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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 hypertension. His blood pressure was reduced by hydrochlorothiazide 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?

A wide variety of peptides play important roles in the regulation of the cardiovascular system by acting at several levels in the body. Many of the peptides act as classic hormones, being transported in the blood from their site of synthesis to act on the heart, blood vessels, and other targets. Others function as paracrine or autocrine regulators, acting close to their site of synthesis. Several of the peptides are also present in the central nervous system where they function as neurotransmitters or neuromodulators (see Chapter 21), regulating brain centers involved in cardiovascular control. Some are present in the autonomic and enteric nervous systems where they frequently function as cotransmitters, with actions on the cardiovascular, gastrointestinal, and other systems (see Chapter 6). A smaller number of neuropeptides enter the circulation and act as neurohormones.

Peptides that participate in cardiovascular control include the vasoconstrictors angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin; and the vasodilators bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, adrenomedullin, relaxin, and the urocortins. This distinction between vasoconstrictor and vasodilator is an oversimplification because, depending on their receptors and associated signaling pathways, some peptides can elicit both responses.

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); relaxin (insulin superfamily); and urocortins (corticotropin releasing hormone 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 hypertension and several cardiovascular diseases including heart failure. Moreover, many drugs that alter the biosynthesis or actions of the peptides have been developed. In previous versions of this chapter, such drugs were often referred to as “being under development” or “having promise.” The present version of this ...

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