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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 311, Issue 1, pp 71–77 | Cite as

Inhibitory effects of mepacrine and eicosatetraynoic acid on cyclic GMP elevations caused by calcium and hormonal factors in rat ductus deferens

  • Cornelie Spies
  • Klaus-Dieter Schultz
  • Günter Schultz
Article

Summary

Stimulation of cyclic GMP formation by hormones and neurotransmitters is restricted to intact cells and requires the presence of Ca2+ and, as shown for some tissues, of oxygen. Since peroxidized free fatty acids and oxygen radicals can stimulate soluble guanylate cyclase preparations, the effects of agents that interfere with the release or peroxidation of arachidonic acid were studied on Ca2+-and hormone-stimulated cyclic GMP levels in rat ductus deferens.

When isolated tissue was preincubated for 30 min in Ca2+-free Krebs-Ringer-bicarbonate buffer, addition of Ca2+ (2 mM) for 3 min increased cyclic GMP levels about 3-fold. Noradrenaline and acetylcholine (0.1 mM each) added with Ca2+ caused 6- and 8-fold increases, respectively. Sodium nitroprusside (0.1 mM), independently of the presence of Ca2+, caused an 8-fold increase. Preincubation with 0.1 mM mepacrine, an inhibitor of phospholipase A2, abolished the effects of Ca2+ and noradrenaline and reduced the effect of acetylcholine whereas the response to sodium nitroprusside was unchanged. Contractile responses were not affected by mepacrine. Preincubation with the arachidonic acid analogue, eicosatetraynoic acid (0.1 mM), which inhibits arachidonate peroxidation, reduced cyclic GMP responses to Ca2+, acetylcholine, noradrenaline and sodium nitroprusside without significant effect on contractile responses. Whereas the cyclooxygenase inhibitor, indomethacin (0.1 mM), did not affect cyclic GMP responses, nordihydroguaiaretic acid (0.1 m), an antioxidant and lipoxigenase inhibitor, reduced cyclic GMP responses to all of the above stimulants but also reduced contractile responses of the tissue.

These findings support the concept that the release of arachidonic acid and possibly other unsaturated fatty acids by Ca2+-stimulated phospholipases and the subsequent formation of peroxidized fatty acids, which are presumably degraded under formation of an active oxygen species, are involved in hormone-induced stimulation of cyclic GMP formation.

Key words

Cyclic GMP formation α-Adrenergic effects Cholinergic effects Sodium nitroprusside Arachidonic acid metabolism 

Abbreviations

PGG2

Prostaglandin G2

PGH2

prostaglandin H2

ETYA

eicosatetraynoic acid

HPETE

hydroperoxyeicosatetraenoic acid

EDTA

ethylenediamine tetraacetic acid

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Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • Cornelie Spies
    • 1
  • Klaus-Dieter Schultz
    • 1
  • Günter Schultz
    • 1
  1. 1.Pharmakologisches InstitutUniversität HeidelbergHeidelbergGermany

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