Published online before print February 9, 2004, doi: 10.1161/01.HYP.0000119190.06968.f1
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(Hypertension. 2004;43:854.)
© 2004 American Heart Association, Inc.
Scientific Contributions |
Effect of Reduced Angiotensin-Converting Enzyme Gene Expression and Angiotensin-Converting Enzyme Inhibition on Angiotensin and Bradykinin Peptide Levels in Mice
From St. Vincent’s Institute of Medical Research and Department of Medicine (D.J.C.), University of Melbourne, Fitzroy; Howard Florey Institute of Experimental Physiology and Medicine (T.A., M.J.M.), University of Melbourne, Parkville, Victoria, Australia; Department of Pathology (H.D.X, S.F., K.E.B), Emory University, Atlanta, Ga; and Institut National de la Santé et de la Recherche Medicale Unit 36 (P.C.), College de France, Paris, France.
Correspondence to Dr D.J. Campbell, St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail J.Campbell{at}medicine.unimelb.edu.au
There is uncertainty about the contribution of angiotensin-converting enzyme (ACE) to angiotensin II formation, with recent studies suggesting that non-ACE enzymes may be the predominant pathway of angiotensin II formation in kidney, heart, and lung. To investigate the role of ACE in angiotensin II formation, we measured angiotensin I and II levels in blood, kidney, and heart of 2 mouse genetic models (ACE.1 and ACE.4) of reduced somatic ACE gene expression and in blood, kidney, heart, lung, adrenal, and brain of mice administered the ACE inhibitor lisinopril. We also measured the levels of bradykinin (1-9) and its ACE metabolite bradykinin (1-7). Reduced ACE gene expression and ACE inhibition had similar effects on angiotensin and bradykinin peptide levels. Angiotensin II levels were reduced by 70% to 97% in blood, 92% to 99% in kidney, 93% to 99% in heart, 97% in lung, and 85% in adrenal and brain. The marked reductions in angiotensin II/angiotensin I ratio indicated that ACE was responsible for at least 90% of angiotensin I conversion to angiotensin II in blood, kidney, heart, lung, and brain, and at least 77% in adrenal. Blood bradykinin (1-9) levels were increased 6.4-fold to 8.4-fold. Heart bradykinin (1-9) levels were increased in ACE.4 mice and the bradykinin (1-7)/bradykinin (1-9) ratio was reduced in kidney and heart of ACE.4 mice and heart of lisinopril-treated mice. These studies demonstrate that ACE is the predominant pathway of angiotensin II formation in blood and tissues of mice and plays a major role in bradykinin (1-9) metabolism in blood and, to a lesser extent, in kidney and heart.
Key Words: mice • angiotensin-converting enzyme • angiotensin I • angiotensin II • bradykinin
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