During a routine check and on two follow-up visits, a 45-year-old man was found to have high blood pressure (160–165/95–100 mm Hg). His physician initially prescribed hydrochlorothiazide, a diuretic commonly used to treat hyper-tension. His blood pressure was reduced by hydrochloro-thiazide but remained at a hypertensive level (145/95 mm Hg), and he was referred to the university hypertension clinic. Because the patient had elevated plasma renin activity and aldosterone concentration, hydrochlorothiazide was replaced with enalapril, an angiotensin-converting enzyme inhibitor. Enalapril lowered his blood pressure to almost normotensive levels. However, after several weeks on enalapril, the patient returned complaining of a persistent cough. In addition, some signs of angioedema were detected. How does enalapril lower blood pressure? Why does it occasionally cause coughing and angioedema? What other drugs could be used to inhibit the renin-angiotensin system and decrease blood pressure, without the adverse effects of enalapril?
Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles as transmitters in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin).
Although these peptides are generally considered individually, many belong to families, the members of which have similarities in structure and function and act on the same or related receptors. Examples are substance P, which belongs to the tachykinin family; calcitonin gene-related peptide and adrenomedullin (calcitonin family); vasoactive intestinal peptide (secretin-glucagon family); and neuropeptide Y (neuropeptide Y family).
Many of these peptides were initially regarded as physiologic curiosities, but subsequent investigation showed that they play important roles not only in physiologic regulation, but also in a variety of disease states. Moreover, many drugs that alter the biosynthesis or actions of the peptides have been synthesized. In previous versions of this chapter, such drugs were often referred to as “being under development” or “having promise.”
The present version of this chapter indicates that many are now in routine clinical use to treat cardiovascular and a wide variety of other diseases.
The pathway for the formation and metabolism of angiotensin II (ANG II) is summarized in Figure 17–1. The principal steps include enzymatic cleavage of angiotensin I (ANG I) from angiotensinogen by renin, conversion of ANG I to ANG II by converting enzyme, and degradation of ANG II by several peptidases.
Renin is an aspartyl protease enzyme that specifically catalyzes the hydrolytic release of the decapeptide ANG I from angiotensinogen. It is synthesized as a prepromolecule that is first processed to prorenin and then to active renin by cleavage of a 43-amino acid N-terminal prosegment. Active renin is a glycoprotein consisting of 340 amino acids.
FIGURE 17–1 Chemistry of the renin-angiotensin system. The amino acid sequence of the amino terminal of human angiotensinogen is shown. R denotes the remainder of the protein molecule. See text for additional steps in the formation and metabolism of angiotensin peptides.