Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 17. Vasoactive Peptides

Vasoactive Peptides: Introduction

Vasoactive peptides are autacoids with significant actions on vascular smooth muscle as well as other tissues. They include vasoconstrictors, vasodilators, and peptides with mixed effects. Antagonists of these peptides or the enzymes that produce them have useful clinical properties.

In addition to their actions on smooth muscle, vasoactive peptides function as neurotransmitters and local and systemic hormones. The better-known endogenous vasoactive peptides include angiotensin, bradykinin, natriuretic peptides, calcitonin gene-related peptide (CGRP), endothelin, neuropeptide Y (NPY), substance P and vasoactive intestinal peptide (VIP) (discussed in this chapter), and vasopressin (Chapters 15 and 37). Many other endogenous peptides with very important actions (eg, insulin, glucagon, opioid peptides) have little or no direct vascular smooth muscle effects.

Vasoactive peptides probably all act on cell surface receptors. Most act via G-protein-coupled receptors and cause the production of well-known second messengers (Table 17-1); a few may open ion channels.

TABLE 17-1 Some vasoactive peptides and their properties.

Peptide Properties Angiotensin II (AII)  IP 3, DAG via AT1 G protein-coupled receptors. Constricts arterioles, increases aldosterone secretion

Bradykinin  IP3, DAG, cAMP, NO. Dilates arterioles, increases capillary permeability, stimulates sensory nerve endings

Brain natriuretic peptide (BNP)  cGMP via ANPA receptors. Dilates vessels, inhibits aldosterone secretion and effects, increases glomerular filtration

Calcitonin gene-related peptide (CGRP) An extremely potent vasodilator; causes hypotension and reflex tachycardia Endothelins  IP3, DAG via G protein-coupled ETA and ETB receptors. Synthesized in vascular endothelium. Constrict most vessels and contract other smooth muscle

Neuropeptide Y Causes vasoconstriction and stimulates the heart. Effects mediated in part by IP3

Substance P, neurokinins Act on NK1, NK2, and NK3 receptors. Dilate arterioles, contract veins, intestinal, and bronchial smooth muscle, cause diuresis; substance P is a transmitter in sensory pain neurons

Vasoactive intestinal peptide (VIP)  cAMP via G protein-coupled receptors VPAC1 and VPAC2. Dilates vessels, relaxes bronchi and intestinal smooth muscle

aANP, atrial natriuretic peptide; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate.

High-Yield Terms to Learn

Kinins Family of vasoactive peptides associated with tissue injury and inflammation, for example, bradykinin Natriuretic peptides Family of peptides synthesized in brain, heart, and other tissues; have vasodilator as well as natriuretic effects Neuropeptides Peptides with prominent roles as neurotransmitters or modulators; many also have potent smooth muscle effects Peptidase Family of enzymes that activate or inactivate peptides by hydrolysis, for example, angiotensin-converting enzyme (dipeptidyl peptidase), neutral endopeptidase Tachykinins Group of 3 potent neuropeptides: substance P, neurokinin A, and neurokinin B Vasoactive peptides Peptides with prominent effects on vascular smooth muscle; many are neuropeptides as well

Angiotensin & Its Antagonists

Source and Disposition

Angiotensin I is produced from circulating angiotensinogen by renin, an enzyme released from the juxtaglomerular apparatus of the kidney. Angiotensin I is an inactive decapeptide, and is converted into angiotensin II (AII), an active octapeptide, by angiotensin-converting enzyme (ACE), also known as peptidyl dipeptidase or kininase II (see Figure 11-3). Angiotensin II, the active form of the peptide, is rapidly degraded by peptidases (angiotensinases).

Effects and Clinical Role

AII is a potent arteriolar vasoconstrictor and stimulant of aldosterone release. AII directly increases peripheral vascular resistance and, through aldosterone, causes renal sodium retention. It also facilitates the release of norepinephrine from adrenergic nerve endings via presynaptic heteroreceptor action (see Chapter 6). All these effects are mediated by the angiotensin AT1 receptor, a Gq-coupled receptor. The AT2 receptor appears to mediate vasodilation via nitric oxide and is probably most important during fetal development.

AII was used in the past by intra-arterial infusion to control bleeding in difficult-to-access sites. The peptide is no longer used for this indication. Its major clinical significance is as a pathophysiologic mediator in some cases of hypertension (high-renin hypertension) and in heart failure. Even in normal- and low-renin hypertension, AII antagonists have demonstrated clinical benefits. Therefore, AII antagonists are of considerable clinical importance.

Angiotensin Antagonists

As noted in Chapters 11 and 13, 2 types of antagonists are available. ACE inhibitors (eg, captopril, enalapril , others) are important agents for the treatment of hypertension and heart failure. AII receptor blockers (eg, losartan, valsartan , others) are orally active nonpeptide inhibitors at the AII AT1 receptor. Block of angiotensin's effects by either of these drug types is often accompanied by a compensatory increase in renin and angiotensin I. Aliskiren , a new orally active renin inhibitor, reduces angiotensin I as well as angiotensin II and is approved for use in hypertension.

Vasopeptidase Inhibitors

The vasopeptidase enzymes include neutral endopeptidase 24.11 and ACE. A class of drugs that block both enzymes is in clinical trials, and these drugs (eg, omapatrilat) show considerable efficacy in hypertension and heart failure. Unfortunately, these drugs also cause angioedema in a significant number of patients and have not been approved for clinical use.


Source and Disposition

Bradykinin is one of several vasodilator kinins produced from kininogen by a family of enzymes, the kallikreins. Bradykinin is rapidly degraded by various peptidases, including ACE.

Effects and Clinical Role

Bradykinin acts through at least 2 receptors (B1 and B2) and causes the production of inositol 1,4,5-trisphosphate (IP 3), diacylglycerol (DAG), cyclic adenosine monophosphate (cAMP), nitric oxide, and prostaglandins in tissues. Bradykinin is one of the most potent vasodilators known. The peptide is involved in inflammation and causes edema and pain when released or injected into tissue. Bradykinin can be found in saliva and may play a role in stimulating its secretion.

Although it has no therapeutic application, bradykinin may play a role in the antihypertensive action of ACE inhibitors, as previously noted (see Chapter 11; Figure 11-3). Icatibant, an orally active bradykinin B2 receptor antagonist, is under intense study in various conditions, especially hereditary angioedema, but at present there are no FDA-approved bradykinin antagonists.

Natriuretic Peptides

Source and Disposition

Natriuretic peptides (atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP]) are synthesized and stored in the cardiac atria of mammals. BNP has also been isolated from brain tissue. They are released from the atria in response to distention of the chambers. A similar peptide, C-type natriuretic peptide, has been isolated from other tissues. BNP appears to be the most important of these peptides.

Effects and Clinical Role

Natriuretic peptides activate guanylyl cyclase in many tissues. They act as vasodilators as well as natriuretic (sodium excretion-enhancing) agents. Their renal action includes increased glomerular filtration, decreased proximal tubular sodium reabsorption, and inhibitory effects on renin secretion. The peptides also inhibit the actions of AII and aldosterone. Although they lack positive inotropic action, endogenous natriuretic peptides may play an important compensatory role in congestive heart failure by limiting sodium retention. Blood levels of endogenous BNP have been shown to correlate with the severity of heart failure and can be used as a diagnostic tool.

BNP has shown some benefit in the treatment of acute severe heart failure and is currently available for clinical use as nesiritide. This drug is approved for intravenous administration in acute severe heart failure (see Chapter 13) but has significant renal toxicity.


Endothelins are peptide vasoconstrictors formed in and released by endothelial cells in blood vessels. Endothelins are believed to function as autocrine and paracrine hormones in the vasculature. Three endothelin peptides (ET-1, ET-2, and ET-3) with minor variations in amino acid sequence have been identified in humans. Two receptors, ETA and ETB, have been identified, both of which are coupled to their effectors with G proteins. The ETA receptor appears to be responsible for the vasoconstriction produced by endothelins.

Endothelins are much more potent than norepinephrine as vasoconstrictors and have a relatively long-lasting effect. The peptides also stimulate the heart, increase natriuretic peptide release, and activate smooth muscle proliferation. The peptides may be involved in some forms of hypertension and other cardiovascular disorders. The first antagonist to become clinically available is bosentan, which is approved for use in pulmonary hypertension.

VIP, Substance P, CGRP, & NPY

VIP (vasoactive intestinal peptide) is an extremely potent vasodilator but is probably more important as a neurotransmitter. It is found in the central and peripheral nervous systems and in the gastrointestinal tract. No clinical application has been found for this peptide.

The neurokinins (substance P, neurokinin A, and neurokinin B) act at NK1 and NK2 receptors in the central nervous system (CNS) and the periphery. Substance P has mixed vascular effects. It is a potent arteriolar vasodilator and a potent stimulant of veins and intestinal and airway smooth muscle. The peptide may also function as a local hormone in the gastrointestinal tract. Highest concentrations of substance P are found in the parts of the nervous system that contain neurons subserving pain. Capsaicin, the "hot" component of chili peppers, releases substance P from its stores in nerve endings and depletes the peptide. Capsaicin has been approved for topical use on arthritic joints and for postherpetic neuralgia.

Neurokinins appear to be involved in certain CNS conditions, including depression and nausea and vomiting. Aprepitant is an oral antagonist at NK1 receptors and is approved for use in chemotherapy-induced nausea and vomiting.

CGRP (calcitonin gene-related peptide) is found (along with calcitonin) in high concentrations in the thyroid but is also present in most smooth muscle tissues. The presence of CGRP in smooth muscle suggests a function as a cotransmitter in autonomic nerve endings. CGRP is the most potent hypotensive agent discovered to date and causes reflex tachycardia. Some evidence suggests that CGRP is involved in migraine headache. Currently, there is no clinical application for this peptide. However, an oral CGRP antagonist, if available, would be of great interest for the treatment of migraine.

NPY (neuropeptide Y) is a potent vasoconstrictor peptide that also stimulates the heart. NPY is found in both the CNS and peripheral nerves. In the periphery, NPY is commonly localized as a cotransmitter in adrenergic nerve endings. In experimental animals, NPY administered in the CNS stimulates feeding and causes hypotension and hypothermia. Peripheral administration causes positive chronotropic and inotropic effects in the heart and hypertension. Several receptor subtypes have been identified, but neither agonists nor antagonists of this peptide have found clinical application.

Skill Keeper: Angiotensin Antagonists

(See Chapter 11)

Discuss the differences between ACE inhibitors and AT1--receptor blockers in the context of the peptides described in this chapter. The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: Angiotensin Antagonists

(See Chapter 11)

Both ACE inhibitors (eg, captopril) and AT1--receptor blockers (eg, losartan) reduce the effects of the renin-angiotensin-aldosterone system and thereby reduce blood pressure. Both result in a compensatory increase in the release of renin and angiotensin I. A major difference between the 2 types of drugs results from the fact that ACE inhibitors increase the circulating levels of bradykinin because bradykinin is normally inactivated by ACE. The increase in bradykinin contributes to the hypotensive action of ACE inhibitors but is probably also responsible for the high incidence of cough associated with ACE inhibitor use. The cough is believed to result from prostaglandins synthesized as a result of the increased bradykinin. AT1--receptor blockers have a lower incidence of cough.


When you complete this chapter, you should be able to:

 Name an antagonist of angiotensin at its receptor and at least 2 drugs that reduce the formation of angiotensin II.

 Outline the major effects of bradykinin and brain natriuretic peptide.

 Describe the functions of converting enzyme (peptidyl dipeptidase, kininase II).

 List 2 potent vasoconstrictor peptides.

 Describe the effects of vasoactive intestinal peptide and substance P.

 Describe the clinical applications of bosentan and aprepitant.

Drug Summary Table: Vasoactive Peptides

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Renin-angiotensin antagonists Aliskiren Renin inhibitor; reduces angiotensin I and II and aldosterone secretion Hypertension Oral Duration: 12 h Angioedema, renal impairment Captopril, enalapril, others ACE inhibitor; reduces angiotensin II and aldosterone secretion; increases bradykinin Hypertension, heart failure Oral Half-life ~2 h but large doses used for duration of effect ~12 h Cough, teratogenic, hyperkalemia Losartan, valsartan, others AT1 receptor inhibitor; reduces effects of angiotensin II

Hypertension Oral Duration: 6-8 h Teratogenic, hyperkalemia Vasopressin agonists Desmopressin V1 and V2 receptor agonist

Pituitary diabetes insipidus Inhaled, parenteral Duration: 4-7 h Hyponatremia Vasopressin antagonists Conivaptan V1 and V2 receptor inhibitor

Hyponatremia Parenteral Duration: 6-10 h Infusion site reactions Tolvaptan: Like conivaptan but much more selective for V2 receptor

Natriuretic peptides Nesiritide BNP receptor agonist Acute heart failure Parenteral Half-life: 18 min Renal damage, hypotension Endothelin antagonists Bosentan ETA and ETB receptor antagonist

Pulmonary hypertension Oral Half-life: 5 h Hepatic impairment; possible teratogen Substance P antagonists Aprepitant Tachykinin NK1 receptor antagonist

Antiemetic for chemotherapy-induced vomiting Oral Half-life: 9-13 h Asthenia, hiccups Capsaicin Releases substance P from nerve endings Topical for painful conditions (joints, postherpetic neuralgia) Topical Duration: 4-6 h Burning, stinging, erythema

ACE, angiotensin-converting enzyme; BNP, brain natriuretic peptide.

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