REGIONAL RENAL NITRIC-OXIDE RELEASE IN STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS

Diminished nitric oxide (NO) production has been implicated in the pat hogenesis of salt-sensitive hypertension. We questioned whether such a defect is responsible for the malignant hypertension and nephrosclero sis 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 studie d 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 releas e, 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 incre ased mostly for neuronal, slightly for endothelial, and negligibly for inducible isoforms of NO syn --thase and was predominantly in the cor tex 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-ome ga-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 acc elerated lesion development. Wistar-Kyoto rats at 16 weeks on the R di et (n=8) had NO levels similar to those of SHRSP-R, showed increased c ortical NO to only 28+/-10 pmol/mg on the S diet (n=9) (P<.05 versus S HRSP-S), but remained normotensive and lesion-free. We conclude that h ypertension and lesion development in SHRSP are not due to deficient r enal NO. Accelerated onset of malignant nephrosclerosis by NO synthase inhibition suggests that NO is protective in these animals, mitigatin g the effects of hypertension and S diet on renal pathology.