The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Robert S Moreland - One of the best experts on this subject based on the ideXlab platform.
-
corrigendum sustained contraction in vascular smooth muscle by activation of l type ca2 channels does not involve ca2 sensitization or caldesmon
Frontiers in Pharmacology, 2016Co-Authors: Hillevi Ets, Chun Y Seow, Robert S MorelandAbstract:Vascular smooth muscle (VSM) is unique in its ability to maintain an intrinsic level of contractile force, known as tone. Vascular tone is believed to arise from the constitutive activity of membrane-bound L-type Ca2+ channels (LTCC). This study used a pharmacological agonist of LTCC, Bay K8644, to elicit a sustained, sub-maximal contraction in VSM that mimics tone. Downstream signaling was investigated in order to determine what molecules are responsible for tone. Medial strips of swine carotid artery were stimulated with 100 nM Bay K8644 to induce a sustained level of force. Force and phosphorylation levels of myosin light chain (MLC), MAP kinase, MYPT1, CPI-17, and caldesmon were measured during Bay K8644 stimulation in the presence and absence of nifedipine, ML-7, U0126, bisindolylmaleimide (Bis), and H-1152. Nifedipine and ML-7 inhibited force and MLC phosphorylation in response to Bay K8644. Inhibition of Rho kinase (H-1152) but not PKC (Bis) inhibited Bay K8644 induced force. U0126 significantly increased Bay K8644-dependent force with no effect on MLC phosphorylation. Neither CPI-17 nor caldesmon phosphorylation were increased during the maintenance of sustained force. Our results suggest that force due to the influx of calcium through LTCCs is partially MLC phosphorylation-dependent but does not involve PKC or caldesmon. Interestingly, inhibition of MLC kinase (MLCK) and PKC significantly increased MAP kinase phosphorylation suggesting that MLCK and PKC may directly or indirectly inhibit MAP kinase activity during prolonged contractions induced by Bay K8544.
Kochupurackal P Mohanakumar - One of the best experts on this subject based on the ideXlab platform.
-
calcium channel agonist Bay K8644 causes an immediate increase in the striatal 1 methyl 4 phenylpyridinium level following systemic administration of the dopaminergic neurotoxin 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine in balb c mice
Neuroscience Letters, 2003Co-Authors: Supriti Samantaray, Kochupurackal P MohanakumarAbstract:In vivo formation of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum, and dopaminergic neurotoxicity following systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the presence and absence of calcium channel agonist (+/-)-Bay K8644 were analyzed in Balb/c mice. We used HPLC-photodiode array detection, HPLC-electrochemical detection and spectrofluorimetric procedures to measure striatal MPP(+) and dopamine (DA) and for the assay of monoamine oxidase-B (MAO-B) activity, respectively. Systemic administration of (+/-)-Bay K8644 resulted in a significant increase in striatal MAO-B activity. An MPTP-induced decrease in striatal MAO-B activity was attenuated by pre-treatment with (+/-)-Bay K8644 initially, but not on the 3rd day. MPP(+) formation in the striatum following systemic administration of MPTP was significantly increased by the pre-treatment of the agonist initially (30 min), but was not different afterwards (at 60 and 90 min). Nevertheless, the total MPP(+) formed over a 90 min period was found to be comparable. (+/-)-Bay K8644 administration prior to MPTP failed to influence the MPTP-induced striatal DA depletion on the 3rd day. While the transient effect of (+/-)-Bay K8644 on striatal MAO-B is reflected as an immediate increase in the levels of MPP(+) in the striatum, it failed to affect MPTP-induced DA neurotoxicity in Balb/c mice.
-
calcium channel agonist Bay K8644 causes a transient increase in striatal monoamine oxidase activity in balb c mice
Neuroscience Letters, 2003Co-Authors: Supriti Samantaray, Goutam Chandra, Kochupurackal P MohanakumarAbstract:Abstract We investigated in vivo effects of the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl) phenyl] pyridine-3-carboxylic acid ((±)-Bay K8644) on mitochondrial monoamine oxidase (MAO) activity and striatal dopamine (DA) content employing fluorimetric and HPLC-electrochemical procedures, respectively. (±)-Bay K8644 administration resulted in visible behavioral dysfunctions in mice. A reversible dose-independent inhibition of striatal DA levels and a significant increase in the brain mitochondrial MAO-A and -B activities were observed in animals treated with the calcium agonist. A positive relationship between the rise in the enzyme activity and decrease in DA content in (±)-Bay K8644 treated animals indicates a direct, but transient effect of this channel activator on DA metabolism, which may be related to acute behavioral syndromes exhibited following administration of the drug. Moreover, a direct involvement of L-type dihydropyridine sensitive calcium channels is indicated in this action, since nicardipine could effectively attenuate (±)-Bay K8644-induced behavioral aberrations, or block the striatal DA depletion and the increase in MAO activity. The present results have far-reaching implications in neuropharmacological research, where co-treatment of calcium channel drugs and MAO inhibitors are warranted.
Michael I Kotlikoff - One of the best experts on this subject based on the ideXlab platform.
-
voltage window for sustained elevation of cytosolic calcium in smooth muscle cells
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Bernd K Fleischmann, Richard K Murray, Michael I KotlikoffAbstract:Abstract Action potentials activate voltage-dependent calcium channels and attendant increases in cytosolic calcium concentration ([Ca2+]i) in many excitable cells. The role of these channels in the regulation of [Ca2+]i in nonspiking cells that do not depolarize to membrane potentials sufficient to activate a substantial fraction of the available current is less clear. Measurements of the peak activation and steady-state inactivation of L-type calcium currents have predicted the existence of a noninactivating current window over a voltage range where channel inactivation is incomplete. The degree to which such small currents might regulate [Ca2+]i, however, has not been established. Here we demonstrate a "calcium window" in nondialyzed, quiescent smooth muscle cells over a small voltage range near the resting membrane potential. Sustained depolarizations in this voltage range, but not to more positive potentials, resulted in sustained rises in calcium, despite the fact that macroscopic inward currents were < 2 pA. The calcium window corresponded well with the predicted window current determined under the same conditions; the peak of the calcium window occurred at -30 mV, with steady-state rises in [Ca2+]i in some cells at -50 mV. Steady-state rises in [Ca2+]i following depolarization were completely blocked by nisoldipine and were augmented and shifted to more negative potentials by Bay K8644. Voltage-dependent calcium channels thus regulate steady-state calcium levels in nonspiking cells over a voltage range where macroscopic currents are only barely detectable. This voltage range is bounded at negative potentials by calcium channel activation and at more positive potentials by channel inactivation.
Patrick M Lippiello - One of the best experts on this subject based on the ideXlab platform.
-
modulation of nicotine evoked 3h dopamine release from rat striatal synaptosomes by voltage sensitive calcium channel ligands
Biochemical Pharmacology, 1996Co-Authors: Richard J Prince, Kay G Fernandes, Joanna C Gregory, Ian D Martyn, Patrick M LippielloAbstract:Abstract The calcium channel subtypes mediating nicotine-evoked [ 3 H]dopamine release from rat striatal synaptosomes were probed with L-, N-, and P-type calcium channel ligands. Responses to nicotine were blocked by the peptides ω-conotoxin GVIA and ω-agatoxin IVA. The affinity constants for these compounds were consistent with their actions at N- and P-type channels, respectively. Together, these channels mediate at least 90% of the calcium-dependent response to nicotine. The L-type antagonists nifedipine, verapamil, and nicardipine were also effective blockers of nicotine-evoked release with maximal effects of 80–100% inhibition. However, these effects occurred at concentrations 2–3 orders of magnitude higher than those necessary to block L-type channels. Moreover, Bay K8644, an L-type agonist, also blocked nicotine-evoked release. Together, these findings argue strongly against the involvement of L-type channels. biochem pharmacol 52;4:613–618, 1996.
Ivan Zahradnik - One of the best experts on this subject based on the ideXlab platform.
-
competitive and cooperative effects of Bay K8644 on the l type calcium channel current inhibition by calcium channel antagonists
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Alexandra Zahradnikova, Igor Minarovic, Ivan ZahradnikAbstract:Phenylalkylamines, benzothiazepines, and dihydropyridines bind noncompetitively to the L-type calcium channel. The molecular mechanisms of this interaction were investigated in enzymatically isolated rat ventricular myocytes using the whole-cell patch-clamp technique. When applied alone, felodipine, verapamil, and diltiazem inhibited the L-type calcium current with values of inhibitory constant ( K B ) of 11, 246, and 512 nM, respectively, whereas 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-[trifluoromethyl]phenyl)-3-pyridine carboxylic acid methyl ester (Bay K8644) activated I Ca with activation constant ( K A ) of 33 nM. Maximal activation of I Ca by 300 nM Bay K8644 strongly reduced the inhibitory potency of felodipine (apparent K B of 165 nM), significantly reduced the inhibitory potency of verapamil (apparent K B of 737 nM), but significantly increased the inhibitory potency of diltiazem (apparent K B of 310 nM). In terms of a new pseudoequilibrium two-drug binding model, the interaction between the dihydropyridine agonist Bay K8644 and the antagonist felodipine was found purely competitive. The interaction between Bay K8644 and verapamil or diltiazem was found noncompetitive, and it could be described only by inclusion of a negative interaction factor ν = –0.60 for verapamil and a positive interaction factor ν = +0.24 for diltiazem. These results suggest that at physiological membrane potentials, the L-type calcium channel cannot be simultaneously occupied by a dihydropyridine agonist and antagonist, whereas it can simultaneously bind a dihydropyridine agonist and a nondihydropyridine antagonist. Generally, the effects of the drugs on the L-type calcium channel support a concept of a channel domain responsible for binding of calcium channel antagonists and agonists changing dynamically with the membrane voltage and occupancy of individual binding sites.
