Affiliation:
1. From the Department of Clinical Pharmacology, University of Groningen (Netherlands).
Abstract
Abstract
—The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1–7) to angiotensin-(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 vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1–5) is unknown. We investigated whether angiotensin-(1–7) and angiotensin-(1–5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1–7) up to 100%, with an IC
50
of 3.0 and 4.0 μmol/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 noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro
10
]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. 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 vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1–5) only inhibits ACE. These results show that angiotensin-(1–7) may be an important modulator of the human renin-angiotensin system.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Cited by
157 articles.
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