Prostacyclin receptor

Standard prostanoids have the following relative efficacies as receptor ligands in binding to and activating IP: PGI₂>>PGD2=PGE2=PGF2α>TXA2. In typical binding studies, PGI₂ has one-half of its maximal binding capacity and cell-stimulating actions at ~1 nanomolar whereas the other prostaglandins are >50-fold to 100-fold weaker than this. However, PGI₂ is very unstable, spontaneously converting to a far less active derivative 6-keto-PGF1 alpha within 1 minute of its formation. This instability makes defining the exact affinity of PGI₂ for IP difficult. It also makes it important to have stable synthetic analogs of PGI₂ for clinical usage. The most potent of these receptor agonists for binding to and activating IP are iloprost, taprostene, and esuberaprost which have K_d values (i.e. concentrations which bind to half of available IP receptors) in the low nanomole/liter range (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).[7]

Several synthetic compounds bind to, but do not activate, IP and thereby inhibit its activation by the activating ligands just described. These receptor antagonists include RO1138452, RO3244794, TG6-129, and BAY-73-1449, all of which have K_d values for IP at or beneath low nanomol/liter levels (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=345/).

IP gene knockout mice (i.e. IP(-/-) mice) exhibit increased tendency to thrombosis in response to experimentally-induced Endothelium, a result which appears to reflect, at least in part, the loss of IP's anti-platelet activity.[12][13] IP activation of animal and human platelets inhibits their aggregation response and as one consequence of this inhibition of platelet-dependent blood clotting. The PGI₂-IP axis along with the production of nitric oxide, acting together additively and potentially synergistically, are powerful and physiological negative regulators of platelet function and thereby blood clotting in humans. Studies suggest that the PGI₂-IP axis is impaired in patients with a tendency to develop pathological thrombosis such as occurs in obesity, diabetes, and coronary artery disease.[10][14]

IP activation stimulates the dilation of arteries and veins in various animal models as well as in humans. It increases the blood flow through, for example, the pulmonary, coronary, retinal and choroid circulation. Inhaled PGI₂ causes a modest fall in diastolic and small fall in systolic blood pressure in humans. This action involves IP's ability to relax vascular smooth muscle and is considered to be one of the fundamental functions of IP receptors. Furthermore, IP(-/-) mice on a high salt diet develop significantly higher levels of hypertension, cardiac fibrosis, and cardiac hypertrophy than control mice. The vasodilating and, perhaps, platelet-inhibiting effects of IP receptors likely underlie its ability suppress hypertension and protect tissues such as the heart in this model as well as the heart, brain, and gastrointestinal tract in various animal models of ischemic injury.[10] Indeed, IP agonists are used to treat patients pathological vasoconstriction diseases.[15] The injection of IP activators into the skin of rodents increases local capillary permeability and swelling; IP(-/-) mice fail to show this increased capillary permeability and swelling in response not only to IP activators but also in a model of carrageenan- or bradykinin-induced paw edema. IP antagonists likewise reduce experimentally-induced capillary permeability and swelling in rats. This actions is also considered a physiological function of IP receptors,[7][10] but can contribute to the toxicity of IP activators in patients by inducing, for example, life-threatening pulmonary edema.[15]

IP activators inhibit the adherence of circulating platelets and leukocytes adherence to vascular endothelium thereby blocking their entry into sites of tissue disturbance. The activators also inhibit vascular smooth muscle cells from proliferation by blocking these cells' growth cycle and triggering their apoptosis (i.e. cell death). These actions, along with its anti-inflammatory effects, may underlie the ability of IP gene knockout in an ApoE(−/−) mouse model to cause an accelerated rate of developing atherosclerosis.[7] [10]

Mouse studies indicate that the PGI₂-IP axis activates cellular signaling pathways that tend to suppress allergic inflammation. The axis inhibits bone marrow-derived dendritic cells (i.e. antigen-presenting cells that process antigen material, present it on their surfaces for delivery to T cells, and otherwise regulate innate and adaptive immune system responses) from producing pro-inflammatory cytokines (e.g. IL-12, TNF-alpha, IL-1-alpha, and IL-6) while stimulating them to increase production of the anti-inflammatory cytokine, IL-10. IP receptor activation of these cells also blocks their lipopolysaccharide-stimulated expression of pro-inflammatory cell surface proteins (i.e. CD86, CD40, and MHC class II molecules) that are critical for developing adaptive immune responses. IL receptor-activated bone marrow-derived dendritic cells showed a greatly reduced ability to stimulate the proliferation of T helper cell as well as the ability of these cells to produce pro-allergic cytokines (i.e. IL-5 and IL-13)s. In a mouse model of allergic inflammation, PGI₂ reduced the maturation and migration of lung mature dendritic cells to Mediastinal lymph nodes while increasing the egress of immature dendritic cells away from the lung. These effects resulted in a decrease in allergen-induced responses of the cells mediating allergic reactivity, TH-2 cells. These IP-induced responses likely contribute to its apparent function in inhibiting certain mouse inflammation responses as exemplified by the failure of IP receptor deficient mice to develop full lung airway allergic responses to ovalbumin in a model of allergic inflammation.[7][6]

In human studies, PGI₂ failed to alter bronchoconstriction responses to allergen but did protect against exercise-induced and ultrasonic water-induced bronchoconstriction in asthmatic patients. It also caused bronchodilation in two asthmatic patients. However, these studies were done before the availability of potent and selective IP agonists. These agonists might produce more effective inhibitor results on airways allergic diseases but their toxicity (e.g. pulmonary edema, hypotension) has tended to restrict there study in asthmatic patients.[6]

IP receptors also appear involved in suppressing non-allergic inflammatory responses. IP receptor-deficient mice exhibit a reduction in the extent and progression of inflammation in a model of collagen-induced arthritis. This effect may result from regulating the expression of arthritis-related, pro-inflammatory genes (i.e. those for IL-6, VEGF-A, and RANKL).[8][10] On the other hand, IP receptors may serve to promote non-allergic inflammatory responses: IP receptor-deficient mice exhibited increased lung inflammation in a model of bleomycin-induced pulmonary fibrosis while mice made to over-express the PGI₂-forming enzyme, Prostacyclin synthase, in their airway epithelial cells were protected against lung injury in this model.[6]

IP(-/-) mice exhibit little or no writhing responses in an acetic acid-induced pain model. The mouse IP receptor also appears to be involved in the development of heat-induced hyperalgesia. These and further studies using IP receptor antagonists in rats indicate that IP receptors on pain-perceiving sensory neurons of the dorsal root ganglia as well as on certain neurons in the spinal cord transmit signals for pain, particularly pain triggered by inflammation.[7][10]

IP receptor agonists, particularly when used intravenously, have been associated with the rapid development of pulmonary edema, hypotension, bleeding due to inhibition of platelet aggregation, and tachycardia.[16][17] Clinical use of these agonists is contraindicated in patients suffering many conditions. For example, the IP agonist iloprost is contraindicated in patients with unstable angina; decompensated cardiac failure (unless under close medical supervision); severe cardiac arrhythmias; congenital or acquired heart valve defects; increased risk of bleeding; a history of myocardial infarction in the past 6 months; or a history of cerebrovascular events (e.g. stroke) within 3 months.

IP receptor agonists are front-line drugs to treat pulmonary hypertension. Major drugs in this category include PGI₂ itself (i.e. epoprostenol), iloprost, treprostinil, and beraprost with epoprostenol being favored in some studies.[16][18][19] However, newly developed IP agonists with favorable pharmacological features such as Selexipag have been granted by the US FDA orphan drug status for the treatment of pulmonary hypertension. IP agonists are also to treat severe vasoconstriction in Raynaud's disease, Raynaud's disease-like syndromes, and scleroderma.[20][21] Epoprostenol causes improvements in hemodynamic parameters and oxygenation in patients suffering the acute respiratory distress syndrome but due to the limited number of randomized clinical trials and lack of studies investigating mortality, its use cannot be recommended as standard of care for this disease and should be reserved for those refractory to traditional therapies.[17] A meta-analysis of 18 clinical trials on the use of prostanoids including principally IP receptor agonists on patients with severe lower limb peripheral artery disease due to diverse causes found that these drugs may reduce the extent of limb tissue that needed to be amputated. However, the studies did not support extensive use of prostanoids in patients with critical limb ischemia as an adjunct to revascularization or as an alternative to major amputation in cases which cannot undergo revascularization.[22]

IP receptor agonists have been used to treat Thromboangiitis obliterans, a disease involving blood clotting and inflammation of the small and medium-sized arteries and veins in the hands and feet.[23]

An adenine (A) to cytosine (C) synonymous substitution at base 984 (i.e. A984C) in exon 3 of PTGIR' is the most frequent single nucleotide polymorphism (SNP) variant in a sampling of Japanese. This variant was associated with an increase in platelet activation responses in vitro and an increase in incidence of cerebral ischemia. Two other synonymous SNP variants, V53V and S328S, in PTGIR in an Italian population study were associated with enhanced platelet activation response and deep vein thrombosis.[24] The rare SNP variant 795C of 794T in the PTGIR gene is associated with an increased incidence of Aspirin-induced asthma and a greater percentage fall in the forced expiratory volume response of airways to inhalation of an aspirin like compound (lysine-acetyl salicylic acid) in a Korean population sample.[25][26]