The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지

Forskolin Changes the Relationship between Cytosolic $Ca^{2+}$ and Contraction in Guinea Pig Ileum

  • Han, Koon-Hee (Department of Internal Medicine, Gangnung Asan Hospital) ;
  • Cheon, Gap-Jin (Department of Internal Medicine, Gangnung Asan Hospital) ;
  • Yeon, Dong-Soo (Department of Physiology, College of Medicine, Kwandong University) ;
  • Kwon, Seong-Chun (Department of Physiology, College of Medicine, Kwandong University)
  • Published : 2009.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

This study was designed to clarify the mechanism of the inhibitory effect of forskolin on contraction, cytosolic $Ca^{2+}$ level $([Ca^{2+}]_i)$, and $Ca^{2+}$ sensitivity in guinea pig ileum. Forskolin (0.1 nM ${\sim}$ 10 ${\mu}M$) inhibited high $K^+$ (25 mM and 40 mM)- or histamine (3 ${\mu}M$)-evoked contractions in a concentration-dependent manner. Histamine-evoked contractions were more sensitive to forskolin than high $K^+$-evoked contractions. Spontaneous changes in $[Ca^{2+}]_i$ and contractions were inhibited by forskolin (1 ${\mu}M$) without changing the resting $[Ca^{2+}]_i$. Forskoln (10 ${\mu}M$ ) inhibited muscle tension more strongly than $[Ca^{2+}]_i$ stimulated by high $K^+$, and thus shifted the $[Ca^{2+}]_i$-tension relationship to the lower-right. In histamine-stimulated contractions, forskolin (1 ${\mu}M$) inhibited both $[Ca^{2+}]_i$ and muscle tension without changing the $[Ca^{2+}]_i$-tension relationship. In ${\alpha}$-toxin-permeabilized tissues, forskolin (10 ${\mu}M$) inhibited the 0.3 ${\mu}M$ $Ca^{2+}$-evoked contractions in the presence of 0.1 mM GTP, but showed no effect on the $Ca^{2+}$-tension relationship. We conclude that forskolin inhibits smooth muscle contractions by the following two mechanisms: a decrease in $Ca^{2+}$ sensitivity of contractile elements in high $K^+$-stimulated muscle and a decrease in $[Ca^{2+}]_i$ in histamine-stimulated muscle.

Keywords

References

  1. Adelstein RS, Conti MA, Hathaway DR, Klee CB. Phosphorylation of smooth muscle myosin light chain kinase by the catalytic subunit of adenosine 3':5'-monophosphate-dependent protein kinase. J Biol Chem 253: 8347−8350, 1978
  2. Ahn HY, Kang SE, Chang KC, Karaki H. Dibutyryl cyclic AMP and forskolin inhibit phosphatidyl-inositol hydrolysis, Ca2＋ influx and contraction in vascular smooth muscle. Jpn J Pharmacol 59: 263−265, 1992. https://doi.org/10.1254/jjp.59.263
  3. Andersson R, Nilsson K. Role of cyclic nucleotides: metabolism and mechanical activity in smooth muscle. In Biochemistry of Smooth Muscle (edited by Stephens NL), 263−291, 1977
  4. Bhalla RC, Webb RC, Singh D, Brock T. Role of cyclic AMP in rat aortic microsomal phosphorylation and calcium uptake. Am J Physiol 234: H508−H514, 1978
  5. Bulbring E, Tomita T. Catecholamine action on smooth muscle. Pharmacol Rev 39: 49−96, 1987
  6. Cooper DM. Molecular and cellular requirements for the regulation adenylate cyclases by calcium. Biochem Soc Trans 31: 912−915, 2003 https://doi.org/10.1042/BST0310912
  7. Eckly-Michel A, Martin V, Lugnier C. Involvement of cyclic nucleotide-dependent protein kinases in cyclic AMP-mediated vasorelaxation. Br J Pharmacol 122: 158−164, 1997 https://doi.org/10.1038/sj.bjp.0701339
  8. Hall IP, Donaldson J, Hill SJ. Inhibition od histamine-stimulated inositol phospholipids hydrolysis by agents which increase cyclic AMP levels in bovine tracheal smooth muscle. Br J Pharmacol 97: 603−613, 1989 https://doi.org/10.1111/j.1476-5381.1989.tb11992.x
  9. Ise S, Nishimura J, Hirano K, Hara N, Kanaide H. Theophylline attenuates $Ca^{2+}$sensitivity and modulates BK channels in porcine tracheal smooth muscle. Br J Pharmacol 140: 939−947, 2003 https://doi.org/10.1038/sj.bjp.0705508
  10. Karaki H. Localization and sensitivity in vascular smooth muscle. Trends Pharmacol Sci 10: 320−325, 1989 https://doi.org/10.1016/0165-6147(89)90066-7
  11. Karaki H, Weiss GB. Calcium channels in smooth muscle. Gastroenterology 87: 960−970, 1984
  12. Kwon SC, Ozaki H, Hori M, Karaki H. Isoproterenol changes the relationship between cytosolic $Ca^{2+}$ and contraction in guinea- pig taneia caecum. Jpn J Pharmacol 61: 57−64, 1993 https://doi.org/10.1254/jjp.61.57
  13. Kwon SC, Ozaki H, Karaki H. NO donor sodium nitroprusside inhibits excitation-contraction coupling in guinea pig taenia coli. Am J Physiol 279: G1235−G1241, 2000a
  14. Kwon SC, Park KY, Ahn, DS, Lee HY, Kang BS. The effect of NO donor on contraction, cytosolic Ca2＋ level and ionic currents in guinea-pig ileal smooth muscle. Korean J Physiol Pharmacol 4: 33−40, 2000b
  15. Kushida M, Takeuchi T, Fujita A, Hata F. Dependence of Ca2＋- induced contraction in a-toxin-permeabilized preparations of rat femoral artery. J Pharmacol Sci 93: 171−179, 2003 https://doi.org/10.1254/jphs.93.171
  16. Lincoln TM, Cornwell TL. Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation. Blood Vessels 28: 129−137, 1991
  17. Morales S, Camello PJ, Mawe GM, Pozo MJ. Cyclic AMP-mediated inhibition of gallbladder contractility: role of$K^+$channel activation and $Ca^{2+}$ handling. Br J Pharmacol 143: 994−1005, 2004 https://doi.org/10.1038/sj.bjp.0706006
  18. Murray KJ. Cyclic AMP and mechanism of vasodilation. Pharmacol Ther 47: 329−354, 1990 https://doi.org/10.1016/0163-7258(90)90060-F
  19. Murthy KS. Signaling for contraction and relaxation in smooth muscle of the gut. Annu Rev Physiol 68: 345−374, 2006 https://doi.org/10.1146/annurev.physiol.68.040504.094707
  20. Nishikori K, Maeno H. Close relationship between adenosine3': 5'-monophosphate-dependent endogenous phosphorylation of a specific protein and stimulation of calcium uptake in rat uterine microsomes. J Biol Chem 254: 6099−6106, 1979
  21. Nishimura J, van Breemen C. Direct regulation of smooth muscle contractile elements by second messengers. Biochem Biophys Res Commun 163: 929−935, 1989 https://doi.org/10.1016/0006-291X(89)92311-5
  22. Ozaki H, Blondfield DP, Hori M, Sanders KM, Publicover NG. Cyclic AMP-mediated regulation of excitation-contraction coupling in canine gastric smooth muscle. J Physiol 447: 351−372, 1992
  23. Ozaki H, Hori M, Kim YS, Kwon SC, Ahn DS, Nakazawa H, Kobaysahi M, Karaki H. Inhibitory mechanism of xestospongin-C on contraction and ion channels in the intestinal smooth muscle. Br J Pharmacol 137: 1207−1212, 2002 https://doi.org/10.1038/sj.bjp.0704988
  24. Pfitzer G, Hofmann F, DiSalvo J, Ruegg JC. cGMP and cAMP inhibit tension development in skinned coronary arteries. Pflugers Arch 401: 277−280, 1984 https://doi.org/10.1007/BF00582596
  25. Porter M, Evans MC, Miner AS, Berg KM, Ward KR, Ratz PH. Convergence of $Ca^{2+}$-desensitizing mechanisms activated by forskolin and phenylephrine, but not 8-bromo-cGMP. Am J Physiol 290: C1552−C1559, 2006 https://doi.org/10.1152/ajpcell.00534.2005
  26. Ratz PH. Receptor activation induces short-term modulation of arterial sontractions: memory in vascular smooth muscle. Am J Physiol 269: C417−C423, 1999
  27. Rembold CM, Chen XL. Mechanisms responsible for forskolin- induced relaxation of rat tail artery. Hypertension 31: 872−877, 1998 https://doi.org/10.1161/01.HYP.31.3.872
  28. Rembold CM, O'Connor MJ, Clarkson M, Wardle RL, Murphy RA. HSP20 phosphorylation in nitroglycerin- and forskolin-induced sustained reductions in swine carotid artery. J Appl Physiol 91: 1460−1466, 2001
  29. Seamon KB, Daly JW. Forskolin: its biological and chemical properties. Adv Cyclic Nucleotide Protein Phosphoryl Res 20: 1−150, 1986.
  30. Wellman GC, Santana LF, Bonev AD, Nelson MT. Role of phospholamban in the modulation of arterial $Ca^{2+}$＋ sparks and $Ca^{2+}$-activated $k^+$channels by cAMP. Am J Physiol 281: C1029−C1037, 2001
  31. Woodrum DA, Brophy CM, Wingard CJ, Beall A, Rasmussen H. Phosphorylation events associated with cyclic nucleotide- dependent inhibition of smooth muscle contraction. Am J Physiol 277: H931−H939, 1999