The Experts below are selected from a list of 897 Experts worldwide ranked by ideXlab platform

Maria Spatz - One of the best experts on this subject based on the ideXlab platform.

  • Endothelin 1 stimulates Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport through ETA receptors and protein kinase C-dependent pathway in cerebral Capillary Endothelium.
    Journal of neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • endothelin 1 stimulates na k atpase and na k cl cotransport through eta receptors and protein kinase c dependent pathway in cerebral Capillary Endothelium
    Journal of Neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • human Brain Capillary Endothelium 2 arachidonoglycerol endocannabinoid interacts with endothelin 1
    Circulation Research, 2000
    Co-Authors: Ye Chen, Richard M. Mccarron, Yukoh Ohara, J Bembry, Nabil A Azzam, Frederick Lenz, Esther Shohami, Raphael Mechoulam, Maria Spatz
    Abstract:

    Abstract—In Brain, the regulatory mechanism of the endothelial reactivity to nitric oxide and endothelin-1 may involve Ca2+, cytoskeleton, and vasodilator-stimulated phosphoprotein changes mediated by the cGMP/cGMP kinase system.1 Endothelium of human Brain capillaries or microvessels is used to examine the interplay of endothelin-1 with the putative vasorelaxant 2-arachidonoyl glycerol, an endogenous cannabimimetic derivative of arachidonic acid. This study demonstrates that 2-arachidonoyl glycerol counteracts Ca2+ mobilization and cytoskeleton rearrangement induced by endothelin-1. This event is independent of nitric oxide, cyclooxygenase, and lipoxygenase and is mediated in part by cannabimimetic CB1 receptor, G protein, phosphoinositol signal transduction pathway, and Ca2+-activated K+ channels. The induced rearrangements of cellular cytoskeleton (actin or vimentin) are partly prevented by inhibition of protein kinase C or high levels of potassium chloride. The 2-arachidonoyl glycerol–induced phosphor...

  • human Brain Capillary Endothelium modulation of k efflux and k ca2 uptake by endothelin
    Neurochemical Research, 1998
    Co-Authors: Maria Spatz, Nobutoshi Kawai, J Bembry, Frederick Lenz, Richard M. Mccarron
    Abstract:

    This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured Endothelium derived from capillaries of human Brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl− cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ETA but not ETB receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ETA receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC.

  • Endothelins stimulate sodium uptake into rat Brain Capillary endothelial cells through endothelin A-like receptors
    Neuroscience letters, 1995
    Co-Authors: Nobutoshi Kawai, Richard M. Mccarron, Maria Spatz
    Abstract:

    Abstract The effect of endothelins (ETs) on sodium/hydrogen (Na + /H + ) antiport system was examined in cultured rat Brain Capillary Endothelium (RBEC). ET 1, ET 2, and ET -3 stimulated Na + upptake into RBEC with similar half-maximal stimulation (EC 50 ) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na + /H + antiport inhibitor, N -(ethyl- N -isopropyl)-amiloride (EIPA). The selective endothelin A (ET A ) receptor-antagonist (cyclo- d -Trp- d -Asp-Pro- d -Val-Leu (BQ123)), but not endothelin B (ET B ) receptor-antagonists ((Cys 11 , Cys 15 )-ET l (IRL1038) or N-cis -2,6-dimethylpiperidinocarbonyl- l -γMeLeu- d -Trp(000Me)- d -Nle-ONa (BQ788)), inhibited both ET-1- and ET-3-stimulated Na + uptake, indicating ET A -receptor mediation. The protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA)) failed to stimulate Na + uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1-stimulated Na + uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of the Na + /H + antiport system is linked to a CaM-dependent and PKC-independent pathway.

William M. Pardridge - One of the best experts on this subject based on the ideXlab platform.

  • Drug transport across the blood-Brain barrier.
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2012
    Co-Authors: William M. Pardridge
    Abstract:

    The blood-Brain barrier (BBB) prevents the Brain uptake of most pharmaceuticals. This property arises from the epithelial-like tight junctions within the Brain Capillary Endothelium. The BBB is anatomically and functionally distinct from the blood-cerebrospinal fluid barrier at the choroid plexus. Certain small molecule drugs may cross the BBB via lipid-mediated free diffusion, providing the drug has a molecular weight

  • Drug targeting to the Brain
    Pharmaceutical Research, 2007
    Co-Authors: William M. Pardridge
    Abstract:

    The goal of Brain drug targeting technology is the delivery of therapeutics across the blood-Brain barrier (BBB), including the human BBB. This is accomplished by re-engineering pharmaceuticals to cross the BBB via specific endogenous transporters localized within the Brain Capillary Endothelium. Certain endogenous peptides, such as insulin or transferrin, undergo receptor-mediated transport (RMT) across the BBB in vivo. In addition, peptidomimetic monoclonal antibodies (MAb) may also cross the BBB via RMT on the endogenous transporters. The MAb may be used as a molecular Trojan horse to ferry across the BBB large molecule pharmaceuticals, including recombinant proteins, antibodies, RNA interference drugs, or non-viral gene medicines. Fusion proteins of the molecular Trojan horse and either neurotrophins or single chain Fv antibodies have been genetically engineered. The fusion proteins retain bi-functional properties, and both bind the BBB receptor, to trigger transport into Brain, and bind the cognate receptor inside Brain to induce the pharmacologic effect. Trojan horse liposome technology enables the Brain targeting of non-viral plasmid DNA. Molecular Trojan horses may be formulated with fusion protein technology, avidin-biotin technology, or Trojan horse liposomes to target to Brain virtually any large molecule pharmaceutical.

  • Molecular biology of the blood-Brain barrier
    Molecular Biotechnology, 2005
    Co-Authors: William M. Pardridge
    Abstract:

    Molecular biological investigations into the Brain Capillary Endothelium and microvasculature, which forms the blood-Brain barrier (BBB) in vivo, can provide the platform for the discovery and the molecular cloning of BBB-specific genes. Novel BBB genes can be discovered with either a genomics-based approach such as subtractive suppressive hybridization, or a proteomics approach using subtractive antibody expression cloning. BBB-specific genes are disproportionately transporter genes encoding either for carrier-mediated transporters, active efflux transporters, or receptor-mediated transporters. The discovery of new BBB transporters can lead to the development of new approaches to Brain drug delivery using endogenous Brain endothelial transporters.

  • The blood-Brain barrier: Bottleneck in Brain drug development
    NeuroRx, 2005
    Co-Authors: William M. Pardridge
    Abstract:

    The blood-Brain barrier (BBB) is formed by the Brain Capillary Endothelium and excludes from the Brain ∼100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the Brain Capillary Endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.

  • Blood-Brain barrier genomics and the use of endogenous transporters to cause drug penetration into the Brain.
    Current opinion in drug discovery & development, 2003
    Co-Authors: William M. Pardridge
    Abstract:

    Blood-Brain barrier (BBB) genomics enables the rapid discovery of novel transporters that are expressed at the Brain Capillary Endothelium. The BBB transporters are potential conduits to the Brain that therapeutic drugs may use to gain passage across the BBB. Due to the small volume of Brain occupied by the Endothelium (10(-3) parts of the Brain), it is necessary to build a BBB genomics program that is separate from a whole-Brain genomics analysis. It is estimated that approximately 15% of all genes selectively expressed at the BBB encode for transporter proteins, and that only approximately 50% of BBB transporters are currently known. The development of a BBB genomics program and the discovery of novel BBB transporters could lead to the invention of new approaches to solving the BBB drug delivery problem.

Richard M. Mccarron - One of the best experts on this subject based on the ideXlab platform.

  • Endothelin 1 stimulates Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport through ETA receptors and protein kinase C-dependent pathway in cerebral Capillary Endothelium.
    Journal of neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • endothelin 1 stimulates na k atpase and na k cl cotransport through eta receptors and protein kinase c dependent pathway in cerebral Capillary Endothelium
    Journal of Neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • human Brain Capillary Endothelium 2 arachidonoglycerol endocannabinoid interacts with endothelin 1
    Circulation Research, 2000
    Co-Authors: Ye Chen, Richard M. Mccarron, Yukoh Ohara, J Bembry, Nabil A Azzam, Frederick Lenz, Esther Shohami, Raphael Mechoulam, Maria Spatz
    Abstract:

    Abstract—In Brain, the regulatory mechanism of the endothelial reactivity to nitric oxide and endothelin-1 may involve Ca2+, cytoskeleton, and vasodilator-stimulated phosphoprotein changes mediated by the cGMP/cGMP kinase system.1 Endothelium of human Brain capillaries or microvessels is used to examine the interplay of endothelin-1 with the putative vasorelaxant 2-arachidonoyl glycerol, an endogenous cannabimimetic derivative of arachidonic acid. This study demonstrates that 2-arachidonoyl glycerol counteracts Ca2+ mobilization and cytoskeleton rearrangement induced by endothelin-1. This event is independent of nitric oxide, cyclooxygenase, and lipoxygenase and is mediated in part by cannabimimetic CB1 receptor, G protein, phosphoinositol signal transduction pathway, and Ca2+-activated K+ channels. The induced rearrangements of cellular cytoskeleton (actin or vimentin) are partly prevented by inhibition of protein kinase C or high levels of potassium chloride. The 2-arachidonoyl glycerol–induced phosphor...

  • human Brain Capillary Endothelium modulation of k efflux and k ca2 uptake by endothelin
    Neurochemical Research, 1998
    Co-Authors: Maria Spatz, Nobutoshi Kawai, J Bembry, Frederick Lenz, Richard M. Mccarron
    Abstract:

    This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured Endothelium derived from capillaries of human Brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl− cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ETA but not ETB receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ETA receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC.

  • Endothelins stimulate sodium uptake into rat Brain Capillary endothelial cells through endothelin A-like receptors
    Neuroscience letters, 1995
    Co-Authors: Nobutoshi Kawai, Richard M. Mccarron, Maria Spatz
    Abstract:

    Abstract The effect of endothelins (ETs) on sodium/hydrogen (Na + /H + ) antiport system was examined in cultured rat Brain Capillary Endothelium (RBEC). ET 1, ET 2, and ET -3 stimulated Na + upptake into RBEC with similar half-maximal stimulation (EC 50 ) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na + /H + antiport inhibitor, N -(ethyl- N -isopropyl)-amiloride (EIPA). The selective endothelin A (ET A ) receptor-antagonist (cyclo- d -Trp- d -Asp-Pro- d -Val-Leu (BQ123)), but not endothelin B (ET B ) receptor-antagonists ((Cys 11 , Cys 15 )-ET l (IRL1038) or N-cis -2,6-dimethylpiperidinocarbonyl- l -γMeLeu- d -Trp(000Me)- d -Nle-ONa (BQ788)), inhibited both ET-1- and ET-3-stimulated Na + uptake, indicating ET A -receptor mediation. The protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA)) failed to stimulate Na + uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1-stimulated Na + uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of the Na + /H + antiport system is linked to a CaM-dependent and PKC-independent pathway.

Nobutoshi Kawai - One of the best experts on this subject based on the ideXlab platform.

  • Endothelin 1 stimulates Na+,K(+)-ATPase and Na(+)-K(+)-Cl- cotransport through ETA receptors and protein kinase C-dependent pathway in cerebral Capillary Endothelium.
    Journal of neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • endothelin 1 stimulates na k atpase and na k cl cotransport through eta receptors and protein kinase c dependent pathway in cerebral Capillary Endothelium
    Journal of Neurochemistry, 2002
    Co-Authors: Nobutoshi Kawai, Toshifumi Yamamoto, Hideko Yamamoto, Richard M. Mccarron, Maria Spatz
    Abstract:

    The effect of endothelins (ET-1 and ET-3) on 86 Rb + uptake as a measure of K + uptake was investigated in cultured rat Brain Capillary Endothelium. ET-1 or ET-3 dose-dependently enhanced K + uptake (EC 50 = 0.60 ± 0.15 and 21.5 ± 4.1 nM, respectively), which was inhibited by the selective ET A receptor antagonist BQ 123 (cyclo-D-Trp-D-Asp-Pro-D-Val-Leu). Neither the selective ET B agonists IRL 1620 [N-succinyl-(Glu 9 ,-Ala 11,15 )-ET-1] and sarafotoxin S6c, nor the ET B receptor antagonist IRL 1038 [(Cys 11 ,Cys 15 )-ET-1] had any effect on K + uptake. Ouabain (inhibitor of Na + ,K + -ATPase) and bumetanide (inhibitor of Na + -K + -Cl - cotransport) reduced (up to 40% and up to 70%, respectively) the ET-1-stimulated K + uptake. Complete inhibition was seen with both agents. Phorbol 12-myristate 13-acetate (PMA), activator of protein kinase C (PKC), stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport. ET-1-but not PMA-stimulated K + uptake was inhibited by 5-(N-ethyl-N-isopropyl)amiloride (inhibitor of Na + /H + exchange system), suggesting a linkage of Na + /H + exchange with ET-1-stimulated Na + ,K + -ATPase and Na + -K + -Cl - cotransport activity that is not mediated by PKC.

  • human Brain Capillary Endothelium modulation of k efflux and k ca2 uptake by endothelin
    Neurochemical Research, 1998
    Co-Authors: Maria Spatz, Nobutoshi Kawai, J Bembry, Frederick Lenz, Richard M. Mccarron
    Abstract:

    This report describes K+ efflux, K+ and Ca2+ uptake responses to endothelins (ET-1 and ET-3) in cultured Endothelium derived from capillaries of human Brain (HBEC). ET-1 dose dependently increased K+ efflux, K+ and Ca2+ uptake in these cells. ET-1 stimulated K+ efflux occurred prior to that of K+ uptake. ET-3 was ineffective. The main contributor to the ET-1 induced K+ uptake was ouabain but not bumetanide-sensitive (Na+-K+-ATPase and Na+-K+-Cl− cotransport activity, respectively). All tested paradigms of ET-1 effects in HBEC were inhibited by selective antagonist of ETA but not ETB receptors and inhibitors of phospholipase C and receptor-operated Ca2+ channels. Activation of protein kinase C (PKC) decreased whereas inhibition of PKC increased the ET-1 stimulated K+ efflux, K+ and Ca2+ uptake in HBEC. The results indicate that ET-1 affects the HBEC ionic transport systems through activation of ETA receptors linked to PLC and modulated by intracellular Ca2+ mobilization and PKC.

  • Endothelins stimulate sodium uptake into rat Brain Capillary endothelial cells through endothelin A-like receptors
    Neuroscience letters, 1995
    Co-Authors: Nobutoshi Kawai, Richard M. Mccarron, Maria Spatz
    Abstract:

    Abstract The effect of endothelins (ETs) on sodium/hydrogen (Na + /H + ) antiport system was examined in cultured rat Brain Capillary Endothelium (RBEC). ET 1, ET 2, and ET -3 stimulated Na + upptake into RBEC with similar half-maximal stimulation (EC 50 ) values (0.7, 0.6, and 1.1 nM, respectively). This reaction was inhibited by the Na + /H + antiport inhibitor, N -(ethyl- N -isopropyl)-amiloride (EIPA). The selective endothelin A (ET A ) receptor-antagonist (cyclo- d -Trp- d -Asp-Pro- d -Val-Leu (BQ123)), but not endothelin B (ET B ) receptor-antagonists ((Cys 11 , Cys 15 )-ET l (IRL1038) or N-cis -2,6-dimethylpiperidinocarbonyl- l -γMeLeu- d -Trp(000Me)- d -Nle-ONa (BQ788)), inhibited both ET-1- and ET-3-stimulated Na + uptake, indicating ET A -receptor mediation. The protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA)) failed to stimulate Na + uptake. The calcium-calmodulin (CaM) inhibitor (W7) reduced ET-1-stimulated Na + uptake by 50%, whereas the PKC inhibitor (staurosporine) had no effect, indicating that ET-1 stimulation of the Na + /H + antiport system is linked to a CaM-dependent and PKC-independent pathway.

Berislav V. Zlokovic - One of the best experts on this subject based on the ideXlab platform.

  • regulate transport of transferrin-bound and
    2016
    Co-Authors: Rashid Deane, Wei Zheng, Berislav V. Zlokovic
    Abstract:

    Brain Capillary Endothelium and choroid plexus epitheliu

  • Brain Capillary Endothelium and choroid plexus epithelium regulate transport of transferrin bound and free iron into the rat Brain
    Journal of Neurochemistry, 2004
    Co-Authors: Rashid Deane, Wei Zheng, Berislav V. Zlokovic
    Abstract:

    Iron transport into the CNS is still not completely understood. Using a Brain perfusion technique in rats, we have shown a significant Brain Capillary uptake of circulating transferrin (Tf)-bound and free 59Fe (1 nm) at rates of 136 +/- 26 and 182 +/- 23 microL/g/min, respectively, while their respective transport rates into Brain parenchyma were 1.68 +/- 0.56 and 1.52 +/- 0.48 microL/g/min. Regional Tf receptor density (Bmax) in Brain Endothelium determined with 125I-holo-Tf correlated well with 59Fe-Tf regional Brain uptake rates reflecting significant vascular association of iron. Tf-bound and free circulating 59Fe were sequestered by the choroid plexus and transported into the CSF at low rates of 0.17 +/- 0.01 and 0.09 +/- 0.02 microL/min/g, respectively, consistent with a 10-fold Brain-CSF concentration gradient for 59Fe, Tf-bound or free. We conclude that transport of circulating Tf-bound and free iron could be equally important for its delivery to the CNS. Moreover, data suggest that entry of Tf-bound and free iron into the CNS is determined by (i) its initial sequestration by Brain capillaries and choroid plexus, and (ii) subsequent controlled and slow release from vascular structures into Brain interstitial fluid and CSF.

  • Antithrombotic, procoagulant, and fibrinolytic mechanisms in cerebral circulation: implications for Brain injury and protection.
    Neurosurgical focus, 1997
    Co-Authors: Berislav V. Zlokovic
    Abstract:

    Maintaining a delicate balance among anticoagulant, procoagulant, and fibrinolytic pathways in the cerebral microcirculation is of major importance for normal cerebral blood flow. Under physiological conditions and in the absence of provocative stimuli, the anticoagulant and fibrinolytic pathways prevail over procoagulant mechanisms. Blood clotting is essential to minimize bleeding and to achieve hemostasis; however, excessive clotting contributes to thrombosis and may predispose the Brain to infarction and ischemic stroke. Conversely, excessive bleeding due to enhanced anticoagulatory and fibrinolytic mechanisms could predispose the Brain to hemorrhagic stroke. Recent studies in the author's laboratory indicate that Brain Capillary Endothelium in vivo produces thrombomodulin (TM), a key cofactor in the TM-protein C system that is of major biological significance to the antithrombotic properties of the blood-Brain barrier (BBB). The BBB Endothelium also expresses tissue plasminogen activator (tPA), a key ...

  • Blood—Brain Barrier Permeability to Peptides and Proteins
    Barriers and Fluids of the Eye and Brain, 1992
    Co-Authors: Berislav V. Zlokovic, J. Gordon Mccomb, Malcolm B. Segal, Hugh Davson
    Abstract:

    The neurons, glial cells, Brain extracellular fluid and cerebrospinal fluid are separated from the blood by the blood-Brain and blood-cerebrospinal fluid barriers (Davson, 1976). The blood-Brain barrier is well characterized morphologically as a complete and continuous cellular layer of the endothelial cells which are sealed by tight junctions (Brightman, 1977). Normal cell-to-cell communications between astrocytes, pericytes, endothelial cells and surrounding neuropil are essential for the expression of blood-Brain barrier phenomena and its homoeostatic mechanisms (Davson and Oldendorf, 1967; Brightman, 1989). Transport, enzymatic and receptor-mediated functions of the blood-Brain barrier and blood-cerebrospinal fluid barrier are highly developed, playing a central role in the regulation of the composition of Brain extracellular fluid and cerebrospinal fluid. The free movement of circulating hydrophilic substrates from blood to Brain extracellular and cerebrospinal fluids is markedly retarded, and it has been accepted that any molecule, above a limiting size, circulating in the blood may gain access to the Brain interstitial space only if there is a specific transport system for that molecule localized in the Brain Capillary Endothelium (Oldendorf, 1987; Betz and Goldstein, 1986; Pardridge, 1988).