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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 343, Issue 4, pp 405–410 | Cite as

Mechanisms underlying the slow onset of action of a new dihydropyridine, NZ-105, on a cultured smooth muscle cell line

  • Tetsutaro Tamura
  • Akihiro Saigusa
  • Shinichiro Kokubun
Article

Summary

The inhibitory effect of a new dihydropyridine derivative, (±)-2-[benzyl(phenyl)amino]ethyl-1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride (NZ-105), on whole cell Ca2+ current (ICa) in cultured vascular smooth muscle cells was investigated with the patch clamp technique. NZ-105 blocked ICa in a concentration-dependent manner when the command pulse ranged from +10 mV to −50 mV. The inhibitory effect of NZ-105 appeared at concentrations higher than 10 μmol/l and it blocked ICa completely at a concentration of 1 nmol/l. The concentration which produced the half-maximal inhibitory effect was estimated to be around 20 μmol/l. NZ-105 (500 pmol/l) completely blocked ICa elicited by depolarization to + 10 mV at a holding potential of −40 mV, whereas it blocked ICa by only 67% at a holding potential of −90 mV. NZ-105 (100 μmol/l) shifted the steady-state inactivation curve by 40 mV to more negative potentials without affecting its slope factor. The blocking time constant of 500 μmol/l NZ-105 was 57.6 + 9.9 s at a holding potential of −70 mV. These results indicate that NZ-105 has characteristics typical of dihydropyridines and binds to Ca2+ channels of vascular smooth muscle cells with a high affinity. They also suggested that the slow onset of its action is due to the slow binding of the drug to Ca2+ channels.

Key words

Ca2+ channel Ca2+ channel blocker Ca2+ current Slow onset of drug action Smooth muscle cell 

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References

  1. Belles B, Hescheler J, Trautwein W, Blomgren K, Kaulsson JO (1988) A possible physiological role of the Ca-dependent protease calpain and its inhibitor calpastatin on the Ca current in guinea pig myocytes. Pflügers Arch 412:554–556CrossRefGoogle Scholar
  2. Fish RD, Sperti G, Colucci AS, Clapham DE (1988) Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line. Circ Res 62:1049–1054CrossRefGoogle Scholar
  3. Hamill OP, Marty A, Neher E, Sackmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflügers Arch 391:85–100CrossRefGoogle Scholar
  4. Hering S, Beech DJ, Bolton TB (1987) A simple method of fast extracellular solution exchange for the study of whole-cell or single channel currents using patch-clamp technique. Pflügers Arch 410:335–337CrossRefGoogle Scholar
  5. Kamp TJ, Sanguinetti MC, Miller RJ (1989) Voltage- and use-dependent modulation of cardiac calcium channels by dihydropyridine (+)-202–791. Circ Res 64:338–351CrossRefGoogle Scholar
  6. Kimes BW, Brandt BL (1976) Characterization of two putative smooth muscle cell lines from rat thoracic aorta. Exp Cell Res 98:349–366CrossRefGoogle Scholar
  7. Kitamura K, Inoue Y, Inoue R, Ohya Y, Okabe K, Kuriyama H (1989) Properties of the inward currents and their regulating agents in smooth muscle cells. Gen Physiol Biophys 8:289–312PubMedGoogle Scholar
  8. Kokubun S, Prod'hom B, Becker C, Porzig H, Reuter H (1986) Studies on Ca channels in intact cardiac cells: voltage-dependent effects and cooperative interactions of dihydropyridine enantiomers. Mol Pharmacol 30:571–584PubMedGoogle Scholar
  9. Masuda Y, Yamashita T, Tekeguchi M, Iwama T, Sakai T, Hibi M, Tanaka S, Shigenobu K, Kasuya Y (1989) Effects of NZ-105 on vascular smooth muscles and cardiac muscles. Jpn J Pharmacol 49:291 PGoogle Scholar
  10. Masuda Y, Takeguchi M, Arakawa C, Sakai T, Hibi M, Tanaka S, Shigenobu K, Kasuya Y (1990) Antihypertensive and diuretic effects of NZ-105, a novel dihydropyridine derivative. Arch Int Pharmacodyn Ther 304:247–264PubMedGoogle Scholar
  11. McCarthy RT, Cohen CJ (1989) Nimodipine block of calcium channels in rat vascular smooth muscle cell lines. Exceptionally high-affinity binding in A7r5 and A10 cells. J Gen Physiol 94:669–692CrossRefGoogle Scholar
  12. Meguro K, Aizawa M, Sohda T, Kawamatsu Y, Nagaoka A (1985) New 1,4-dihydropyridine derivatives with potent and long-lasting hypotensive effects. Chem Pharm Bull 33:3789–3797CrossRefGoogle Scholar
  13. Ohya Y, Kitamura K, Kuriyama H (1987) Modulation of ionic currents in smooth muscle balls of the rabbit intestine by intracellularly perfused ATP and cyclic AMP. Pflügers Arch 408:465–473CrossRefGoogle Scholar
  14. Okabe K, Terada K, Kitamura K, Kuriyama H (1987) Selective and long-lasting inhibitory actions of the dihydropyridine derivative, CV-4093, on calcium currents in smooth muscle cells of the rabbit pulmonary artery. J Pharmacol Exp Ther 243:703–710PubMedGoogle Scholar
  15. Ruegg UT, Doyle VM, Zuber J, Hof RP (1985) A smooth muscle cell line suitable for the study of voltage sensitive calcium channels. Biochem Biophy Res Commun 130:447–453CrossRefGoogle Scholar
  16. Soejima M, Kokubun S (1988) Single anion-selective channel and its ion selectivity in the vascular smooth muscle cell. Pflügers Arch 411:304–311CrossRefGoogle Scholar
  17. Yamashita T, Masuda Y, Sakai T, Tanaka S, Kasuya Y (1990) Effects of NZ-105, a novel 1,4-dihydropyridine calcium antagonist, on receptor binding and 45Ca-uptake. Jpn J Pharmacol 52:345PCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Tetsutaro Tamura
    • 1
  • Akihiro Saigusa
    • 1
  • Shinichiro Kokubun
    • 1
  1. 1.Department of PhysiologyJikei University, School of MedicineMinato-ku, TokyoJapan

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