Idiopathic pulmonary arterial hypertension (PAH) is a pro-gressive and potentially fatal condition; signs and symptoms include dyspnea, chest pain, syncope, cardiac arrhythmias, and right heart failure. Continuous nasal oxygen supplementation is required for most patients and anticoagulants are commonly used. Medical treatments directed at elevated pulmonary vascular resistance have been less successful than those used in ordinary hypertension (see Chapter 11). In addition to the endothelin antagonists mentioned in the text (bosentan, ambrisentan, and macitentan are approved for use in PAH), vasoactive agents that have been promoted for PAH include prostaglandins (epoprostenol, treprostinil, iloprost), nitric oxide, PDE-5 inhibitors (sildenafil, tadalafil), and Ca2+ channel blockers (nifedipine, amlodipine, diltiazem). Riociguat, a small-molecule activator of soluble guanylyl cyclase, increases cGMP independently of nitric oxide, reduces pulmonary vascular pres-sure, and increases exercise duration. Riociguat was approved in the USA in 2013. Selexipag is an oral nonprostanoid prodrug that is rapidly hydrolyzed to the selective prostaglandin I recep-tor agonist ACT-333679. It has a mechanism of action similar to prostacyclin and was approved in 2015 (see Chapter 18). It is extraordinarily expensive. Fasudil is an investigational selective RhoA/Rho kinase (ROCK) inhibitor that appears to reduce pul-monary artery pressure in PAH. Surgical treatment for advanced disease includes creation of a right atrial to left atrial shunt and lung transplantation.
VIP exerts significant effects on the cardiovascular system. It produces marked vasodilation in most vascular beds and in this regard is more potent on a molar basis than acetylcholine. In the heart, VIP causes coronary vasodilation and exerts positive inotropic and chronotropic effects. It may thus participate in the regulation of coronary blood flow, cardiac contraction, and heart rate.
The effects of VIP are mediated by two G protein-coupled receptors, VPAC1 and VPAC2. Both receptors are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. VIP has a high affinity for both receptor subtypes. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by inositol trisphosphate synthesis and calcium mobilization. VIP can also bind with low affinity to the VIP-like peptide pituitary adenylyl cyclase-activating peptide receptor, PAC1.
In view of its potent vasodilator action, VIP has potential for the treatment of systemic and pulmonary hypertension and heart failure, but this is limited by its short half-life in the circulation. However, PB1046 (Vasomera), a stable long-acting form of VIP that is selective for VPAC2 receptors, has been developed. Vasomera reduces blood pressure in animal models of hypertension and heart failure and has been shown to be safe and well tolerated after single subcutaneous or intravenous injection in phase 1 studies in patients with essential hypertension.
Substance P belongs to the tachykinin family of peptides, which share the common carboxyl terminal sequence Phe-Gly-Leu-Met. Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and B are decapeptides.