1 research outputs found
ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?
OBJECTIVE: The objective of this study was to investigate ACE- and
chymase-dependent angiotensin I-to-II conversion in human coronary
arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ
baths, and concentration-response curves to angiotensin II, angiotensin I,
and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I
(PA-angiotensin I) were constructed. All angiotensins displayed similar
efficacy. For a given vasoconstriction, bath (but not interstitial)
angiotensin II during angiotensin I and PA-angiotensin I was lower than
during angiotensin II, indicating that interstitial (and not bath)
angiotensin II determines vasoconstriction. PA-angiotensin I increased
interstitial angiotensin II less efficiently than angiotensin I. Separate
inhibition of ACE (with captopril) and chymase (with C41 or chymostatin)
shifted the angiotensin I concentration-response curve approximately
5-fold to the right, whereas a 10-fold shift occurred during combined ACE
and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced
bath angiotensin II and abolished PA-Ang I-induced vasoconstriction.
Perfused HCA segments, exposed luminally or adventitially to angiotensin
I, released angiotensin II into the luminal and adventitial fluid,
respectively, and this release was blocked by chymostatin. CONCLUSIONS:
Both ACE and chymase contribute to the generation of functionally active
angiotensin II in HCAs. However, because angiotensin II loss in the organ
bath is chymase-dependent, ACE-mediated conversion occurs more efficiently
(ie, closer to AT(1) receptors) than chymase-mediated conversion