[9] When bound to PGI2 or other of its agonists, IP stimulates one or more of three types of G protein complexes, depending on cell type: a) Gs alpha subunit-Gβγ complexes which release Gs that then stimulates adenyl cyclase to raise intracellular levels of cAMP and thereby activate cAMP-regulated protein kinases A-dependent cell signaling pathways (see PKA); b) Gq alpha subunit-Gβγ complexes which release Gq that then stimulates other cell signaling pathways (e.g. phospholipase C/IP3/cell Ca2+ mobilization/diacylglycerol/protein kinase Cs, calmodulin-modulated myosin light chain kinase, RAF/MEK/Mitogen-activated protein kinases, PKC/Ca2+/Calcineurin/Nuclear factor of activated T-cells; and EGF cellular receptors; and c) Gi alpha subunit-Giβγ) complexes which releases Gi that then simulates phospholipase C to cleave phosphatidylinositol triphosphate into inositol triphosphate that raises intracellular CaCa2 levels thereby regulating Calcium signaling pathways and diacylglycerol that activates certain protein kinase C enzymes )that phosphorylate and thereby regulate target proteins involved in cell signaling (see Protein kinase C#Function).
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.
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.
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.
[9][11] 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.
[8][11] 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.
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.
[17][19][20] 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.
[21][22] 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.
[23] 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.
[24] 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.
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.
[25] 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.