Vasoconstriction by in situ formed angiotensin II: role of ACE and chymase.
OBJECTIVE
To assess the importance, for vasoconstriction, of in situ angiotensin (Ang) II generation, as opposed to ang II delivery to AT receptors via the organ bath fluid.


METHODS
Ang I and II concentration-response curves in human and porcine coronary arteries (HCAs, PCAs) were constructed in relation to estimates of the clearances of Ang I and II (ClAngI, ClAngII) from the organ bath and the release of newly formed Ang II (RAngII) into the bath fluid. HCAs were from 25 heart valve donors (age 5-54 years), and PCAs from 14 pigs (age 3 months).


RESULTS
Ang I- and II-evoked constrictions were inhibited by the AT1 receptor antagonist, irbesartan, and were not influenced by the AT2 receptor antagonist, PD123319. In HCAs Ang II was only three times more potent than Ang I, wheres, in the experiments with Ang I, comparison of ClAngI with ClAngII and RAngII indicated that most of the arterially produced Ang II did not reach the bath fluid. Also in PCAs Ang I and II showed similar potency. In HCAs both the ACE inhibitor, captopril, and the chymase inhibitor, chymostatin, inhibited Ang I-evoked vasoconstriction, while only chymostatin had a significant effect on ClAngI. In PCAs Ang I-evoked vasoconstriction was almost completely ACE-dependent.


CONCLUSIONS
This study points towards the functional importance of in situ ACE- and chymase-dependent Ang II generation, as opposed to Ang II delivery via the circulation. It also indicates that functionally relevant changes in local Ang I-II conversion are not necessarily reflected by detectable changes in circulating Ang II.
MaassenVanDenBrink
A
A
Department of Pharmacology, Erasmus University, Rotterdam, The Netherlands.
de Vries
R
R
Saxena
P R
PR
Schalekamp
M A
MA
Danser
A H
AH
D000293:Adolescent; D000328:Adult; D000803:Angiotensin I / Q000032:analysis; D000804:Angiotensin II / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D053818:Chymases; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D000077405:Irbesartan; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009842:Oligopeptides; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D000803:Angiotensin I; C002101:chymostatin; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; D000077405:Irbesartan