Skip to main content
SpringerLink
Log in

Role of the soluble guanylyl cyclase α1/α2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Carbon monoxide (CO) has been shown to cause enteric smooth muscle relaxation by activating soluble guanylyl cyclase (sGC). In gastric fundus, the sGCα1β1 heterodimer is believed to be the most important isoform. The aim of our study was to investigate the role of the sGCα1/α2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus using wild-type (WT) and sGCα1 knock-out (KO) mice. In WT mice, CO (bolus)-induced relaxations were abolished by the sGC inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), while CORM-2- and CO (infusion)-induced relaxations were only partially inhibited by ODQ. In sGCα1 KO mice, relaxant responses to CO and CORM-2 were significantly reduced when compared with WT mice, but ODQ still had an inhibitory effect. The sGC sensitizer 1-benzyl-3-(5′-hydroxymethyl-2′-furyl-)-indazol (YC-1) was able to potentiate CO- and CORM-2-induced relaxations in WT mice but lost this potentiating effect in sGCα1 KO mice. Both in WT and sGCα1 KO mice, CO-evoked relaxations were associated with a significant cGMP increase; however, basal and CO-elicited cGMP levels were markedly lower in sGCα1 KO mice. These data indicate that besides the predominant sGCα1β1 isoform, also the less abundantly expressed sGCα2β1 isoform plays an important role in the relaxant effect of CO in murine gastric fundus; however, the sGC stimulator YC-1 loses its potentiating effect towards CO in sGCα1 KO mice. Prolonged administration of CO—either by the addition of CORM-2 or by continuous infusion of CO—mediates gastric fundus relaxation in both a sGC-dependent and sGC-independent manner.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Brüne B, Ullrich V (1987) Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase. Mol Pharmacol 32:497–504

    PubMed  Google Scholar 

  • Buys ES, Sips P, Vermeersch P, Raher MJ, Rogge E, Ichinose F, Dewerchin M, Bloch KD, Janssens S, Brouckaert P (2008) Gender-specific hypertension and responsiveness to nitric oxide in sGC{alpha}1 knockout mice. Cardiovasc Res (in press)

  • Cary SP, Winger JA, Derbyshire ER, Marletta MA (2006) Nitric oxide signaling: no longer simply on or off. Trends Biochem Sci 31:231–239

    Article  PubMed  CAS  Google Scholar 

  • Chlopicki S, Olszanecki R, Marcinkiewicz E, Lomnicka M, Motterlini R (2006) Carbon monoxide released by CORM-3 inhibits human platelets by a mechanism independent of soluble guanylate cyclase. Cardiovasc Res 71:393–401

    Article  PubMed  CAS  Google Scholar 

  • Colpaert EE, Timmermans JP, Lefebvre RA (2002) Investigation of the potential modulatory effect of biliverdin, carbon monoxide and bilirubin on nitrergic neurotransmission in the pig gastric fundus. Eur J Pharmacol 457:177–186

    Article  PubMed  CAS  Google Scholar 

  • De Backer O, Lefebvre RA (2007) Mechanisms of relaxation by carbon monoxide-releasing molecule-2 in murine gastric fundus and jejunum. Eur J Pharmacol 572:197–206

    Article  PubMed  Google Scholar 

  • De Backer O, Elinck E, Sips P, Brouckaert P, Lefebvre RA (2007) Role of sGCa1 in the relaxant effect of carbon monoxide-releasing molecule-2 in murine gastric fundus. 5th International Heme Oxygenases Congress, O IV2.

  • Farrugia G, Miller SM, Rich A, Liu X, Maines MD, Rae JL, Szurszewki JH (1998) Distribution of heme oxygenase and effects of exogenous carbon monoxide in canine jejunum. Am J Physiol Gastrointest Liver Physiol 274:350–358

    Google Scholar 

  • Friebe A, Müllershausen F, Smolenski A, Walter U, Schultz G, Koesling D (1998) YC-1 potentiates nitric oxide- and carbon monoxide-induced cyclic GMP effects in human platelets. Mol Pharmacol 54:962–967

    PubMed  CAS  Google Scholar 

  • Gibbons SJ, Farrugia G (2004) The role of carbon monoxide in the gastrointestinal tract. J Physiol 556:325–336

    Article  PubMed  CAS  Google Scholar 

  • Harteneck C, Koesling D, Soling A, Schultz G, Böhme E (1990) Expression of soluble guanylyl cyclase. Catalytic activity requires two enzyme subunits. FEBS Lett 272:221–223

    Article  PubMed  CAS  Google Scholar 

  • Harteneck C, Wedel B, Koesling D, Malkewitz J, Böhme E, Schultz G (1991) Molecular cloning and expression of a new alpha-subunit of soluble guanylyl cyclase. Interchangeability of the alpha-subunits of the enzyme. FEBS Lett 292:217–222

    Article  PubMed  CAS  Google Scholar 

  • Hussain MB, MacAllister RJ, Hobbs AJ (2001) Reciprocal regulation of cGMP-mediated vasorelaxation by soluble and particulate guanylate cyclases. Am J Physiol Heart Circ Physiol 280:1151–1159

    Google Scholar 

  • Kharitonov VG, Sharma VS, Pilz RB, Magde D, Koesling D (1995) Basis of guanylate cyclase activation by carbon monoxide. Proc Natl Acad Sci U S A 92:2568–2571

    Article  PubMed  CAS  Google Scholar 

  • Kharitonov VG, Sharma VS, Magde D, Koesling D (1999) Kinetics and equilibria of soluble guanylate cyclase ligation by CO: effect of YC-1. Biochemistry 38:10699–10706

    Article  PubMed  CAS  Google Scholar 

  • Lim I, Gibbons SJ, Lyford GL, Miller SM, Strege PR, Sarr MG, Chatterjee S, Szurszewki JH, Shah VH, Farrugia G (2005) Carbon monoxide activates human intestinal smooth muscle L-type Ca2+ channels through a nitric oxide-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 288:7–14

    Article  Google Scholar 

  • McLaughlin BE, Chretein ML, Choi C, Brien JF, Nakatsu K, Marks GS (2000) Potentiation of carbon monoxide-induced relaxation of rat aorta by YC-1 [3-(5¢-hydroxymethyl-2¢-furyl)-1-benzylindazole]. Can J Physiol Pharmacol 78:343–349

    Article  PubMed  CAS  Google Scholar 

  • Mergia E, Russwurm M, Zoidl G, Koesling D (2003) Major occurrence of the new alpha2beta1 isoform of NO-sensitive guanylyl cyclase in brain. Cell Signal 15:189–195

    Article  PubMed  CAS  Google Scholar 

  • Mergia E, Friebe A, Dangel O, Russwurm M, Koesling D (2006) Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system. J Clin Invest 116:1731–1737

    Article  PubMed  CAS  Google Scholar 

  • Motterlini R (2007) Carbon monoxide-releasing molecules (CO-RMs): vasodilatory, anti-ischaemic and anti-inflammatory activities. Biochem Soc Trans 35:1142–1146

    Article  PubMed  CAS  Google Scholar 

  • Muraki K, Imaizumi Y, Watanabe M (1991) Sodium currents in smooth muscle cells freshly isolated from stomach fundus of the rat and ureter of the guinea-pig. J Physiol 442:351–375

    PubMed  CAS  Google Scholar 

  • Ny L, Alm P, Ekstrom P, Larsson B, Grundemar L, Andersson KE (1996) Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter. Br J Pharmacol 118:392–399

    PubMed  CAS  Google Scholar 

  • Ny L, Pfeiffer A, Aszodi A, Ahmad M, Alm P, Hedlund P, Fassler R, Andersson KE (2000) Impaired relaxation of stomach smooth muscle in mice lacking cyclic GMP-dependent protein kinase I. Br J Pharmacol 129:395–401

    Article  PubMed  CAS  Google Scholar 

  • Rattan S, Al Haj R, De Godoy MA (2004) Mechanism of internal anal sphincter relaxation by CORM-1, authentic CO, and NANC nerve stimulation. Am J Physiol Gastrointest Liver Physiol 287:605–611

    Article  Google Scholar 

  • Russwurm M, Behrends S, Harteneck C, Koesling D (1998) Functional properties of a naturally occurring isoform of soluble guanylyl cyclase. Biochem J 335:125–130

    PubMed  CAS  Google Scholar 

  • Russwurm M, Wittau N, Koesling D (2001) Guanylyl cyclase/PSD-95 interaction: targeting of the nitric oxide-sensitive alpha2beta1 guanylyl cyclase to synaptic membranes. J Biol Chem 276:44647–44652

    Article  PubMed  CAS  Google Scholar 

  • Ryter SW, Alam J, Choi AMK (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650

    Article  PubMed  CAS  Google Scholar 

  • Sha L, Farrugia G, Harmsen WS, Szurszewki JH (2007) Membrane potential gradient is carbon monoxide-dependent in mouse and human small intestine. Am J Physiol Gastrointest Liver Physiol 293:438–445

    Article  Google Scholar 

  • Sharma VS, Magde D, Kharitonov VG, Koesling D (1999) Soluble guanylate cyclase: effect of YC-1 on ligation kinetics with carbon monoxide. Biochem Biophys Res Commun 254:188–191

    Article  PubMed  CAS  Google Scholar 

  • Vanneste G, Dhaese I, Sips P, Buys E, Brouckaert P, Lefebvre RA (2007) Gastric motility in soluble guanylate cyclase a1 knock-out mice. J Physiol 584:907–920

    Article  PubMed  CAS  Google Scholar 

  • Vermeersch P, Buys E, Pokreisz P, Marsboom G, Ichinose F, Sips P, Pellens M, Gillijns H, Swinnen M, Graveline A, Collen D, Dewerchin M, Brouckaert P, Bloch KD, Janssens S (2007) Soluble guanylate cyclase-alpha1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia. Circulation 116:936–943

    Article  PubMed  CAS  Google Scholar 

  • Wang R, Wang Z, Wu L (1997) Carbon monoxide-induced vasorelaxation and the underlying mechanisms. Br J Pharmacol 121:927–934

    Article  PubMed  CAS  Google Scholar 

  • Wu L, Wang R (2005) Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 57:585–630

    Article  PubMed  CAS  Google Scholar 

  • Xi Q, Tcheranova D, Parfenova H, Horowitz B, Leffler CW, Jaggar JH (2004) Carbon monoxide activates KCa channels in newborn arteriole smooth muscle cells by increasing apparent Ca2+ sensitivity of alpha-subunits. Am J Physiol Heart Circ Physiol 286:610–618

    Article  Google Scholar 

  • Zabel U, Kleinschnitz C, Oh P, Nedvetsky P, Smolenski A, Muller H, Kronich P, Kugler P, Walter U, Schnitzer JE, Schmidt HH (2002) Calcium-dependent membrane association sensitizes soluble guanylyl cyclase to nitric oxide. Nat Cell Biol 4:307–311

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

O.D.B. is a research assistant of the Fund of Scientific Research Flanders. This study was financially supported by the Special Investigation Fund of Ghent University (GOA 1251004) and the Fund of Scientific Research Flanders (G.0053.02). The authors thank Mr Valère Geers for technical assistance.

Author information

Authors and Affiliations

  1. Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 9000, Ghent, Belgium

    Ole De Backer, Ellen Elinck & Romain A. Lefebvre

  2. Department of Internal Medicine, Ghent University Hospital, Ghent, Belgium

    Ole De Backer

  3. Department for Molecular Biomedical Research, VIB, Ghent, Belgium

    Patrick Sips, Emmanuel Buys & Peter Brouckaert

  4. Department of Molecular Biology, Ghent University, Ghent, Belgium

    Patrick Sips, Emmanuel Buys & Peter Brouckaert

Authors
  1. Ole De Backer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ellen Elinck
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Sips
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emmanuel Buys
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Brouckaert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Romain A. Lefebvre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Romain A. Lefebvre.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Backer, O., Elinck, E., Sips, P. et al. Role of the soluble guanylyl cyclase α1/α2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus. Naunyn-Schmied Arch Pharmacol 378, 493–502 (2008). https://doi.org/10.1007/s00210-008-0315-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-008-0315-6

Keywords

Search

Navigation