title: A model on the induction of adverse vascular long-term effects of NSAIDs.
abstract: The causes of increased rates of myocardial infarctions and strokes by application of non-steroidal anti-inflammatory agents (NSAIDs) are unclear. Here we present a biochemical model that the long-term vascular effects of NSAIDs can be consequences of their antiproliferative cellular mechanism. The analysis of the model suggests that the intramitochondrial uncoupling of oxidative phosphorylation induced by NSAIDs increases, through a reduced activity of ATP-dependent ionic pumps, the intra-cellular calcium x phosphate product with a consecutively increased formation and export of various calcium phosphate compounds. The latter cause, by chemical replication mechanisms of arterial hydroxyapatite deposits, a metatstatic calcifying vascular process. This sclerogenic vascular mineralization corresponds to an early arteriosclerotic development resembling the Mönckeberg's media calcification. The mechanism shows direct analogies to the accelerated and metastatic calcification of coronary arteries seen in chronic kidney disease and dialysis. This appears an extra-cellular time-lapse version of the protracted cell model. The induction of this degenerative mechanism may explain the increased number of adverse cardiovascular, renovascular and cerebrovascular effects of NSAIDs as they are observed in long-term therapies.
authors.affiliation: Pharmed Institute of Cybernetics, Munich, Germany. liedtke@pharmed.de
authors.forename: Rainer K
authors.initials: RK
authors.lastname: Liedtke
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002114:Calcinosis / Q000139:chemically induced; D002130:Calcium Phosphates / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009203:Myocardial Infarction / Q000139:chemically induced; D010085:Oxidative Phosphorylation / Q000187:drug effects; D020521:Stroke / Q000139:chemically induced
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002130:Calcium Phosphates; D007473:Ion Channels; D000255:Adenosine Triphosphate; C020243:calcium phosphate