Pharmacologic Interruption of the Renin-Angiotensin System

In 1 959, at a symposium on polypeptides that affect smooth muscle and blood vessels, Elliott recounted how, following elucidation of structure of decapeptide, angiotensin I, he set out to synthesize agent and found that synthetic product had only about I % of activity of angiotensin II on rat blood pressure despite close chemical resemblance ( l). Elliott's key point in his talk was that carboxy terminal amino acid, phenylalanine, contained almost equal mixtures of 0and L-forms. Given freedom of a symposium setting, he went on to make daring and perceptive speculation that the peptide containing o-phenylalanine was acting as a powerful inhibitor of hypertensin in vivo. He pointed out that proof required unequivocal synthesis of a peptide containing pure o-phenylalanine, and expressed hope that this would soon be achieved. Unfortunately, that synthesis was never reported and importance of carboxy terminal amino acid for development of angiotensin antagonists was apparently forgotten for over a decade. Given potential importance of pharmacologic interruption of renin-angiotensin system in dissecting angiotensin'S role in physiology and pathophysiology, failure of discussion that followed presentations on angiotensin to respond to Elliott's novel suggestion was surprising, and perhaps discouraging. In 1 970 two groups, Khairallah, Bumpus, and their colleagues at Cleve­ land Clinic Foundation and Marshall, Vine & Needleman in 8t. Louis