Review of Nisoldipine Binding Studies

  • R. A. Janis
  • A. V. Shrikhande
  • R. Greguski
  • M. Pan
  • A. Scriabine
Conference paper

Summary

Nisoldipine exhibits very high affinity binding to smooth and cardiac muscle membranes. Calcium channels in isolated membranes probably exist in the inactivated state, and electrophysiological studies by Kass et al. [17] have shown that this state of the channel has the highest affinity for nisoldipine. Therefore, it is likely that binding studies allow us to examine the high affinity association of drug with inactivated calcium channels.

[3H] (±) nisoldipine exhibits one of the highest affinities of the Ca2+ antagonists that we have studied, and its rate of dissociation from cardiac membranes is extremely slow [24]. The binding of the racemic mixture of [3H]nisoldipine to cardiac membranes exhibits complex on and off rates [25]. These results are probably due to the presence of two radiolabelled isomers and also to the presence of high- and low- affinity binding sites.

We have now studied the binding of the enantiomer [3H](+)nisoldipine to rat and rabbit ventricular microsomes and to bovine aortic sarcolemma. This ligand exhibits the expected high affinity binding to cardiac and smooth muscle membranes (Kd = 0.04 nM at 25°C). Adler et al. [1] found a similar affinity using purified cardiac sarcolemma membranes from dog ventricle. The dissociation rate of [3H](+)nisoldipine did not exhibit two phases. At 25°C, the t1/2 for the dissociation of [3H](+)nisoldipine was 10 times that for [3H]nifedipine, in general agreement with the results obtained using the racemic mixture. The partitioning of nisoldipine into biological membranes is also much greater than that of nifedipine (Herbette, L. personal communication), and this should also contribute to its greater apparent affinity of binding. These factors are likely to contribute to the long duration of action of nisoldipine.

Keywords

Entropy Enthalpy Rubber Prolactin Verapamil 

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References

  1. 1.
    Adler PN, Yoshida A, Messineo FC (1986) Phenylakylamine receptor sites in purified canine sarcolemma appear to be decreased in number by dihydropyridines. J Mol Cell Cardiol 18 (suppl 3): 8CrossRefGoogle Scholar
  2. 2.
    Bellemann P, Schade A, Towart R (1983) Dihydropyridine receptor in rat brain labeled with[3H]nimodipine. Proc Natl Acad Sci USA 80: 2356–2360PubMedCrossRefGoogle Scholar
  3. 3.
    Bolger GT, Gengo P, Klockowski R, Luchowski E, Siegel H, Janis RA, Triggle AM, Triggle DJ (1983) Characterization of binding ofthe Ca2+ channel antagonist, [3H]nitrendipine, to guinea pigileal smooth muscle. J Pharmacol Exp Ther 225: 291–309PubMedGoogle Scholar
  4. 4.
    Cohen C, McCarthy RT (1986) Ca2+ channels in clonal vascular smooth muscle. In: Smooth Muscle Function Symposium Proceedings. Banff, Alberta, Canada pp 56–57Google Scholar
  5. 5.
    Enyeart JJ, Aizawa T, Hinkle PM (1985) Dihydropyridine Ca2+ antagonists: Potent inhibitors of secretion from normal and transformed pituitary cells. Am J Physiol 248:C510-519PubMedGoogle Scholar
  6. 6.
    Freedman SB, Miller RJ (1984) Effects of nitrendipine on voltage sensitive calcium channels in brain and neuronal cultured cells. In: Scriabine A (ed) Nitrendipine. Urban & Schwarzenberg Baltimore, MD, pp 79–90Google Scholar
  7. 7.
    Godfraind T, Wibo M (1985) Subcellular localization of [3H]nitrendipine binding sites in guinea pig ileal smooth muscle. Br J Pharmacol 85: 335–340PubMedGoogle Scholar
  8. 8.
    Gould RJ, Murphy KMM, Snyder SH (1982) [3H]Nitrendipine-labeled calcium channels discriminate inorganic calcium agonists and antagonists. Proc Natl Acad Sci USA 79: 3656–3660PubMedCrossRefGoogle Scholar
  9. 9.
    Gould RJ, Murphy KMM, Snyder SH (1984) Tissue heterogeneity of calcium channel antagonist binding sites labeled by PH]nitrendipine. Mol Pharmacol 25: 235–241PubMedGoogle Scholar
  10. 10.
    Itoh T, Kanmura Y, Kuriyama H, Suzuki H (1984) Nisoldipine-induced relaxation in intact and skinned smooth muscles of rabbit coronary arteries. Br J Pharmacol 83: 243–258PubMedGoogle Scholar
  11. 11.
    Janis RA, Bellemann P, Sarmiento JG, Triggle DJ (1985) The dihydropyridine receptors. In: Fleckenstein A, van Breemen C, Gross R, Hoffmeister F (eds) Cardiovascular Effects of Dihydropyridine-type Calcium Antagonists and Agonists. Bayer-Symposium IX, Springer, Berlin Heidelberg, pp 140–155Google Scholar
  12. 12.
    Janis RA, Krol GJ, Noe AJ, Pan M (1983) Radioreceptor and high-performance liquid chromatographic assays for the calcium channel antagonist nitrendipine in serum. J Clin Pharmacal 23: 266–273Google Scholar
  13. 13.
    Janis RA, Sarmiento JG, Maurer SC, Bolger GT, Triggle DJ (1984) Characteristics ofthe binding of [3H]nitrendipine to rabbit ventricular membranes. Modification by other Ca2+ channel antagonists and by a Ca2+ channel agonist, BAY K 8644. J Pharmacal Exp Ther 231: 8–15Google Scholar
  14. 14.
    Janis RA, Silver PJ, Triggle DJ (1987) Drug action and celluar Ca2+ regulation. Advances in Drug Research 16: 309–589Google Scholar
  15. 15.
    Jong JW DE, Huizer T (1984) Nisoldipine has a strong affinity for silicon rubber tubing. J Mol Cell Cardio1 16 (Supp13): 18Google Scholar
  16. 16.
    Kass RS (1982) Nisoldipine- a new, more selective calcium current blocker in cardiac purkinjefibers. J Pharmacal Exp Ther 223: 446–456Google Scholar
  17. 17.
    Kass RS, Sanguinetti MC, Bennett PB, Coplin BE, Krafte DS (1985) Voltage-dependent modulation of cardiac Ca-channels by dihydropyridines. In: Fleckenstein A, van Breemen C, Gross R, Hoffmeister F (eds) Cardiovascular effects of dihydropyridine-type calcium antagonists and agonists. Springer, Berlin Heidelberg New York, pp 198–215Google Scholar
  18. 18.
    Kazda S, Towart R (1982) The duration of action of calcium antagonists in vitro: a comparison of nifedipine and nisoldipine (BAY K 5552). Br J Pharmacal 76: 255PGoogle Scholar
  19. 19.
    Kazda S, Garth off B, Meyer H, Schlossmann K, Stoepel K (1980) Pharmacology of a new calcium antagonistic compound, isobutyl methyl 1 ,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate (nisoldipine, BAY K 5552). Arzneim Forsch 30: 2144–2162Google Scholar
  20. 20.
    Kazda S, Garthoff B, Rämsch K-D, Schülster G (1983) Nisoldipine. In: Scriabine A (ed) New Drugs Annual: Cardiovascular Drugs Vol 1 Raven Press New York, pp 243–258Google Scholar
  21. 21.
    Kazda S, Garth off B, Knorr A (1985) Interference of the calcium antagonist nisoldipine with the abnormal response of vessels from hypertensive rats to α-adrenergic stimulation. J Cardiovasc Pharmacal 7 (Suppi6):S61-S65CrossRefGoogle Scholar
  22. 22.
    Knorr A (1982) A new calcium antagonist. Antihypertensive effect in conscious, unrestrained renal hypertensive dogs. Arch Int Pharmacodyn Ther 260: 141–150PubMedGoogle Scholar
  23. 23.
    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
  24. 24.
    Pan M, Janis RA, Triggle DJ (1983) Comparison of the equilibrium and kinetic binding characteristics oftritiated Ca2+ channel inhibitors, nisoldipine, nimodipine, nitrendipine and nifedipine. Pharmacologist 25: 202Google Scholar
  25. 25.
    Pan M, Janis RA, Triggle DJ (1984) [3H]Nisoldipine binding to rat ventricular membranes: Binding characteristics and modification by the calcium channel agonist, Bay K 8644 Fed Proc 43: 448Google Scholar
  26. 26.
    Quirion R (1985) Characterization of binding sites for two classes of calcium channel antagonists in human forebrain. Eur J Pharmaco1 117: 139–142CrossRefGoogle Scholar
  27. 27.
    Rampe D, Luchowski E, Rutledge A, Janis RA, Triggle DJ (1987) Comparative aspects of [3H]1,4-dihydropyridine Ca2+ channel antagonist and activator binding to neuronal and muscle membranes. Can J Physiol Pharmaco1 65: 1452–1460CrossRefGoogle Scholar
  28. 28.
    Rios E, Brum G (1987) Involvement of 1,4-dihydropyridine receptors in excitation-contraction coupling in skeletal muscle. Nature (Lond.) 325: 717–720CrossRefGoogle Scholar
  29. 29.
    Shrikhande AV, Sarmiento JG, Janis RA, Rutledge E, Triggle DJ (1985) Characteristics of binding of BAY K 8644 to high and low affinity sites on cardiac membranes. Biophys J 47: 265aGoogle Scholar
  30. 30.
    Thayer SA, Welcome M, Chhabra A, Fairhurst AS (1985) Effects of calcium channel blocking drugs on rat brain muscarinic and α-adrenergic receptors. Biochem Pharmacol 34: 175–180PubMedCrossRefGoogle Scholar
  31. 31.
    Triggle DJ, Janis RA (1984) Calcium channel antagonists: new perspectives from the radio ligand binding assay. In: Spector S ( ed) Modern Methods in Pharmacology. Alan R. Liss Inc New York, pp 1–28Google Scholar
  32. 32.
    Warltier DC, Zyvoloski MG, Gross GJ, Brooks HL (1984) Comparative actions of dihydropyridine slow channel calcium blocking agents in conscious dogs: alterations in baroreflex sensitivity. J Pharmacol Exp Ther 230: 376–382PubMedGoogle Scholar
  33. 33.
    Weiland GA, Molinoff PB (1981) Quantitative analysis of drug-receptorinteractions: I. Determination of kinetic and equilibrium properties. Life Sci 29: 313–330PubMedCrossRefGoogle Scholar
  34. 34.
    Williams LT, Tremble P (1982) Binding of a calcium antagonist [3H]nitrendipine, to high affinity sites in bovine aortic smooth muscle and canine cardiac membranes. J Clin Invest 70: 209–212PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1987

Authors and Affiliations

  • R. A. Janis
  • A. V. Shrikhande
  • R. Greguski
  • M. Pan
  • A. Scriabine

There are no affiliations available

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