Objective. Uncoupling of isolated mitochondria by nonsteroidal antiinflammatory drugs (NSAIDs) has been considered relevant to the development of gastrointestinal (GI) side effects. We investigated the occurrence of NSAID-induced uncoupling of mitochondria in intact cells (rat thymocytes) compared with the effects of a selective cyclooxygenase 2 (COX-2) inhibitor.Methods. Oxygen consumption and mitochondrial membrane potential were simultaneously measured amperometrically and by distribution of radioactive tracer molecules, respectively, in the presence and absence of pharmacologically relevant concentrations of the NSAIDs indomethacin and diclofenac and the selective COX-2 inhibitor SC-236. Analysis of data by a technique related to top-down elasticity analysis permitted assessment of the influence of these compounds on individual components of cellular energy metabolism.Results. Indomethacin, diclofenac, and SC-236 increased proton leak in isolated mitochondria. Both diclofenac and SC-236 significantly stimulated proton leak in intact cells and simultaneously inhibited substrate oxidation and ATP turnover. Oxygen consumption rates of isolated cells remained unchanged over a wide concentration range of the drugs, despite significant effects on subsystems of cellular energy metabolism.Conclusion. NSAIDs and selective COX-2 inhibitors have significant and equally directed effects on cellular energy metabolism. They both uncouple mitochondrial respiration and inhibit substrate oxidation and ATP turnover. However, the topical effect and selective COX-2 inhibition may not be sufficient to cause NSAID-like damage to the GI tract.

Immune mechanisms and circulating mediators may be important in the pathogenesis of preeclampsia. We review our findings on agonistic antibodies against the angiotensin II (Ang II) receptor (AT1-AA) and their possible role in the pathogenesis of this disorder. AT1-AA appear in the course of preeclampsia and are largely gone by 6 weeks after delivery. AT1-AA detection relies on a bioassay using spontaneously beating neonatal rat cardiomyocytes. Their specificity has been documented by other methods, including Western blotting, co-localization, and co-immunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including transcription factor activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proved with certainty. However, we believe the findings are compelling and warrant further study.

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