ANGIOTENSIN-(1-7) CONTRIBUTES TO THE ANTIHYPERTENSIVE EFFECTS OF BLOCKADE OF THE RENIN-ANGIOTENSIN SYSTEM

Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT(1)) antagonist losartan augm ents circulating levels of the bioactive peptide: angiotensin-(1-7) [A ng-(1-7)]. Hence, we determined whether Ang-(1-7) contributes to the h ypotensive effects produced by the combined administration of lisinopr il and losartan in spontaneously hypertensive rats by blocking the pep tide's synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisi nopril and losartan elicited an elevation of mean arterial pressure th at was sustained throughout the infusion period and for 20 minutes the reafter, The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1-7) and no change in plasma angiotensi n II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar,(1)Thr(8)]-Ang II abolished any addition al presser effects of either neprilysin inhibitor in spontaneously hyp ertensive rats treated with lisinopril or losartan. However, neither t he endothelin A antagonist BQ123 nor the kinin B2, antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inh ibition of Ang-(1-7) formation in rats exposed to the combined blockad e of Ang II production and activity is associated with a reversal of t he antihypertensive actions produced by these therapies. Thus, endogen ous Ang-(1-7) functions as a vasodilator hormone in this form of genet ic hypertension.