OPPOSING ACTIONS OF ANGIOTENSIN-(1-7) AND ANGIOTENSIN-II IN THE BRAINOF TRANSGENIC HYPERTENSIVE RATS

Lack of specific antagonists to the amino-terminal heptapeptide angiot ensin-(1-7) [Ang-(1-7)] prompted us to evaluate the central effects of delivering a specific affinity-purified Ang-(1-7) antibody on the blo od pressure and heart rate of 12-week-old conscious homozygous female rats (n=12) expressing the mouse submandibular Ren-2(d) gene [(mRen-2( d))27] in their genome. Another group of transgenic hypertensive and s train-matched Sprague-Dawley controls were injected with a specific An g II monoclonal antibody (KAA8). Cerebroventricular administration of the affinity-purified Ang-(1-7) antibody in conscious transgenic hyper tensive rats caused significant dose-related elevations in blood press ure associated with tachycardia. The hypertensive response was augment ed in transgenic rats studied 7 to 10 days after cessation of lisinopr il therapy. Neutralization of Ang II with the Ang II antibody caused a hemodynamic response opposite to that obtained with the Ang-(1-7) ant ibody. All doses of the Ang II antibody produced hypotension and brady cardia. The magnitude of the depressor response was significantly augm ented in transgenic rats weaned off lisinopril therapy. In contrast, c entral administration of either the Ang-(1-7) or Ang II antibodies had no effect on normotensive rats. Central injections of an affinity-pur ified IgG fraction were ineffective in bath control and transgene-posi tive rats. These data suggest that in the brain of transgenic hyperten sive rats, Ang-(1-7) opposes the action of Ang II on the central mecha nism or mechanisms that contribute to the maintenance of this model of hypertension. In addition, these studies showed an important contribu tion of the brain renin-angiotensin system to the maintenance of this form of monogenetic hypertension.