Vasoconstrictor Effect of the Angiotensin-Converting Enzyme–Resistant, Chymase-Specific Substrate [Pro 11 D -Ala 12 ] Angiotensin I in Human Dorsal Hand Veins

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Abstract
Background [Pro 11 D -Ala 12 ] 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 [Pro 11 D -Ala 12 ] 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 mean±SEM venoconstrictor response of 45±11%, 40±10%, 55±8%, and 4±4% 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 ( P =0.002). [Pro 11 D -Ala 12 ] Ang I induced a mean venoconstrictor response of 42±9%, 49±9%, 48±10%, and 54±11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro 11 D -Ala 12 ] Ang I. Conclusions We have demonstrated that [Pro 11 D -Ala 12 ] 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.

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