THE CHYMASE-ANGIOTENSIN SYSTEM IN HUMANS - BIOCHEMISTRY, MOLECULAR-BIOLOGY AND POTENTIAL ROLE IN CARDIOVASCULAR-DISEASES

Angiotensin I-converting enzyme (ACE) inhibitors are highly effective in the treatment of cardiovascular diseases. However, the relationship among the antihypertensive effects of ACE inhibitors, ACE inhibition and plasma angiotensin II levels is complex. During chronic therapy with ACE inhibition, plasma angiotensin II levels return to normal despite a continued antihypertensive effect. Recent studies show that a conversion of angiotensin I to angiotensin II in tissues can proceed despite complete ACE inhibition. In the search for a potential ACE inhibitor-resistant angiotensin II-forming enzyme activity tissue, chymase was identified as a major angiotensin II-forming enzyme. In primates, chymase-like angiotensin II-forming activity is localized in a number of tissues including the heart, blood vessels and lungs. Within the human heart, mast cells and endothelial cella are the sites of synthesis and storage of chymase, but a high level of the secreted chymase is also found in the cardiac interstitium, associated with the extracellular alpha and beta. alpha-chymases, such as human chymase, including several rat and mouse chymases, have a broad substrate specificity like chymotrypsin and do not form angiotensin II. In human and baboons only a single chm gene of the alpha-subtype can be identified. By using an angiotensin I analogue that is selectively converted to angiotensin II formation has recently been demonstrated in conscious baboons. Because of the deleterious growth effects of angiotensin II on the heart and blood vessels and the potential for incomplete suppression of tissue angiotensin II formation during ACE inhibitor therapy, it is hypothesized that the inhibition of chymase and ACE may be more efficacious in the treatment of cardiovascular diseases than ACE inhibitor therapy alone.