Anti-calmodulins and Tricyclic Adjuvants in Pain Therapy Block the TRPV1 Channel

Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca2+-uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+-channels but not affecting motoneurons

Hydraulic evaluation of the hypogenic karst area in Budapest (Hungary)

The Buda Thermal Karst area, in central Hungary, is in the focus of research interest because of its thermal water resources and the on-going hypogenic karstification processes at the boundary of unconfined and confined carbonates. Understanding of the discharge phenomena and the karstification processes requires clarification of the groundwater flow conditions in the area. Consequently, the aim of the present study was to present a hydraulic evaluation of the flow systems based on analyzes of the archival measured hydraulic data of wells. Pressure vs. elevation profiles, tomographic fluid-potential maps and hydraulic cross sections were constructed, based on the data distribution. As a result, gravitational flow systems, hydraulic continuity, and the modifying effects of aquitard units and faults were identified in the karst area. The location of natural discharge areas could be explained and the hydraulic behavior of the Northeastern Margin Fault of the Buda Hills could be determined. The flow pattern determines the differences in the discharge distribution (one- and two-component) and related cave-forming processes between the Central System (Rózsadomb area) and Southern System (Gellért Hill area) natural discharge areas. Among the premises of hypogenic karstification, regional upward flow conditions were confirmed along the main discharge zone of the River Danube. The flow pattern determines the differences in the discharge distribution (one- and two-component) and related cave-forming processes between the Central System (Rózsadomb area) and Southern System (Gellért Hill area) natural discharge areas. Among the premises of hypogenic karstification, regional upward flow conditions were confirmed along the main discharge zone of the River Danube. The flow pattern determines the differences in the discharge distribution (one- and two-component) and related cave-forming processes between the Central System (Rózsadomb area) and Southern System (Gellért Hill area) natural discharge areas. Among the premises of hy