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Cytochrome P450 Pathway Contributes to Methanandamide-induced Vasorelaxation in Rat Aorta

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Abstract

Purpose

The generation of hyperpolarising vasorelaxant endothelial cytochrome P450 epoxygenase (CYP)—derived metabolites of arachidonic may provide beneficial effects for the treatment of cardiovascular diseases in which the bioavailability of NO is impaired. The cannabinoid methanandamide has vasodilatory properties linked to hyperpolarisation. The aim of the present work was to investigate the vasorelaxant effects of methanandamide in rat aorta, focusing on the role of cytochrome P450 pathway.

Methods

Changes in isometric tension in response to a cumulative concentration-response curve of methanandamide (1 nM–100 μM) were recorded in aortic rings from male Wistar rats. The involvement of cannabinoid receptors, endothelial nitric oxide (NO)-, prostacyclin- and some hyperpolarising-mediated pathways were investigated. The activation of large-conductance Ca2+-activated K+ (BKCa) channels have also been evaluated.

Results

Methanandamide provoked an endothelium-dependent vasorelaxation in rat aorta, reaching a maximal effect (Rmax) of 67% ± 2.6%. This vasorelaxation was clearly inhibited by the combination of CB1 and CB2 cannabinoid antagonists (Rmax: 21.6% ± 1.3%) and by the combination of guanylate cyclase and CYP inhibitors (Rmax: 16.7% ± 1.1%). The blockade induced separately by guanylate cyclase (31.3% ± 2.8%) or CYP (36.3% ± 6.6%) inhibitors on methanandamide vasorelaxation was not significantly modified by either CB1 or CB2 inhibition. BKCa channels inhibition caused a partial and significant inhibition of the methanandamide vasorelaxation (Rmax: 39.9% ± 3.3%).

Conclusions

Methanandamide endothelium-dependent vasorelaxation is mediated by CB1 and CB2 cannabinoid receptors. The NO- and CYP-mediated pathways contribute in a concurrent manner in this vascular effect. Stimulation of both cannabinoid receptor subtypes is indistinctly linked to NO or CYP routes to cause vasorelaxation.

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References

  1. Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev. 2002;82:31–85.

    Google Scholar 

  2. Spector AA, Norris AW. Action of epoxyeicosatrienoic acids on cellular function. Am J Physiol Cell Physiol. 2007;292:C996–C1012.

    Article  PubMed  CAS  Google Scholar 

  3. Fleming I. Cytochrome P450 epoxygenases as EDHF synthase(s). Pharmacol Res. 2004;49:525–33.

    Article  PubMed  CAS  Google Scholar 

  4. Bauersachs J, Popp R, Hecker M, Sauer E, Fleming I, Busse R. Nitric oxide attenuates the release of endothelium-derived hyperpolarizing factor. Circulation. 1996;94:3341–7.

    PubMed  CAS  Google Scholar 

  5. Hercule HC, Schunck WH, Gross V, et al. Interaction between P450 eicosanoids and nitric oxide in the control of arterial tone in mice. Arterioscler Thromb Vasc Biol. 2009;29:54–60.

    Article  PubMed  CAS  Google Scholar 

  6. Spector AA. Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res. 2009;50:S52–6.

    Article  PubMed  Google Scholar 

  7. Kunos G, Járai Z, Bátkai S, et al. Endocannabinoids as cardiovascular modulators. Chem Phys Lipids. 2000;108:159–68.

    Article  PubMed  CAS  Google Scholar 

  8. Randall MD, Harris D, Kendall DA, Ralevic V. Cardiovascular effects of cannabinoids. Pharmacol Ther. 2002;95:191–202.

    Article  PubMed  CAS  Google Scholar 

  9. López-Miranda V, Herradón E, Martín MI. Vasorelaxation caused by cannabinoids: mechanisms in different vascular beds. Curr Vasc Pharmacol. 2008;6:335–46.

    Article  Google Scholar 

  10. Dannert MT, Alsasua A, Herradón E, Martín MI, López-Miranda V. Vasorelaxant effect of Win 55, 212-2 in rat aorta: new mechanisms involved. Vascul Pharmacol. 2007;46:16–23.

    Article  PubMed  CAS  Google Scholar 

  11. Herradón E, Martín MI, López-Miranda V. Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta. Br J Pharmacol. 2007;152:699–708.

    Article  PubMed  Google Scholar 

  12. Grainger J, Boachie-Ansah G. Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels. Br J Pharmacol. 2001;134:1003–12.

    Article  PubMed  CAS  Google Scholar 

  13. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003;424:434–8.

    Article  PubMed  CAS  Google Scholar 

  14. Ho WSV, Randall MD. Endothelium-dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2-arachidonoylglycerol. Br J Pharmacol. 2007;150:641–51.

    Article  PubMed  CAS  Google Scholar 

  15. Kozłowska H, Baranowska M, Schlicker E, Kozłowski M, Laudañski J, Malinowska B. Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product. Br J Pharmacol. 2008;155:1034–42.

    Article  PubMed  Google Scholar 

  16. Lake KD, Compton DR, Varga K, Martin BR, Kunos G. Cannabinoid-induced hypotension and bradycardia in rats is mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther. 1997;281:1030–7.

    PubMed  CAS  Google Scholar 

  17. Malinowska B, Kwolek G, Göthert M. Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn-Schmiedeberg’s Arch Pharmacol. 2001;364:562–9.

    Article  CAS  Google Scholar 

  18. Wang Y, Kaminski NE, Wang DH. VR1-mediated depressor effects during high-salt intake: role of anandamide. Hypertension. 2005;46:986–91.

    Article  PubMed  CAS  Google Scholar 

  19. Vanheel B, Van de Voorde J. Regional differences in anandamide- and methanandamide-induced membrane potential changes in rat mesenteric arteries. J Pharmacol Exp Ther. 2001;296:322–8.

    PubMed  CAS  Google Scholar 

  20. Breyne J, Vanheel B. Methanandamide hyperpolarizes gastric arteries by stimulation of TRPV1 receptors on perivascular CGRP containing nerves. J Cardiovasc Pharmacol. 2006;47:303–9.

    Article  PubMed  CAS  Google Scholar 

  21. Sade H, Muraki K, Ohya S, Hatano N, Imaizumi Y. Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids. Am J Physiol Cell Physiol. 2006;290:C77–86.

    Article  PubMed  CAS  Google Scholar 

  22. López-Miranda V, Herradón E, Dannert MT, Alsasua A, Martín MI. Anandamide vehicles: a comparative study. Eur J Pharmacol. 2004;505:151–61.

    Article  PubMed  Google Scholar 

  23. Zhao J, Majewski H. Endothelial nitric oxide attenuates Na+/Ca2+ exchanger-mediated vasoconstriction in rat aorta. Br J Pharmacol. 2008;154:982–90.

    Article  PubMed  CAS  Google Scholar 

  24. Van der Zypp A, Kang KB, Majewski H. Age-related involvement of the endothelium in b-adrenoceptor-mediated relaxation of rat aorta. Eur J Pharmacol. 2000;397:129–38.

    Article  PubMed  Google Scholar 

  25. Woodman OL, Malakul W. 3′, 4′-Dihydroxyflavonol prevents diabetes-induced endothelial dysfunction in rat aorta. Life Sci. 2009;85:54–9.

    Article  PubMed  CAS  Google Scholar 

  26. Wagner JA, Varga K, Jarai Z, Kunos G. Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension. 1999;33:429–34.

    PubMed  CAS  Google Scholar 

  27. Wagner JA, Jarai Z, Bátkai S, Kunos G. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors. Eur J Pharmacol. 2001;423:203–10.

    Article  PubMed  CAS  Google Scholar 

  28. Ralevic V, Kendall DA, Zygmunt PM, Movahed P, Högestätt ED. Vanilloid receptors on capsaicin-sensitive sensory nerves mediate relaxation to methanandamide in the rat isolated mesenteric arterial bed. Br J Pharmacol. 2000;130:1483–8.

    Article  PubMed  CAS  Google Scholar 

  29. Breyne J, Van de Voorde J, Vanheel B. Characterization of the vasorelaxation to methanandamide in rat gastric arteries. Can J Physiol Pharmacol. 2006;84:1121–32.

    Article  PubMed  CAS  Google Scholar 

  30. Mukhopadhyay S, Chapnick BM, Howlett AC. Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. Am J Physiol Heart Circ Physiol. 2002;282:H2046–54.

    PubMed  CAS  Google Scholar 

  31. Randall MD, Kendall DA, O’Sullivan S. The complexities of the cardiovascular actions of cannabinoids. Br J Pharmacol. 2004;142:20–6.

    Article  PubMed  CAS  Google Scholar 

  32. Mukhopadhyay S, Howlett AC. Chemically distinct ligands promote differential CB1 cannabinoid receptor-Gi protein interactions. Mol Pharmacol. 2005;67:2016–24.

    Article  PubMed  CAS  Google Scholar 

  33. Wagner JA, Abesser M, Karcher J, Laser M, Kunos G. Coronary vasodilator effects of endogenous cannabinoids in vasopressin-preconstricted unpaced rat isolated hearts. J Cardiovasc Pharmacol. 2005;46:348–55.

    Article  PubMed  CAS  Google Scholar 

  34. Járai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endotelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA. 1999;96:14136–41.

    Article  PubMed  Google Scholar 

  35. Mendizabal VE, Orliac ML, Adler-Graschinsky E. Long-term inhibition of nitric oxide synthase potentiates effects of anandamide in the rat mesenteric bed. Eur J Pharmacol. 2001;427:251–62.

    Article  PubMed  CAS  Google Scholar 

  36. Högestätt ED, Zygmung PM. Cardiovascular pharmacology of anandamide. Prostaglandins Leukot Essent Fatty Acids. 2002;66:343–51.

    Article  PubMed  Google Scholar 

  37. Poblete IM, Orliac ML, Briones R, Adler-Graschinsky E, Huidobro-Toro JP. Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol. 2005;568:539–51.

    Article  PubMed  CAS  Google Scholar 

  38. McCollum L, Howlett AC, Mukhopadhyay S. Anandamide-mediated CB1/CB2 cannabinoid receptor-independent nitric oxide production in rabbit aortic endothelial cells. J Pharmacol Exp Ther. 2007;321:930–7.

    Article  PubMed  CAS  Google Scholar 

  39. Luria A, Weldon SM, Kabcenell AK, Ingraham RH, Matera D, Jiang H, et al. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice. J Biol Chem. 2007;282:2891–8.

    Article  PubMed  CAS  Google Scholar 

  40. Gollasch M, Wellman GC, Knot HJ, Jaggar JH, Damon DH, Bonev AD, et al. Ontogeny of loval sarcoplasmic reticulum Ca2+ signals in cerebral arteries: Ca2+ sparks as elementary physiological events. Circ Res. 1998;83:1104–14.

    PubMed  CAS  Google Scholar 

  41. Lohn M, Jessner W, Furstenau M, et al. Regulation of calcium sparks and spontaneous transient outward currents by RyR3 in arterial vascular smooth muscle cells. Circ Res. 2001;89:1051–7.

    Article  PubMed  CAS  Google Scholar 

  42. Félétou M. Calcium-activated potassium channels and endothelial dysfunction: therapeutic options? Br J Pharmacol. 2009;156:545–62.

    Article  PubMed  Google Scholar 

  43. Busse R, Edward G, Félétou M, Fleming I, Vanhoutte PM, Weston AH. EDHF: bringing the concepts together. Trends Pharmacol Sci. 2002;23:374–80.

    Article  PubMed  CAS  Google Scholar 

  44. Félétou M, Vanhoutte PM. Endothelium-derived hyperpolarizing factor: where are we now? Arterioscler Thromb Vasc Biol. 2006;26:1215–25.

    Article  PubMed  Google Scholar 

  45. Yang Z, Zhang A, Altura BT, Altura BM. Hydrogen peroxide-induced endothelium-dependent relaxation of rat aorta involvement of Ca2+ and other cellular metabolites. Gen Pharmacol. 1999;33:325–36.

    Article  PubMed  CAS  Google Scholar 

  46. Chen JK, Chen J, Imig JD, et al. Identification of novel endogenous cytochrome p450 arachidonate metabolites with high affinity for cannabinoid receptors. J Biol Chem. 2008;283:24514–24.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grants from Ministerio de Educación y Ciencia SAF2006-13391-C03-01 and SAF2009-12422-C02-01, and grants from Comunidad de Madrid S-SAL/0261/2006.

We thank Sanofi Recherche (Montpellier, France) and for generous supply of rimonabant and SR144528.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Dpto. Farmacología y Nutrición, Facultad Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. Atenas s/n, 28922, Alcorcón, Madrid, Spain

    Visitación López-Miranda, Esperanza Herradón & M. Isabel Martín

  2. Dpto. Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Avda. Complutense s/n, 28040, Madrid, Spain

    M. Teresa Dannert & Angela Alsasua

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  1. Visitación López-Miranda
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  2. M. Teresa Dannert
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  5. M. Isabel Martín
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Correspondence to Visitación López-Miranda.

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López-Miranda, V., Dannert, M.T., Herradón, E. et al. Cytochrome P450 Pathway Contributes to Methanandamide-induced Vasorelaxation in Rat Aorta. Cardiovasc Drugs Ther 24, 379–389 (2010). https://doi.org/10.1007/s10557-010-6261-9

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  • DOI: https://doi.org/10.1007/s10557-010-6261-9

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