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17 Vasoactive Peptides
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Ian A. Reid, PhD

C ASE STUD Y

During a routine check and on two follow-up visits, a with enalapril, an angiotensin-converting enzyme inhibitor.
45-year-old man was found to have high blood pressure Enalapril lowered his blood pressure to almost normotensive
(160–165/95–100 mm Hg). His physician initially prescribed levels. However, after several weeks on enalapril, the patient
hydrochlorothiazide, a diuretic commonly used to treat hyper- returned complaining of a persistent cough. In addition, some
tension. His blood pressure was reduced by hydrochloro- signs of angioedema were detected. How does enalapril lower
thiazide but remained at a hypertensive level (145/95 mm Hg), blood pressure? Why does it occasionally cause coughing
and he was referred to the university hypertension clinic. and angioedema? What other drugs could be used to inhibit
Because the patient had elevated plasma renin activity and the renin-angiotensin system and decrease blood pressure,
aldosterone concentration, hydrochlorothiazide was replaced without the adverse effects of enalapril?

Peptides are used by most tissues for cell-to-cell communica- The present version of this chapter indicates that many are now
tion. As noted in Chapters 6 and 21, they play important roles as in routine clinical use to treat cardiovascular and a wide variety
transmitters in the autonomic and central nervous systems. Several of other diseases.
peptides exert important direct effects on vascular and other smooth
muscles. These peptides include vasoconstrictors (angiotensin II,
vasopressin, endothelins, neuropeptide Y, and urotensin) and ■ ANGIOTENSIN
vasodilators (bradykinin and related kinins, natriuretic peptides,
vasoactive intestinal peptide, substance P, neurotensin, calcitonin BIOSYNTHESIS OF ANGIOTENSIN
gene-related peptide, and adrenomedullin).
Although these peptides are generally considered individu- The pathway for the formation and metabolism of angiotensin II
ally, many belong to families, the members of which have simi- (ANG II) is summarized in Figure 17–1. The principal steps
larities in structure and function and act on the same or related include enzymatic cleavage of angiotensin I (ANG I) from
receptors. Examples are substance P, which belongs to the angiotensinogen by renin, conversion of ANG I to ANG II
tachykinin family; calcitonin gene-related peptide and adre- by converting enzyme, and degradation of ANG II by several
nomedullin (calcitonin family); vasoactive intestinal peptide peptidases.
(secretin-glucagon family); and neuropeptide Y (neuropeptide
Y family). Renin
Many of these peptides were initially regarded as physiologic
curiosities, but subsequent investigation showed that they play Renin is an aspartyl protease enzyme that specifically catalyzes the
important roles not only in physiologic regulation, but also in hydrolytic release of the decapeptide ANG I from angiotensino-
a variety of disease states. Moreover, many drugs that alter the gen. It is synthesized as a prepromolecule that is first processed to
biosynthesis or actions of the peptides have been synthesized. prorenin and then to active renin by cleavage of a 43-amino acid
In previous versions of this chapter, such drugs were often N-terminal prosegment. Active renin is a glycoprotein consisting
referred to as “being under development” or “having promise.” of 340 amino acids.

300