Page 327 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 17 Vasoactive Peptides 313

The Treatment of Pulmonary Hypertension

Idiopathic pulmonary arterial hypertension (PAH) is a pro- blockers (nifedipine, amlodipine, diltiazem). Riociguat, a small-
gressive and potentially fatal condition; signs and symptoms molecule activator of soluble guanylyl cyclase, increases cGMP
include dyspnea, chest pain, syncope, cardiac arrhythmias, and independently of nitric oxide, reduces pulmonary vascular pres-
right heart failure. Continuous nasal oxygen supplementation sure, and increases exercise duration. Riociguat was approved
is required for most patients and anticoagulants are commonly in the USA in 2013. Selexipag is an oral nonprostanoid prodrug
used. Medical treatments directed at elevated pulmonary that is rapidly hydrolyzed to the selective prostaglandin I recep-
vascular resistance have been less successful than those used tor agonist ACT-333679. It has a mechanism of action similar to
in ordinary hypertension (see Chapter 11). In addition to the prostacyclin and was approved in 2015 (see Chapter 18). It is
endothelin antagonists mentioned in the text (bosentan, extraordinarily expensive. Fasudil is an investigational selective
ambrisentan, and macitentan are approved for use in PAH), RhoA/Rho kinase (ROCK) inhibitor that appears to reduce pul-
vasoactive agents that have been promoted for PAH include monary artery pressure in PAH. Surgical treatment for advanced
prostaglandins (epoprostenol, treprostinil, iloprost), nitric disease includes creation of a right atrial to left atrial shunt and
2+
oxide, PDE-5 inhibitors (sildenafil, tadalafil), and Ca channel lung transplantation.

in cholinergic presynaptic neurons in the central nervous system, and ■ SUBSTANCE P
in peripheral peptidergic neurons innervating diverse tissues includ-
ing the heart, lungs, gastrointestinal and urogenital tracts, skin, eyes, Substance P belongs to the tachykinin family of peptides,
ovaries, and thyroid gland. Many blood vessels are innervated by VIP which share the common carboxyl terminal sequence Phe-Gly-
neurons. VIP is also present in key organs of the immune system Leu-Met. Other members of this family are neurokinin A and
including the thymus, spleen, and lymph nodes. Although VIP is neurokinin B. Substance P is an undecapeptide, while neuroki-
present in blood, where it undergoes rapid degradation, it does not nins A and B are decapeptides.
appear to function as a hormone. VIP participates in a wide variety Substance P is widely distributed in the central and periph-
of biologic functions including metabolic processes, secretion of eral nervous systems and in the cardiovascular system. It is also
endocrine and exocrine glands, cell differentiation, smooth muscle present in the gastrointestinal tract, where it may play a role as a
relaxation, and modulation of the immune response. transmitter in the enteric nervous system and as a local hormone
VIP exerts significant effects on the cardiovascular system. It (see Chapter 6).
produces marked vasodilation in most vascular beds and in this Substance P is the most important member of the tachykinin
regard is more potent on a molar basis than acetylcholine. In the family. It exerts a variety of central actions that implicate the
heart, VIP causes coronary vasodilation and exerts positive inotro- peptide in behavior, anxiety, depression, nausea, and emesis. It is
pic and chronotropic effects. It may thus participate in the regula- present in peripheral afferent pain fibers and participates in noci-
tion of coronary blood flow, cardiac contraction, and heart rate. ception. It is a potent arteriolar vasodilator, producing marked
The effects of VIP are mediated by two G protein-coupled hypotension in humans and several animal species. The vasodila-
receptors, VPAC1 and VPAC2. Both receptors are widely dis- tion is mediated by release of nitric oxide from the endothelium.
tributed in the central nervous system and in the heart, blood Substance P causes contraction of venous, intestinal, and bron-
vessels, and other tissues. VIP has a high affinity for both recep- chial smooth muscle. It stimulates secretion by the salivary glands
tor subtypes. Binding of VIP to its receptors results in activation and causes diuresis and natriuresis by the kidneys.
of adenylyl cyclase and formation of cAMP, which is responsible The actions of substance P and neurokinins A and B are medi-
for the vasodilation and many other effects of the peptide. Other ated by three G protein-coupled tachykinin receptors designated
q
actions may be mediated by inositol trisphosphate synthesis and NK , NK , and NK . Substance P is the preferred ligand for the
1
2
3
calcium mobilization. VIP can also bind with low affinity to the NK receptor. This receptor is widespread throughout the body
1
VIP-like peptide pituitary adenylyl cyclase-activating peptide and is the predominant tachykinin receptor in the human brain.
receptor, PAC1. However, neurokinins A and B also possess considerable affinity
In view of its potent vasodilator action, VIP has potential for for this receptor. In humans, most of the central and peripheral
the treatment of systemic and pulmonary hypertension and heart effects of substance P are mediated by NK receptors. All three
1
failure, but this is limited by its short half-life in the circulation. receptor subtypes are coupled to inositol trisphosphate synthesis
However, PB1046 (Vasomera), a stable long-acting form of VIP and calcium mobilization.
that is selective for VPAC2 receptors, has been developed. Vasom- Several nonpeptide NK receptor antagonists have been devel-
1
era reduces blood pressure in animal models of hypertension and oped. These compounds are highly selective and orally active, and
heart failure and has been shown to be safe and well tolerated after enter the brain. Recent clinical trials have shown that these antag-
single subcutaneous or intravenous injection in phase 1 studies in onists may be useful in treating depression and other disorders and
patients with essential hypertension. in preventing chemotherapy-induced emesis. The first of these