The dihydropyridine S(-)-Bay K 8644 (Bay K), the benzoylpyrrole FPL 64176 (FPL) and the benzodiazocine CGP 48506 (CGP) are structurally unrelated L-type Ca2+ channels agonists. The aim of our study was to investigate whether these three drugs interact with different binding sites and thereby modulate the behaviour of L-type Ca2+ channels in a qualitatively different manner. Single-channel recordings were performed on CHO cells stably expressing the alpha1C-b subunit of the L-type Ca2+ channel. Mean open time and open probability were determined sweep by sweep and the effects of CGP (10(-4) M), Bay K (10(-6) M) and FPL (10(-6) M) were compared. All three compounds increased mean open time and open probability when applied alone. However, the gating pattern changes induced by each drug were qualitatively and quantitatively different. We also applied binary mixtures and analysed the resulting sweeps with respect to their gating pattern. The application of mixtures did result in a gating pattern not seen with any of the single drugs. The mixture of CGP and FPL led to a prolonged mean open time compared with each single drug. The mixture of Bay K and FPL exhibited an open probability lower than with each single drug. The mixture of CGP and Bay K increased the mean open time per sweep like Bay K, but the number of openings was similar to the level seen with CGP alone. These results cannot be explained by assuming alternative binding of the drugs to a single binding site. We therefore conclude that Bay K, CGP and FPL bind to different but interacting sites on the L-type Ca2+ channel.
From these results we conclude that: (a) leukocytes exert an aggravating effect in arrhythmogenesis during ischemia/reperfusion, (b) the arrhythmogenic substrate for this effect may consist of an enhanced dispersion of potential duration and (c) that inhibition of leukocyte accumulation can at least partially reduce arrhythmogenesis and may be of therapeutic interest as an additional treatment.
Host-modulating therapies have become an important focus in the development of novel concepts for improved management of tuberculosis (TB). Previous in vitro studies revealed that the p38 MAP kinase signaling pathway coordinates several inflammatory and stress responses in Mycobacterium tuberculosis (Mtb)-infected host cells. Here we extend these findings and show that in vivo treatment of Mtb-infected C57BL/6 mice with doramapimod, a p38 MAP-kinase inhibitor, results in reduced inflammation, granuloma formation and lung pathology. Moreover, doramapimod, together with standard antibiotic treatment, significantly reduced lung and spleen mycobacterial loads compared to antibiotic treatment alone. Our in vivo data suggest the opportunity to repurpose p38 MAPK inhibitors for adjunct host directed therapies. We also provide first data on safety of p38 MAPK inhibition which is of relevance for future application of these substances in inflammatory diseases and concomitant TB. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the major killer among infectious agents which led to 1.5 million deaths in 2018 1. Treatment of TB requires combinations of antibiotics for several months, a strategy which becomes increasingly complicated in times of rising numbers of multi-drug resistant Mtb-isolates 1. Adjunctive host directed therapy (HDT) might improve and accelerate treatment by modifying host pathways targeted by Mtb 2-6. In HDT, one promising approach is to manipulate signaling pathways that contribute to immunopathology by causing hyperinflammation, necrosis and tissue damage. We have recently shown that genetic or chemical inhibition of p38 mitogen-activated protein kinase (MAPK) in vitro results in abrogation of Mtb-induced host cell death and decreased release of inflammatory alarmins such as High-Mobility-Group-Protein B1 (HMGB1) ex vivo 7. p38 MAPK is a validated target in autoimmune and inflammatory diseases and several small molecule inhibitors have been tested in clinical trials mainly against rheumatoid arthritis, psoriasis and Crohn's disease 8. This provides an opportunity to repurpose these substances with excellent safety profiles as adjunct therapeutics in combination with anti-mycobacterial drugs against active TB. As a serine/threonine protein kinase, p38 MAPK plays an important role in orchestrating the immune response of the host by coordinating the release of proinflammatory cytokines such as interleukin (IL-) 1-beta (β) or tumor necrosis factor (TNF) upon infection 8. Clinical application of p38 MAPK inhibitors theoretically
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