Function of cyclic GMP in acetylcholine-induced contraction of coronary smooth muscle

  • W. R. Kukovetz
  • S. Holzmann
  • G. Pöch
Article

Summary

Increasing evidence indicates that cyclic GMP is involved in smooth muscle relaxation by various nitrocompounds which stimulate guanylate cyclase. Since, however, rises in cGMP were also observed in association with contractile effects, the role of cGMP in acetylcholine-induced contraction was studied in isolated bovine coronary artery strips.

Concentration response experiments were performed with acetylcholine (ACh) in the absence and in the presence of a) the cGMP-phosphodiesterase inhibitor M & B 22,948, and of b) methylene blue which was found to inhibit NO-, and azide-induced stimulation of guanylate cyclase (Katsuki et al. 1977b), and changes in cGMP-levels (RIA) and in smooth muscle tone were monitored.
  1. 1.

    ACh (55 nM to 55 μM) concentration dependently raised cGMP up to the 4.4-fold control value concomitantly with, but slightly prior to its contractile effects.

     
  2. 2.

    In the presence of 370 μM M & B 22,948, cGMP-levels as well as their ACh-induced increases were 2–3 times higher than in its absence, whereas the contractile responses to ACh were diminished at normal (2.68 mM) K+ (DR=8.7) and —to a lesser extent — also at high (26.8 mM) K+-concentration (DR=2.2).

     
  3. 3.

    Methylene blue (50 μM) at normal K+ (2.68 mM) attenuated the ACh-induced rises in cGMP-levels (DR=4.4; lower maximum response) but potentiated the contractile effects (DR=4.0; higher maximum response). At high (26.8 mM) K+ the changes in dose ratios were less pronounced but the lower maximum rise in cGMP and the higher maximum contractile response were even more pronounced than at normal K+.

     
  4. 4.

    These results demonstrate that the rises in cyclic GMP-levels under the different conditions studied are inversely correlated with the magnitude of the contractile responses, suggesting that cGMP is likely to function as a physiologic negative feedback signal to limit and/or to reverse the contractile effects of ACh in smooth muscle.

     

Key words

Acetylcholine Cyclic GMP Smooth muscle relaxation PDE-inhibition Methylene blue 

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References

  1. Dunham EW, Haddox MK, Goldberg ND (1974) Alteration of vein cyclic 3′:5′-nucleotide concentrations during changes in contractility. Proc Natl Acad Sci USA 71:815–819Google Scholar
  2. Goldberg ND, Haddox MK (1977) Cyclic GMP metabolism and involvement in biological regulation. Ann Rev Biochem 46:823–896Google Scholar
  3. Goldberg ND, Haddox MK, Hartle DK, Hadden JW (1973) The biological role of cyclic 3′,5′-guanosine monophosphate. In: Pharmacology and the future of man. Proc 5th Int Congr Pharmacology San Francisco 1972, vol. 5. Karger, Basel, pp 146–169Google Scholar
  4. Gruetter CA, Barry BK, McNamara DB, Gruetter DY, Kadowitz PJ, Ignarro LJ (1979) Relaxation of bovine coronary artery and activation of guanylate cyclase by nitric oxide, nitroprusside and a carcinogenic nitrosoamine. J Cyclic Nucleotide Res 5:211–224Google Scholar
  5. Gruetter CA, Kadowitz PJ, Ignarro LJ (1981) Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrite, and amyl nitrite. Can J Physiol Pharmacol 59:150–156Google Scholar
  6. Holzmann S, Wurm A, Kukovetz WR, Pöch G (1979) Role of cyclic GMP in acetylcholine-induced contraction of coronary smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 308:R20Google Scholar
  7. Ignarro LJ, Gruetter CA (1980) Requirement of thiols for activation of coronary arterial guanylate cyclase by glyceryl trinitrate and sodium nitrate. Biochem Biophys Acta 631:221–231Google Scholar
  8. Katsuki S, Murad F (1977) Regulation of adenosine cyclic 3′,5′-monophosphate and guanosine cyclic 3′,5′-monophosphate levels and contractility in bovine tracheal smooth muscle. Mol Pharmacol 13:330–341Google Scholar
  9. Katsuki S, Arnold WP, Murad F (1977a) Effects of sodium nitroprusside, nitroglycerin, and sodium azide on levels of cyclic nucleotides and mechanical activity of various tissues. J Cyclic Nucleotide Res 3:239–247Google Scholar
  10. Katsuki S, Arnold W, Mittal Ch, Murad F (1977b) Stimulation of guanylate cyclase by sodium nitroprusside, nitroglycerin and nitric oxide in various tissue preparations and comparison to the effects of sodium azide and hydroxylamine. J Cyclic Nucleotide Res 3:23–35Google Scholar
  11. Kukovetz WR, Scholz N, Paietta E (1976) Influence of extracellular Ca2+ on acetylcholine-induced changes in cyclic nucleotides and tone of smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 294:R13Google Scholar
  12. Kukovetz WR, Holzmann S, Wurm A, Pöch G (1979) Evidence for cyclic GMP-inediated relaxant effects of nitro-compounds in coronary smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol 310: 129–138Google Scholar
  13. Kukovetz WR, Holzmann S, Wurm A (1980) Effect of cyclic GMP on coronary smooth muscle. Naunyn-Schmiedeberg's Arch Pharmacol (Suppl) 311:R29Google Scholar
  14. Kukovetz WR, Holzmann S, Pöch G (1981) Function of cyclic GMP in acetylcholine-induced vasoconstriction. Abstr. O-83 of the 8th Int Congr Pharmacol, Tokyo, p 844Google Scholar
  15. Lee TP, Kuo JF, Greengard P (1972) Role of muscarinic cholinergic receptors in regulation of guanosine 3′:5′-cyclic monophosphate content in mammalian brain, heart muscle, and intestinal smooth muscle. Proc Natl Acad Sci USA 69:3287–3291Google Scholar
  16. Schultz G, Hardman JG, Schultz K, Baird CE, Sutherland EW (1973) The importance of calcium ions for the regulation of guanosine 3′:5′-cyclic monophosphate levels. Proc Natl Acad Sci USA 70:3889–3893Google Scholar
  17. Schultz KD, Schultz K, Schultz G (1977) Sodium nitroprusside and other smooth muscle-relaxants increase cyclic GMP levels in rat ductus deferens. Nature 265:750–751Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • W. R. Kukovetz
    • 1
  • S. Holzmann
    • 1
  • G. Pöch
    • 1
  1. 1.Department of Pharmacodynamics and ToxicologyUniversity of GrazGrazAustria

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