Skip to main content

Advertisement

SpringerLink
Log in

C2-ceramide induces vasodilation in phenylephrine-induced pre-contracted rat thoracic aorta: role of RhoA/Rho-kinase and intracellular Ca2+ concentration

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

Abstract

It is known that ceramide may play an important regulatory role in vascular tone although its effect on vascular tone and the mechanisms involved are controversial. The present study was designed to investigate the effects of ceramide and its key initial regulators, TNF-α and neutral sphingomyelinase (SMase), on vascular tone of isolated rat thoracic aortic rings and elucidate the mechanisms involved in the changes in vascular tone induced by ceramide. Contractile responses and Fura-2 Ca2+ signals were measured in rat thoracic aortic rings or strips. 10−5 M C2-ceramide, 0.1 U/ml neutral sphingomyelinase (SMase), and 5×10−7 g/ml TNF-α had no effect on resting tone in rat thoracic aortic rings. However, in phenylephrine-induced pre-contracted rings, treatment with ceramide, SMase, and TNF-α evoked a gradual but sustained vasodilation. Vasodilation effect in response to 10−5 M C2-ceramide was not significantly changed by the absence or presence of endothelium, a cyclooxygenase pathway inhibitor (10−6 M indomethacin), or PKC inhibitors (10−5 M H-7 & 5×10−7 M calphostin-C). Pretreatment with 1 μM Y-27632, a RhoA/Rho-kinase inhibitor, significantly inhibited the phenylephrine-induced contraction itself as well as the C2-ceramide-induced vasodilation. Pre-treatment with 10−5 M C2-ceramide had no effect on phasic rise in [Ca2+]i and tension evoked by stimulation with 10−8 M phenylephrine, but post-treatment of C2-ceramide significantly reduced the phenylephrine-induced secondary tonic [Ca2+]i and tension plateau. Our results indicate that C2-ceramide induces vasodilation in phenylephrine-induced pre-contracted rat thoracic aorta. Furthermore, inhibition of phenylephrine-induced activation of RhoA/Rho-kinase pathway as well as phenylephrine-induced elevations in [Ca2+]i are clearly a key factors in C2-ceramide-induced vasodilation.

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

  • Alewijnse AE, Peters SLM, Michel MC (2004) Cardiovascular effects of sphingosine-1-phosphate and other sphingomyelin metabolites. Br J Pharmacol 143:666–684

    Article  PubMed  CAS  Google Scholar 

  • Ballou LR (1992) Sphingolipids and cell function. Immunol Today 13:339–341

    Article  PubMed  CAS  Google Scholar 

  • Bradley AB, Morgan KG (1987) Alterations in cytoplasmic calcium sensitivity during porcine coronary artery contractions as detected by aequorin. J Physiol 385:437–448

    PubMed  CAS  Google Scholar 

  • Czyborra P, Saxe M, Fetscher C, Meyer Zu Heringdorf D, Herzig S, Jakobes KH, Michel MC, Bischoff A (2002) Transient relaxation of rat mesenteric microvessels by ceramides. Br J Pharmacol 135:417–426

    Article  PubMed  CAS  Google Scholar 

  • Exton JH (1985) Mechanisms involved in α-adrenergic phenomena. Am J Physiol 248:E634–E647

    Google Scholar 

  • Gong MC, Iizuka K, Nixon G, Browne JP, Hall A, Eccleston JF, Sugai M, Kobayashi S, Somlyo AV, Somlyo AP (1996) Role of guanine nucleotide-binding proteins-ras-family or trimeric proteins or both-in Ca2+ sensitization of smooth muscle. Proc Natl Acad Sci U S A 93:1340–1345

    Article  PubMed  CAS  Google Scholar 

  • Hannun YA (1994) The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 269:3125–3128

    PubMed  CAS  Google Scholar 

  • Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859

    Article  PubMed  CAS  Google Scholar 

  • Hannun YA, Bell RM (1993) The sphingomyelin cycle: a prototypic sphingolipid signaling pathway. Adv Lipid Res 25:27-41

    PubMed  CAS  Google Scholar 

  • Himpens B, Kitazawa T, Somlyo AP (1990) Agonist-dependent modulation of Ca2+ sensitivity in rabbit pulmonary artery smooth muscle. Pflugers Arch 417:21–28

    Article  PubMed  CAS  Google Scholar 

  • Hirano K, Hirano M, Eto W, Nishimura J, Kanaide H (2000) Mitogen-induced up-regulation of non-smooth muscle isoform of α-tropomyosin in rat aortic smooth muscle cells. Eur J Pharmacol 406:209–218

    Article  PubMed  CAS  Google Scholar 

  • Hirata K, Kikuchi A, Sasaki T, Kuroda S, Kaibuchi K, Matsuura Y, Seki H, Saida K, Takai Y (1992) Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. J Biol Chem 267:8719–8722

    PubMed  CAS  Google Scholar 

  • Jayadev S, Linardic CM, Hannun YA (1994) Identification of arachidonic acid as a mediator of sphingomyelin hydrolysis in response to tumor necrosis factor. J Biol Chem 269:5757–5763

    PubMed  CAS  Google Scholar 

  • Johns MJ, Murray AW (1995) Evidence that ceramide selectivity inhibits protein kinase C-α translocation and modulates bradykinin activation of phospholipase D. J Biol Chem 266:5007–5013

    Google Scholar 

  • Johns DG, Osborn H, Webb RC (1997) Ceramide: a novel cell signaling mechanism for vasodilation. Biochem Biophys Res Commun 237:95–97

    Article  PubMed  CAS  Google Scholar 

  • Johns DG, Jin JS, Webb RC (1998) The role of the endothelium in ceramide-induced vasodilation. Eur J Pharmacol 349:R9–R10

    Article  PubMed  CAS  Google Scholar 

  • Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273:245–248

    Article  PubMed  CAS  Google Scholar 

  • Kolesnick R (1994) Signal transduction through the sphingomyelin pathway. Mol Chem Neuropathol 21:287–297

    Article  PubMed  CAS  Google Scholar 

  • Li PL, Zhang DX, Zou AP, Campbell WB (1999) Effect of ceramide on Kca channel activity and vascular tone in coronary arteries. Hypertension 33:1441–1446

    PubMed  CAS  Google Scholar 

  • Morgan KG (1990) The role of calcium in the control of vascular tone as assessed by the Ca2+ indicator aequorin. Cardiovasc Drugs Ther 4:1355–1362

    Article  PubMed  CAS  Google Scholar 

  • Mueed I, Bains P, Zhang L, MacLeod KM (2004) Differential participation of protein kinase C and Rho kinase in α-1adrenoceptor mediated contraction in rat arteries. Can J Physiol Pharmacol 82:895–902

    Article  PubMed  CAS  Google Scholar 

  • Rembold CM (1990) Modulation of the [Ca2+] sensitivity of myosin phosphorylation in intact swine arterial smooth muscle. J Physiol 429:77–94

    PubMed  CAS  Google Scholar 

  • Somlyo AP, Somlyo AV (2000) Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol 522:177–185

    Article  PubMed  CAS  Google Scholar 

  • Werber AH, Morgan RA, Zhou P, Yang C (1997) Intracellular mechanisms of constriction of rat aorta by ethanol. Alcohol 14:351–360

    Article  PubMed  CAS  Google Scholar 

  • Wettschureck N, Offermanns S (2002) Rho/rho-kinase mediated signaling in physiology and pathophysiology. J Mol Med 80:629–638

    Article  PubMed  CAS  Google Scholar 

  • Wong K, Li XB, Hunchuk N (1995) N-acethylsphingosine (C2-ceramide) inhibited neutrophil superoxide formation and calcium influx. J Biol Chem 270:3056–3062

    Article  PubMed  CAS  Google Scholar 

  • Yeon DS, Kim JS, Ahn DS, Kwon SC, Kang BS, Morgan KG, Lee YH (2002) Role of protein kinase C- or RhoA-induced Ca2+-sensitization in stretch-induced myogenic tone. Cardiovasc Res 53:431–438

    Article  PubMed  CAS  Google Scholar 

  • Zhang DX, Zou AP, Li PL (2001) Ceramide reduces endothelium-dependent vasodilation by increasing superoxide production in small bovine coronary arteries. Circ Res 88:824–831

    Article  PubMed  CAS  Google Scholar 

  • Zheng T, Li W, Altura BT, Altura BM (1998) C2-ceramide attenuates prostaglandin F2α-induced vasoconstriction and elevation of [Ca2+]i in canine cerebral vascular smooth muscle. Neurosci Lett 256:113–116

    Article  PubMed  CAS  Google Scholar 

  • Zheng T, Li W, Altura BT, Altura BM (1999) C2-ceramide attenuates phenylephrine-induced vasoconstriction and elevation of [Ca2+]i in rat thoracic aortic smooth muscle. Lipids 34:689–695

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a faculty research grant of Yonsei University College of Medicine for 2003 (No. 2003–05).

Author information

Authors and Affiliations

  1. Department of Physiology, College of Medicine & BK 21 Project for Medical Sciences, Yonsei University, C.P.O. Box 8044, Seoul, 120-752, South Korea

    Gil-Jin Jang, Young-Eun Cho & Young-Ho Lee

  2. Department of Physiology, College of Medicine, Yonsei University, C.P.O. Box 8044, Seoul, 120-752, South Korea

    Duck Sun Ahn

  3. Signal Transduction Group, Boston Biomedical Research Institute, Watertown, MA, 02472, USA

    Kathleen G. Morgan

  4. Cardiovascular Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA

    Kathleen G. Morgan

Authors
  1. Gil-Jin Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Duck Sun Ahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young-Eun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen G. Morgan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young-Ho Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Young-Ho Lee.

Additional information

G.-J. Jang and D.-S. Ahn contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jang, GJ., Ahn, D.S., Cho, YE. et al. C2-ceramide induces vasodilation in phenylephrine-induced pre-contracted rat thoracic aorta: role of RhoA/Rho-kinase and intracellular Ca2+ concentration. Naunyn Schmied Arch Pharmacol 372, 242–250 (2005). https://doi.org/10.1007/s00210-005-0008-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-005-0008-3

Keywords

Search

Navigation