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.
|Keywords||Adolescent, Adult, Angiotensin I/metabolism, Angiotensin II/*metabolism/physiology, Angiotensin-Converting Enzyme Inhibitors/pharmacology, Captopril/pharmacology, Comparative Study, Coronary Vessels/drug effects/*enzymology/*metabolism, Extracellular Space/chemistry, Female, Humans, In Vitro, Isotonic Solutions, Male, Middle aged, Oligopeptides/pharmacology, Peptidyl-Dipeptidase A/*metabolism, Perfusion, Serine Endopeptidases/*metabolism, Serine Proteinase Inhibitors/pharmacology, Substrate Specificity/drug effects, Vasoconstriction/physiology|
Tom, B., Garrelds, I.M., Scalbert, E., Stegmann, A.P.A., Boomsma, F., Saxena, P.R., & Danser, A.H.J.. (2003). ACE-versus chymase-dependent angiotensin II generation in human coronary arteries: a matter of efficiency?. Arteriosclerosis, Thrombosis, and Vascular Biology. Retrieved from http://hdl.handle.net/1765/10104