Diminished
nitric oxide (NO) production has been implicated in the pathogenesis of
salt-sensitive
hypertension. We questioned whether such a defect is responsible for the
malignant hypertension and
nephrosclerosis in
stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-
salt/
stroke-prone diet (S) versus a regular diet (R). NO release from 30-minute incubates of cortex and outer and inner medulla were studied in SHRSP
at 10, 12, and 16 weeks of age on the S diet versus R diet. SHRSP-S (n=16) exhibited a marked age-dependent increase in NO release, especially in the cortex. Increases were only modest in SHRSP-R (n=21). At 16 weeks, cortical NO was 93+/-25 versus 6+/-1 pmol/mg tissue in SHRSP-S versus SHRSP-R (P<.001). Immunohistochemical staining increased mostly for neuronal, slightly for endothelial, and negligibly for inducible
isoforms of
NO synthase and was predominantly in the cortex of SHRSP-S versus SHRSP-R. Despite similar
hypertension in SHRSP-S versus SHRSP-R (mean arterial pressure, 174+/-7 versus 177+/-2 mm Hg), malignant
nephrosclerosis was seen only in SHRSP-S, affecting 22+/-6% of glomeruli and 23+/-4 vessels per 100 glomeruli by 16 weeks.
N omega-nitro-L-arginine (15 mg/kg per day) in SHRSP-S (n=6) abrogated the increase in cortical NO but further augmented the
hypertension and accelerated lesion development. Wistar-Kyoto rats at 16 weeks on the R diet (n=8) had NO levels similar to those of SHRSP-R, showed increased cortical NO to only 28+/-10 pmol/mg on the S diet (n=9) (P<.05 versus SHRSP-S), but remained normotensive and lesion-free. We conclude that
hypertension and lesion development in SHRSP are not due to deficient renal NO. Accelerated onset of malignant
nephrosclerosis by
NO synthase inhibition suggests that NO is protective in these animals, mitigating the effects of
hypertension and S diet on renal pathology.