Angiotensin II-Forming Pathways in Normal and Failing Human Hearts

• Published in: Circulation research Vol. 66; no. 4; pp. 883 - 890
• Main Authors: Urata, Hidenori, Healy, Bernadine, Stewart, Robert W, Bumpus, F Merlin, Husain, Ahsan
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.04.1990; Lippincott
• Subjects: Adolescent; Adult; Angiotensin I - blood; Angiotensin I - metabolism; Angiotensin II - blood; Angiotensin II - physiology; Antihypertensive agents; Biological and medical sciences; Captopril - pharmacology; Cardiac Output, Low - physiopathology; Cardiovascular system; Female; Glycine max - metabolism; Heart - physiology; Heart - physiopathology; Heart Ventricles; Humans; Male; Medical sciences; Middle Aged; Myocardium - enzymology; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Reference Values; Trypsin Inhibitors - pharmacology; Human; Heart failure; Enzymatic activity; Angiotensin I; Angiotensin converting enzyme; Enzyme inhibitor; Cardiovascular disease; Angiotensin II; In vitro; Biological activity; Isolated organ
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.66.4.883

Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang H on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring, the conversion of [I] angiotensin I (Ang I) to [I]Ang II. LV [I]Ang II-forming activity in normal hearts (35.5±2.7 fmol/min/mg, n=8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5±2.9 fmol/min/mg, n=9) and was 48% lower (p < 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5±+1.9 fmol/min/mg, n=15). In LV tissue from normal hearts and in hearts from patients with idiopathic and ischemic cardiomyopathy, the ACE inhibitor captopril (1 mM) inhibited total [I]Ang II-forming activity by 11±4%, 11±3%, and 4±3%, respectively (p < 0.05 for each group), illustrating that ACE is not the major Ang II-forming enzyme in the LV. In LV tissue from normal hearts and in hearts from patients with idiopathic and ischemic cardiomyopathy, the serine proteinase inhibitor (soybean trypsin inhibitor, 100 μg/ml) inhibited total [I]Ang II-forming activity by 80±3% in all three groups (p < 0.001 for each group), further illustrating that the majority of [I]Ang II-forming activity in the LV is due to one or more membrane-bound serine proteinases. In normal human serum (n=5), [I] Ang II formation was completely inhibited by 1 mM captopril and was not inhibited by 100 μg/ml soybean trypsin inhibitor. These in vitro studies suggest that chronic ACE inhibitor therapy may decrease angiotensinergic input to the vessels by inhibiting Ang II formation in blood. Since plasma Ang I levels are markedly elevated during chronic ACE inhibitor therapy and our studies show that the heartʼs major enzymatic pathway for Ang II formation is not blocked by ACE inhibitors, it seems likely that cardiac Ang II formation is not abolished during chronic therapy. The latter suggests sustained or even enhanced inotropic benefit of angiotensin in the heart in the face of circulating renin-angiotensin system blockade with ACE inhibitors.