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


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.
McDonald
J E
JE
CRI in Heart Failure, Department of Medicine and Therapeutics, University of Glasgow, Scotland, UK.
Padmanabhan
N
N
Petrie
M C
MC
Hillier
C
C
Connell
J M
JM
McMurray
J J
JJ
D000284:Administration, Oral; D000787:Angina Pectoris / Q000188:drug therapy / Q000503:physiopathology*; D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000096:biosynthesis; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001713:Biphenyl Compounds / Q000008:administration & dosage; D002216:Captopril / Q000008:administration & dosage; D002908:Chronic Disease; D053818:Chymases; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006225:Hand / Q000098:blood supply; D006801:Humans; D007262:Infusions, Intravenous; D000077405:Irbesartan; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D015203:Reproducibility of Results; D012697:Serine Endopeptidases / Q000378:metabolism; D013379:Substrate Specificity; D013777:Tetrazoles / Q000008:administration & dosage; D014661:Vasoconstriction / Q000187:drug effects*; D014680:Veins / Q000187:drug effects* / Q000503:physiopathology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D013777:Tetrazoles; C087635:angiotensin I, Pro(11)-Ala(12)-; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; D000077405:Irbesartan