure and decreased survival in SHR. Hypertension strongly increases the vulnerability to cardiovascular risk factors that compromise the NO-system.
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center (Room F03.226), P.O. Box 85500, 3508 GA, Utrecht, Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Verhagen
authors.forename: H A
authors.initials: HA
authors.lastname: Koomans
authors.forename: J A
authors.initials: JA
authors.lastname: Joles
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology*; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D016019:Survival Analysis; D013599:Systole; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D019001:Nitric Oxide Synthase