Vasoconstrictor Effect of the Angiotensin-Converting Enzyme–Resistant, Chymase-Specific Substrate [ProD-Ala] Angiotensin I in Human Dorsal Hand Veins In Vivo Demonstration of Non-ACE Production of Angiotensin II in Humans

Background—[ProD-Ala ] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II–generating pathway exists in human dorsal hand veins. Methods and Results—Using a modified Aellig technique, we studied the response to Ang I and [ProD-Ala ] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean6SEM venoconstrictor response of 45611%, 40610%, 5568%, and 464% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P50.002). [ProD-Ala ] Ang I induced a mean venoconstrictor response of 4269%, 4969%, 48610%, and 54611% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [ProD-Ala ] Ang I. Conclusions—We have demonstrated that [ProD-Ala ] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase. (Circulation. 2001;104:1805-1808.)