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Channel Modulators (channel + modulator)
Selected AbstractsThe neuronal apoptotic death in global cerebral ischemia in gerbil: Important role for sodium channel modulator,JOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2009Manoja Kumar Brahma Abstract Global ischemia was induced in gerbil by bilateral occlusion of the common carotid arteries for 5 min. Sodium ionophore monensin or sodium channel blocker tetrodotoxin (TTX) was administered at doses of 10 ,g/kg, i.p., 30 min before ischemia induction; the dose was repeated after 22 hr. Subsequently, brain infarct occurred, determined at 24 hr after occlusion. Large, well-demarcated infarcts were observed in both hemispheres, an important observation because it critically influences the interpretation of the data. Because nitric oxide (NO) production is thought to be related to ischemic neuronal damage, we examined increases in Ca2+ influx, which lead to the activation of nitric oxide synthase (NOS). Then we evaluated the contributions of neuronal NOS, endothelial NOS, and inducible NOS to NO production in brain cryosections. The cytosolic release of apoptogenic molecules like cytochrome c and p53 were confirmed after 24 hr of reflow. TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) labeling detected the apoptotic cells, which were confirmed in neuron-rich cell populations. After 24 hr, all the ischemic changes were amplified by monensin and significantly attenuated by TTX treatment. Additionally, the nesting behavior and histological outcomes were examined after 7 day of reflow. The neuronal damage in the hippocampal area and significant decrease in nesting scores were observed with monensin treatment and reduced by TTX pretreatment after day 7 of reflow. To our knowledge, this report is the first to highlight the involvement of the voltage-sensitive Na+ channel in possibly regulating in part NO system and apoptosis in a cytochrome c,dependent manner in global ischemia in the gerbil, and thus warrants further investigation. © 2008 Wiley-Liss, Inc. [source] Solution structure of the cyclic peptide contryphan-Vn, a Ca2+ -dependent K+ channel modulatorBIOPOLYMERS, Issue 3 2004Tommaso Eliseo Abstract The solution structure of contryphan-Vn, a cyclic peptide with a double cysteine S,S bridge and containing a D -tryptophan extracted from the venom of the cone snail Conus ventricosus, has been determined by NMR spectroscopy using a variety of homonuclear and heteronuclear NMR methods and restrained molecular dynamics simulations. The main conformational features of backbone contryphan-Vn are a type IV ,-turn from Gly 1 to Lys 6 and a type I ,-turn from Lys 6 to Cys 9. As already found in other contryphans, one of the two prolines,the Pro4,is mainly in the cis conformation while Pro7 is trans. A small hydrophobic region probably partly shielded from solvent constituted from the close proximity of side chains of Pro7 and Trp8 was observed together with a persistent salt bridge between Asp2 and Lys6, which has been revealed by the diagnostic observation of specific nuclear Overhauser effects. The salt bridge was used as a restraint in the molecular dynamics in vacuum but without inserting explicit electrostatic contribution in the calculations. The backbone of the unique conformational family found of contryphan-Vn superimposes well with those of contryphan-Sm and contryphan-R. This result indicates that the contryphan structural motif represents a robust and conserved molecular scaffold whose main structural determinants are the size of the intercysteine loop and the presence and location in the sequence of the D -Trp and the two Pro residues. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004 [source] Diazoxide, a KATP opener, accelerates restitution of ethanol or indomethacin-induced gastric ulceration in rats independent of polyaminesJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 3 2001M Rahgozar Abstract Background and Aims: Experimental acute gastric ulcerations (EAGU) are healed very rapidly. This healing process has two steps; mucosal restitution and delayed repair. Adenosine 5,-triphosphate (ATP)-dependent potassium channels (KATP) have a regulatory role in the gastrointestinal physiology. In the present study, the effects of KATP channel modulators; diazoxide (channel opener) and glibenclamide (channel antagonist) on the healing of EAGU were investigated. The effect of polyamine (mediators presumably responsible for restitution) biosynthesis by difluoromethylornithine (DFMO) on diazoxide-induced alterations, and the effects of acid secretion inhibitors (cimetidine, omeprazole and atropine) on the mucosal restitution of EAGU were also studied. Methods: Groups of 10 male rats were starved for 24 h and EAGU was induced by oral administration of 1 mL 60% ethanol or a subcutaneous injection of 30 mg/kg indomethacin. Different groups were subjected to various doses of diazoxide (5, 15, 45 mg/kg) and/or glibenclamide (2, 6, 18 mg/kg) administered intraperitoneally (i.p.) after EAGU induction. Polyamine biosynthesis was inhibited by a single i.p. injection of DFMO (500 mg/kg), administered 10 min before EAGU induction. Cimetidine, omeprazole or atropine were administered intraperitoneally at doses of 200, 5 and 1 mg/kg, respectively, after EAGU induction. Animals were killed and their gastric mucosa was examined for ulcerations. Results: Diazoxide accelerated the healing of EAGU, whereas glibenclamide aggravated EAGU. The concomitant administration of glibenclamide antagonized the diaoxide effect. Diazoxide-induced acceleration of mucosal restitution was not abolished by DFMO. Cimetidine, omeprazole and atropine had no effect on the healing of EAGU. Conclusion: The KATP channels may play an important role in the gastric mucosal restitution independent of polyamines. Acid inhibition cannot reverse EAGU. [source] F90927: A New Member in the Class of Cardioactive SteroidsCARDIOVASCULAR THERAPEUTICS, Issue 3 2007Markus Keller ABSTRACT F90927 is a newly developed cardioactive drug with a steroid-like structure. It acts directly and agonistically on the cardiac L-type Ca2+ channel by shifting its voltage-dependent activation toward more negative potentials. This leads to an increased influx of Ca2+ and, therefore, to a stronger contraction; however, no arrhythmias occur. Calcium current stimulation can already be observed at nanomolar concentrations, but higher concentrations of F90927 elevate intracellular Ca2+ concentration, causing a reduction of the myocardial compliance and an increased diastolic blood pressure. Vessels also react to F90927 and contract in its presence. Binding of F90927 with the L-type Ca2+ channel presumably occurs in the vicinity of the transmembrane domains III and IV of the ,1 subunit. F90927 exhibits no use dependence and interacts with Ca2+ channel inhibitors of all three known classes of channel modulators (dihydropyridines, phenylalkylamines, and benzothiazepines), suggesting that it is a member of a new class of Ca2+ channel modulators. Due to its adverse effects on blood pressure and vessel contraction, F90927 is not an ideal drug candidate. It has, however, some unique properties, which makes it a promising tool to study the function of the L-type Ca2+ channel. [source] | ||||||||||