A Family That Grows From Within

Hydrolytic cleavage of large, inert proteins into smaller, active products is a common event in biology. The active products usually enjoy brief useful lifespans before they themselves are cleaved into inactive fragments. Prototypic participants in this process include clotting factors, complement, and digestive enzymes. Angiotensin II (Ang II) was the first polypeptide hormone recognized as the active intermediate in a proteolytic sequence starting with an inactive precursor and ending in "inactive" fragments. It is now considered a universal feature of polypeptide hormones that they arise from larger precursors ("prepro-hormones") and are destroyed by further proteolysis. Insulin, parathyroid hormone, and atrial natriuretic factor are good examples. Until the recent work of the group led by Carlos Ferrario at the Qeveland Clinic, one chapter of which is reported in this issue of Hypertension,* it was conventional wisdom to regard the C-terminal amino acid residue of Ang II as crucial for biological activity. Phenylalanine in position 8 was found in traditional agonists, whereas aliphatic substitutions in that position yielded partial agonists or competitive antagonists. The fact that manipulation of the C-terminal residue could lead to formation of competitive antagonists was taken by many as proof of the crucial nature of that position. Cleavage at the C-terminus was assumed to be one step that created inactive fragments. It has come as a surprise to most of us who work with angiotensins that complete removal of the C-terminal residue leaves a polypeptide that still exerts powerful effects in the brain. As shown by Ferrario and his coworkers, angiotensin-(l-7) (Ang-[l-7]), also called des-Phe-Ang II, stimulates vasopressin release and modulates baroreceptor reflex sensitivity with a potency equal to that of Ang II. Therefore, it is incorrect to regard the C-terminal eighth residue of angiotensin as crucial, and it is simplistic to consider Ang-(l-7) as an inactive fragment. Although Ang II remains by far the most powerful vasoconstrictor known to be produced by renin action, cleavage of Ang II at either end yields fragments