Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 357, Issue 2, pp 159–168

Peripheral versus central potencies of N-type voltage-sensitive calcium channel blockers

  • Y.-X. Wang
  • S. Bezprozvannaya
  • S. S. Bowersox
  • L. Nadasdi
  • G. Miljanich
  • G. Mezo
  • D. Silva
  • K. Tarczy-Hornoch
  • R. R. Luther
Original article

DOI: 10.1007/PL00005150

Cite this article as:
Wang, Y., Bezprozvannaya, S., Bowersox, S. et al. Naunyn-Schmiedeberg's Arch Pharmacol (1998) 357: 159. doi:10.1007/PL00005150

Abstract

The ability of a series of synthetic analogues of ω-conopeptides MVIIA (SNX-111) and TVIA (SNX-185) to prevent electrically-evoked norepinephrine release from rat tail artery and hippocampal slice preparations was determined in an effort to identify voltage-sensitive calcium channel (VSCC) blockers that selectively target N-type VSCCs in central nervous system tissue. Electrical field stimulation (3 Hz, 1 ms in duration, 80 V for 1 min) caused a high and consistent tritium outflow from rat tail artery and hippocampal slice preparations preloaded with [3H]-norepinephrine. All conopeptides, chosen for their selective affinities for high-affinity SNX-111 binding sites (i.e., N-type VSCCs) over high-affinity ω-conopeptides MVIIC (SNX-230) binding sites (i.e., P/Q-type VSCCs), produced a concentration-dependent inhibition of calcium dependent electrically-evoked tritium outflow from both tail arteries and hippocampal slices; IC50s ranged from 1.2 nM to 1.2 μM. Blocking potencies (IC50s) in the tail artery assay were significantly correlated with those measured in the hippocampal slice preparation (r = 0.91, P = 0.00000012). There was a significant correlation between IC50s for blockade of hippocampal norepinephrine release and the inhibition of high-affinity [125I]-SNX-111 binding in rat brain synaptosomes (r = 0.76, P = 0.00028). Blockade of hippocampal norepinephrine release was not significantly correlated with the inhibition of high-affinity SNX-230 binding (r = 0.46, P = 0.056). Maximum inhibition of tritium outflow in the tail artery assay was 22 ± 1.4% of control, approximating the value (20.9 ± 16.0% of control) obtained in the absence of extracellular Ca2+. In contrast, the maximum inhibition of tritium release from hippocampal slices was 36.8 ± 2.5% of control (P < 0.05, compared to that of the tail artery assay). These results suggest that (1) N-type VSCCs alone mediate low frequency electrical stimulation-evoked neurotransmitter release from peripheral sympathetic efferents (tail artery) while both N-type and non-N type(s) mediate neurotransmitter release from CNS neurons (hippocampus); and (2) analogues of ω-conopeptides MVIIA and TVIA do not differentiate between N-type VSCCs mediating norepinephrine release from central and peripheral neural tissues.

Key words Calcium channelsω-conotoxinConopeptideN-type calcium channelsTransmitterreleaseSNX-111Norepinephrine

Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • Y.-X. Wang
    • 1
  • S. Bezprozvannaya
    • 2
  • S. S. Bowersox
    • 1
  • L. Nadasdi
    • 3
  • G. Miljanich
    • 2
  • G. Mezo
    • 3
  • D. Silva
    • 3
  • K. Tarczy-Hornoch
    • 2
  • R. R. Luther
    • 1
  1. 1.Departments of Pharmacology, Neurex Corporation, 3760 Haven Avenue, Menlo Park, CA 94025, USAUS
  2. 2.Department of Biochemistry, Neurex Corporation, 3760 Haven Avenue, Menlo Park, CA 94025, USAUS
  3. 3.Department of Synthetic Chemistry, Neurex Corporation, 3760 Haven Avenue, Menlo Park, CA 94025, USAUS