Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Jan;114(1):143–151. doi: 10.1111/j.1476-5381.1995.tb14918.x

Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40.

S J Cook 1, K Archer 1, A Martin 1, K H Buchheit 1, J R Fozard 1, T Müller 1, A J Miller 1, K R Elliott 1, R W Foster 1, R C Small 1
PMCID: PMC1510160  PMID: 7712010

Abstract

1. SCA40 (1nM-10 microM), isoprenaline (1-300 nM) and levcromakalim (100 nM-10 microM) each produced concentration-dependent suppression of the spontaneous tone of guinea-pig isolated trachea. Propranolol (1 microM) markedly (approximately 150 fold) antagonized isoprenaline but did not antagonize SCA40. The tracheal relaxant action of SCA40 was unaffected by suramin (100 microM) or 8-(p)-sulphophenyltheophylline (8-SPT; 140 microM). 2. An isosmolar, K(+)-rich (80 mM) Krebs solution increased tracheal tone, antagonized SCA40 (approximately 60 fold), antagonized isoprenaline (approximately 20 fold) and very profoundly depressed the log concentration-effect curve for levcromakalim. Nifedipine (1 microM) did not itself modify the relaxant actions of SCA40, isoprenaline or levcromakalim. However, nifedipine prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by the K(+)-rich medium. In contrast, nifedipine did not prevent the equivalent antagonism of levcromakalim. 3. Charybdotoxin (100 nM) increased tracheal tone, antagonized SCA40 (approximately 4 fold) and antagonized isoprenaline (approximately 3 fold). Nifedipine (1 microM) prevented the rise in tissue tone and the antagonism of SCA40 and isoprenaline induced by charybdotoxin. 4. Quinine (30 microM) caused little or no change in tissue tone and did not modify the relaxant action of isoprenaline. However, quinine antagonized SCA40 (approximately 2 fold). Nifedipine (1 microM) prevented the antagonism of SCA40 induced by quinine. 5. Tested on spontaneously-beating guinea-pig isolated atria SCA40 (1 nM-10 microM) increased the rate of beating in a concentration-dependent manner. Over the concentration-range 1 microM-10 microM, SCA40 also caused an increase in the force of atrial contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
146

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen S. L., Beech D. J., Foster R. W., Morgan G. P., Small R. C. Electrophysiological and other aspects of the relaxant action of isoprenaline in guinea-pig isolated trachealis. Br J Pharmacol. 1985 Dec;86(4):843–854. doi: 10.1111/j.1476-5381.1985.tb11106.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Allen S. L., Boyle J. P., Cortijo J., Foster R. W., Morgan G. P., Small R. C. Electrical and mechanical effects of BRL34915 in guinea-pig isolated trachealis. Br J Pharmacol. 1986 Oct;89(2):395–405. doi: 10.1111/j.1476-5381.1986.tb10273.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beavo J. A., Reifsnyder D. H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. doi: 10.1016/0165-6147(90)90066-H. [DOI] [PubMed] [Google Scholar]
  4. Bonnet P. A., Michel A., Laurent F., Sablayrolles C., Rechencq E., Mani J. C., Boucard M., Chapat J. P. Synthesis and antibronchospastic activity of 8-alkoxy- and 8-(alkylamino)imidazo[1,2-a]pyrazines. J Med Chem. 1992 Sep 4;35(18):3353–3358. doi: 10.1021/jm00096a008. [DOI] [PubMed] [Google Scholar]
  5. Collis M. G., Jacobson K. A., Tomkins D. M. Apparent affinity of some 8-phenyl-substituted xanthines at adenosine receptors in guinea-pig aorta and atria. Br J Pharmacol. 1987 Sep;92(1):69–75. doi: 10.1111/j.1476-5381.1987.tb11297.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dixon J. S., Small R. C. Evidence of poor conduction of muscle excitation in the longitudinal axis of guinea-pig isolated trachea. Br J Pharmacol. 1983 May;79(1):75–83. doi: 10.1111/j.1476-5381.1983.tb10498.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dunn P. M., Blakeley A. G. Suramin: a reversible P2-purinoceptor antagonist in the mouse vas deferens. Br J Pharmacol. 1988 Feb;93(2):243–245. doi: 10.1111/j.1476-5381.1988.tb11427.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elliott K. R., Berry J. L., Bate A. J., Foster R. W., Small R. C. The isoenzyme selectivity of AH 21-132 as an inhibitor of cyclic nucleotide phosphodiesterase activity. J Enzyme Inhib. 1991;4(3):245–251. doi: 10.3109/14756369109035848. [DOI] [PubMed] [Google Scholar]
  9. Foster R. W., Small R. C., Weston A. H. Evidence that the spasmogenic action of tetraethylammonium in guinea-pig trachealis is both direct and dependent on the cellular influx of calcium ion. Br J Pharmacol. 1983 May;79(1):255–263. doi: 10.1111/j.1476-5381.1983.tb10519.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gustafsson L. E. Adenosine antagonism and related effects of theophylline derivatives in guinea pig ileum longitudinal muscle. Acta Physiol Scand. 1984 Oct;122(2):191–198. doi: 10.1111/j.1748-1716.1984.tb07498.x. [DOI] [PubMed] [Google Scholar]
  11. Harris A. L., Connell M. J., Ferguson E. W., Wallace A. M., Gordon R. J., Pagani E. D., Silver P. J. Role of low Km cyclic AMP phosphodiesterase inhibition in tracheal relaxation and bronchodilation in the guinea pig. J Pharmacol Exp Ther. 1989 Oct;251(1):199–206. [PubMed] [Google Scholar]
  12. Hoyle C. H., Knight G. E., Burnstock G. Suramin antagonizes responses to P2-purinoceptor agonists and purinergic nerve stimulation in the guinea-pig urinary bladder and taenia coli. Br J Pharmacol. 1990 Mar;99(3):617–621. doi: 10.1111/j.1476-5381.1990.tb12979.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Huang J. C., Garcia M. L., Reuben J. P., Kacsorowski G. J. Inhibition of beta-adrenoceptor agonist relaxation of airway smooth muscle by Ca(2+)-activated K+ channel blockers. Eur J Pharmacol. 1993 Apr 22;235(1):37–43. doi: 10.1016/0014-2999(93)90817-2. [DOI] [PubMed] [Google Scholar]
  14. Jones T. R., Charette L., Garcia M. L., Kaczorowski G. J. Selective inhibition of relaxation of guinea-pig trachea by charybdotoxin, a potent Ca(++)-activated K+ channel inhibitor. J Pharmacol Exp Ther. 1990 Nov;255(2):697–706. [PubMed] [Google Scholar]
  15. Laurent F., Michel A., Bonnet P. A., Chapat J. P., Boucard M. Evaluation of the relaxant effects of SCA40, a novel charybdotoxin-sensitive potassium channel opener, in guinea-pig isolated trachealis. Br J Pharmacol. 1993 Mar;108(3):622–626. doi: 10.1111/j.1476-5381.1993.tb12851.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Michel A., Laurent F., Bompart J., Hadj-Kaddour K., Chapat J. P., Boucard M., Bonnet P. A. Cardiovascular effects of SCA40, a novel potassium channel opener, in rats. Br J Pharmacol. 1993 Nov;110(3):1031–1036. doi: 10.1111/j.1476-5381.1993.tb13917.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Murray M. A., Berry J. L., Cook S. J., Foster R. W., Green K. A., Small R. C. Guinea-pig isolated trachealis: the effects of charybdotoxin on mechanical activity, membrane potential changes and the activity of plasmalemmal K(+)-channels. Br J Pharmacol. 1991 Jul;103(3):1814–1818. doi: 10.1111/j.1476-5381.1991.tb09868.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Reeves M. L., Leigh B. K., England P. J. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J. 1987 Jan 15;241(2):535–541. doi: 10.1042/bj2410535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Small R. C., Berry J. L., Burka J. F., Cook S. J., Foster R. W., Green K. A., Murray M. A. Potassium channel activators and bronchial asthma. Clin Exp Allergy. 1992 Jan;22(1):11–18. doi: 10.1111/j.1365-2222.1992.tb00109.x. [DOI] [PubMed] [Google Scholar]
  20. Small R. C., Chiu P., Cook S. J., Foster R. W., Isaac L. Beta-adrenoceptor agonists in bronchial asthma: role of k+-channel opening in mediating their bronchodilator effects. Clin Exp Allergy. 1993 Oct;23(10):802–811. doi: 10.1111/j.1365-2222.1993.tb00257.x. [DOI] [PubMed] [Google Scholar]
  21. Thompson W. J., Terasaki W. L., Epstein P. M., Strada S. J. Assay of cyclic nucleotide phosphodiesterase and resolution of multiple molecular forms of the enzyme. Adv Cyclic Nucleotide Res. 1979;10:69–92. [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES