Mechanisms of anti-ischemic action of prostaglandin E1 in peripheral arterial occlusive disease.
The mechanisms of anti-ischemic effects of PGE1 in patients with peripheral arterial occlusive disease (PAD) are probably complex and clearly not limited to a direct vasodilator action. In addition to the known effects on blood flow, viscosity, fibrinolysis and platelet aggregation, the compound also inhibits monocyte and neutrophil function, suggesting that PGE1 will also have anti-inflammatory effects. Recent research has detected additional actions of PGE1 and prostacyclin analogs which might be relevant to its clinical efficacy. This includes inhibition of expression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1), release of inflammatory cytokines (TNFalpha, MCP-1), matrix components and generation and release of growth factors (CYR61, CTGF). These actions may also contribute to the long-term effects of PGE1, particularly in more advanced stages of PAD. Gene-expression experiments with chemically stable prostacyclins and PGE1 suggest that several genes in vascular smooth muscle cells and fibroblasts are modified by prostaglandins at the transcriptional level. This includes TNFalpha-induced VCAM expression in vascular smooth muscle cells which appears to be inhibited via the prostaglandin EP2 receptor as well as IL-1-induced expression of the type-1 collagen gene in fibroblasts. Thus, regulation of gene transcription by PGE1 may contribute to tissue protection in critical ischemia of the lower limbs.
Institut für Pharmakologie und Klinische Pharmakologie, UniversitätsKlinikum Düsseldorf, Heinrich-Heine-Universität, Germany. kschroer@uni-duesseldorf.de
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D000527:Alprostadil / Q000008:administration & dosage*; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D001158:Arteries / Q000187:drug effects / Q000503:physiopathology; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D008955:Models, Cardiovascular; D016491:Peripheral Vascular Diseases / Q000188:drug therapy* / Q000503:physiopathology*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D014665:Vasodilator Agents / Q000008:administration & dosage
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D000527:Alprostadil