Angiotensin-(1-7) is a modulator of the human renin-angiotensin system

The renin-angiotensin system is important for cardiovascular homeostasis. C urrently, therapies for different cardiovascular diseases are based on inhi bition of angiotensin-converting enzyme (ACE) or angiotensin II receptor bl ockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiote nsin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances v asodilation and inhibits vascular contractions to angiotensin II. The funct ion of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1 -7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vas oconstrictions in humans. ACE activity in plasma and atrial tissue was inhi bited by angiotensin-(1-7) up to 100%, with an IC50 of 3.0 and 3.0 mu mol/L , respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro(11),D-Ala(12) ]-angiotensin I were antagonized by angiotensin-(1-7) (10(-5) mol/L) in a n oncompetitive way, with a 60% inhibition of the maximal response to angiote nsin II. Contractions to ACE-specific substrate [Pro(10)]-angiotensin I wer e also inhibited, an effect only partly accounted for by antagonism of angi otensin TI, Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstric tion and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) on ly inhibits ACE. These results show that angiotensin-(1-7) may be an import ant modulator of the human renin-angiotensin system.