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INTRODUCTION

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CASE STUDY

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

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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). This chapter focuses on the smooth muscle actions of the peptides and on drugs that alter their biosynthesis or actions.

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ANGIOTENSIN

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BIOSYNTHESIS OF ANGIOTENSIN

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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.

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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.

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Renin
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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 processed to prorenin, which has poorly understood actions, and then to active renin, a glycoprotein consisting of 340 amino acids.

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Renin in the circulation originates in the kidneys. Enzymes with renin-like activity are present in several extrarenal tissues, including blood vessels, uterus, salivary glands, and adrenal cortex, but no physiologic role for these enzymes has been established. Within the kidney, renin is synthesized and stored in the juxtaglomerular apparatus ...

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