Chapter 17. Vasoactive Peptides

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 vasoactive peptides include angiotensin, bradykinin, natriuretic peptides, calcitoningene-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 less 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.

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 (ANGII, also known as 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

ANGII is a potent arteriolar vasoconstrictor and stimulant of aldosterone release. ANGII 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. ANGII is also mitogenic and plays a role in cardiac remodeling.

ANGII is no longer used for clinical indications. Its major significance is as an endogenous pathophysiologic mediator in some cases of hypertension (high-renin hypertension) and in heart failure. Regardless of renin levels, ANGII antagonists have demonstrated clinical benefits in hypertension and heart failure. Therefore, ANGII 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. ANGII receptor blockers (eg, losartan, valsartan, others) are orally active nonpeptide inhibitors at the ANGII 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, an orally active renin inhibitor, reduces angiotensin I as well as angiotensin II and is approved for use in hypertension.

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. They reduce the concentration of ANGII and increase the concentration of natriuretic peptides. 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 (IP3), 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). Bradykinin also plays a role in hereditary angioedema. Ecallantide, a parenteral kallikrein inhibitor, and icatibant, an oral bradykinin B2-receptor antagonist, are approved for use in angioedema.

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 via a membrane-spanning enzyme receptor. 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 ANGII 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 marker.

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 very significant toxicity.

Endothelins are peptide vasoconstrictors formed in and released by endothelial cells in blood vessels. Endothelins appear 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. ETA antagonists available for the treatment of pulmonary hypertension include bosentan and ambrisentan.

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 post-herpetic 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 (calcitoningene-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 the CNS and peripheral nerves; it 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.

(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.

(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.