Brain “Ouabain” and Angiotensin II in Salt-Sensitive Hypertension in Spontaneously Hypertensive Rats

Abstract

Spontaneously hypertensive rats (SHR) received from 5 to 9 weeks of age a high or regular sodium diet and concomitant intracerebroventricular infusions via minipumps of the following compounds: antibody Fab fragments (200 μg/d), which bind ouabain and related steroids with high affinity; the angiotensin II (Ang II) type 1 receptor blocker losartan (1 mg/kg per day); a combination of Fab fragments and losartan; and as control, γ-globulins (200 μg/d). The same doses of Fab fragments and losartan were also given intravenously. At 9 weeks of age, compared with SHR on regular sodium, SHR on high sodium that were treated with γ-globulins had higher resting blood pressure and showed significantly enhanced excitatory responses of blood pressure, renal sympathetic nerve activity, and heart rate to air stress and inhibitory responses to the central α 2 -agonist guanabenz. Central Fab fragments and losartan alone or combined prevented all these effects of high sodium. Intravenous Fab fragments or losartan was ineffective. Compared with control SHR on high sodium, SHR on high sodium that were treated with Fab fragments had significantly increased sympathoexcitatory and pressor responses to central Ang II injection, consistent with a decrease in brain Ang II receptor occupancy. These data indicate that both increased brain “ouabain” and Ang II contribute to salt-sensitive hypertension in SHR. Brain Ang II receptor stimulation appears to be downstream of “ouabain” in the pathways mediating sympathoexcitatory and pressor effects of high sodium.