BRAIN OUABAIN AND ANGIOTENSIN-II IN SALT-SENSITIVE HYPERTENSION IN SPONTANEOUSLY HYPERTENSIVE RATS

Spontaneously hypertensive rats (SHR) received from 5 to 9 weeks of ag e a high or regular sodium diet and concomitant intracerebroventricula r infusions via minipumps of the following compounds: antibody Fab fra gments (200 mu g/d), which bind ouabain and related steroids with high affinity; the angiotensin II (Ang II) type 1 receptor blocker losarta n (1 mg/kg per day); a combination of Fab fragments and losartan; and as control, gamma-globulins (200 mu g/d). The same doses of Fab fragme nts and losartan were also given intravenously. At 9 weeks of age, com pared with SHR on regular sodium, SHR on high sodium that were treated with gamma-globulins had higher resting blood pressure and showed sig nificantly enhanced excitatory responses of blood pressure, renal symp athetic nerve activity, and heart rate to air stress and inhibitory re sponses to the central alpha 2-agonist guanabenz. Central Fab fragment s and losartan alone combined prevented all these effects of high sodi um. Intravenous Fab fragments or losartan was ineffective. Compared wi th control SHR on high sodium, SHR on high sodium that were treated wi th Fab fragments had significantly increased sympathoexcitatory and pr esser responses to central Ang IT injection, consistent with a decreas e in brain Ang II receptor occupancy. These data indicate that both in creased brain ''ouabain'' and Ang II contribute to salt-sensitive hype rtension in SHR. Brain Ang II receptor stimulation appears to be downs tream of ''ouabain'' in the pathways mediating sympathoexcitatory and presser effects of high sodium.