Vasoconstrictor effect of the angiotensin-converting enzyme-resistant, chymase-specific substrate [Pro(D)(11)-Ala(12)] angiotensin I in human dorsal hand veins - In vivo demonstration of non-ACE production of angiotensin II in humans

Background-[Pro(D)(11)-Ala(12)] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a function ally 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 respo nse to Ang I and [Pro(D)(11)Ala(12)] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effec t of each peptide given before and after a 6.25-mg oral dose of the ACE inh ibitor captopril or matching placebo. Placebo or captopril was given in a d ouble-blind, randomized fashion. Ang I induced a mean SEM venoconstrictor r esponse of 45 +/- 11%, 40 +/- 10%, 55 +/-8%, and 4 +/-4% before placebo, af ter placebo, before captopril, and after captopril, respectively. Hence, th e response to Ang I was reproducible and was reduced significantly only aft er treatment with captopril (P=0.002). [Pro(D)(11)-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 t o [Pro(D)(11)-Ala(12)] Ang I. Conclusions-We have demonstrated that [Pro(D)(11)-Ala(12)] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacologi cal probe, we have shown that a non-ACE pathway capable of generating Ang I I exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.