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

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