Chapter 26

### INTRODUCTION

The renin–angiotensin system (RAS) participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy. This realization has led to a thorough exploration of the RAS and the development of new approaches for inhibiting its actions. This chapter discusses the biochemistry, molecular and cellular biology, and physiology of the RAS; the pharmacology of drugs that interrupt the RAS; and the clinical utility of inhibitors of the RAS. Therapeutic applications of drugs covered in this chapter are also discussed in Chapters 27 and 28.

### THE RENIN–ANGIOTENSIN SYSTEM

History. In 1898, Tiegerstedt and Bergman found that crude saline extracts of the kidney contained a pressor substance that they named renin. In 1934, Goldblatt and his colleagues demonstrated that constriction of the renal arteries produced persistent hypertension in dogs. In 1940, Braun-Menéndez and his colleagues in Argentina and Page and Helmer in the U.S. reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of the actual pressor material, a peptide, that was named hypertensin by the former group and angiotonin by the latter. These two terms persisted for nearly 20 years until it was agreed to rename the pressor substance angiotensin and to call the plasma substrate angiotensinogen. In the mid-1950s, two forms of angiotensin were recognized, a decapeptide (angiotensin I [AngI]) and an octapeptide (angiotensin II [AngII]) formed by proteolytic cleavage of AngI by an enzyme termed angiotensin-converting enzyme (ACE). The octapeptide was shown to be the more active form, and its synthesis in 1957 by Schwyzer and by Bumpus made the material available for intensive study.

It was later shown that the kidneys are important for aldosterone regulation and that angiotensin potently stimulates the production of aldosterone in humans. Moreover, renin secretion increased with depletion of Na+. Thus, the RAS came to be recognized as a mechanism to stimulate aldosterone synthesis and secretion and an important homeostatic mechanism in the regulation of blood pressure and electrolyte composition.

In the early 1970s, polypeptides were discovered that either inhibited the formation of AngII or blocked AngII receptors. These inhibitors revealed important physiological and pathophysiological roles for the RAS and inspired the development of a new and broadly efficacious class of antihypertensive drugs: the orally active ACE inhibitors. Studies with ACE inhibitors uncovered roles for the RAS in the pathophysiology of hypertension, heart failure, vascular disease, and renal failure. Selective and competitive antagonists of AngII receptors were developed that yielded losartan, the first orally active, highly selective, and potent nonpeptide AngII receptor antagonist. Subsequently, many other AngII receptor antagonists have been developed. Recently aliskiren, a direct renin inhibitor, was approved for antihypertensive therapy (see Chapter 27).

#### Components of the Renin–Angiotensin System

Overview. AngII, the most active angiotensin peptide, is derived from angiotensinogen in two proteolytic steps. First, renin, an enzyme released from the kidneys, cleaves ...

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