Advertisement

Cannabinoids and Cardiovascular System

  • Alexander I. BondarenkoEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1162)

Abstract

Cannabinoids influence cardiovascular variables in health and disease via multiple mechanisms. The chapter covers the impact of cannabinoids on cardiovascular function in physiology and pathology and presents a critical analysis of the proposed signalling pathways governing regulation of cardiovascular function by endogenously produced and exogenous cannabinoids. We know that endocannabinoid system is overactivated under pathological conditions and plays both a protective compensatory role, such as in some forms of hypertension, atherosclerosis and other inflammatory conditions, and a pathophysiological role, such as in disease states associated with excessive hypotension. This chapter focuses on the mechanisms affecting hemodynamics and vasomotor effects of cannabinoids in health and disease states, highlighting mismatches between some studies. The chapter will first review the effects of marijuana smoking on cardiovascular system and then describe the impact of exogenous cannabinoids on cardiovascular parameters in humans and experimental animals. This will be followed by analysis of the impact of cannabinoids on reactivity of isolated vessels. The article critically reviews current knowledge on cannabinoid induction of vascular relaxation by cannabinoid receptor-dependent and –independent mechanisms and dysregulation of vascular endocannabinoid signaling in disease states.

Keywords

Cannabis Endocacannabinoids Cannabinoid receptors Endothelial cells Vascular 

Abbreviations

2-AG

2-Arachidonoylglycerol

ACPA

arachidonylcyclopropylamide

BKCa

large conductance calcium-activated potassium channel, KCa1.1

CB1

cannabinoid receptor type 1

CB2

cannabinoid receptor type 2

CBe

endothelial cannabinoid receptor

CGRP

calcitonin gene-related peptide

COX

cyclooxygenase, prostaglandin-endoperoxide synthase

DOC salt hypertension

deoxycorticosterone acetate-induced hypertension

EDHF

endothelium-derived hyperpolarizing factor

FAAH

fatty acid amide hydrolase

IKCa

intermediate conductance calcium-activated potassium channel, KCa3.1

KATP

ATP-sensitive potassium channel

NAGly

N-arachidonoyl glycine

NCX

Na+-Ca2+ exchanger

NO

nitric oxide

PPAR

peroxisome proliferator-activated receptor

SHR

spontaneously hypertensive rats

TASK

TWIK-related acid-sensitive potassium channel

THC

Δ9-tetrahydrocannabinol

TRPA

transient receptor potential cation channel subfamily A (ankyrin)

TRPV

transient receptor potential cation channel subfamily V (vanniloid)

Notes

Acknowledgements

The author gratefully acknowledges financial support from the Austrian Science Fund, FWF, grant # P27238-B27.

References

  1. 1.
    Pacher P, Steffens S (2009) The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol 31(1):63–77PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Batkai S, Pacher P, Osei-Hyiaman D, Radaeva S, Liu J, Harvey-White J et al (2004) Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 110(14):1996–2002PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Carbone F, Mach F, Vuilleumier N, Montecucco F (2014) Cannabinoid receptor type 2 activation in atherosclerosis and acute cardiovascular diseases. Curr Med Chem 21(35):4046–4058PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Godlewski G, Alapafuja SO, Batkai S, Nikas SP, Cinar R, Offertaler L et al (2010) Inhibitor of fatty acid amide hydrolase normalizes cardiovascular function in hypertension without adverse metabolic effects. Chem Biol 17(11):1256–1266PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hopps JJ, Dunn WR, Randall MD (2012) Enhanced vasorelaxant effects of the endocannabinoid-like mediator, oleamide, in hypertension. Eur J Pharmacol 684(1-3):102–107PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Bondarenko AI, Panasiuk O, Okhai I, Montecucco F, Brandt KJ, Mach F (2018) Ca2+-dependent potassium channels and cannabinoid signaling in the endothelium of apolipoprotein E knockout mice before plaque formation. J Mol Cell Cardiol 115:54–63PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Capettini LS, Savergnini SQ, da Silva RF, Stergiopulos N, Santos RA, Mach F et al (2012) Update on the role of cannabinoid receptors after ischemic stroke. Mediat Inflamm 2012:824093CrossRefGoogle Scholar
  8. 8.
    Montecucco F, Di Marzo V (2012) At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol Sci 33(6):331–340PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond Ser B Biol Sci 367(1607):3353–3363CrossRefGoogle Scholar
  10. 10.
    Martin Gimenez VM, Noriega SE, Kassuha DE, Fuentes LB, Manucha W (2018) Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease. Ther Adv Cardiovasc Dis 12(7):177–190PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Sierra S, Luquin N, Navarro-Otano J (2017) The endocannabinoid system in cardiovascular function: novel insights and clinical implications. Clin Auton Res 8Google Scholar
  12. 12.
    Baron EP (2015) Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: what a long strange trip it’s been. Headache 55(6):885–916PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Wolff V, Jouanjus E (2017) Strokes are possible complications of cannabinoids use. Epilepsy Behav 70(Pt B):355–363PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Pacher P, Steffens S, Hasko G, Schindler TH, Kunos G (2017) Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 15(3):151–166PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Singh A, Saluja S, Kumar A, Agrawal S, Thind M, Nanda S et al (2018) Cardiovascular complications of marijuana and related substances: a review. Cardiol Ther 7(1):45–59PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Lerner M (1963) Marihuana: tetrahydrocannabinol and related compounds. Science 140(3563):175–176PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284):561–564PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365(6441):61–65PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Howlett AC (1995) Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 35:607–634PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Guo Z, Liu YX, Yuan F, Ma HJ, Maslov L, Zhang Y (2015) Enhanced vasorelaxation effect of endogenous anandamide on thoracic aorta in renal vascular hypertension rats. Clin Exp Pharmacol Physiol 42(9):950–955PubMedCrossRefGoogle Scholar
  21. 21.
    Schley M, Stander S, Kerner J, Vajkoczy P, Schupfer G, Dusch M et al (2009) Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans. Brain Res Bull 79(5):333–337PubMedCrossRefGoogle Scholar
  22. 22.
    Brusco A, Tagliaferro PA, Saez T, Onaivi ES (2008) Ultrastructural localization of neuronal brain CB2 cannabinoid receptors. Ann N Y Acad Sci 1139:450–457PubMedCrossRefGoogle Scholar
  23. 23.
    Xi ZX, Peng XQ, Li X, Song R, Zhang HY, Liu QR et al (2011) Brain cannabinoid CB(2) receptors modulate cocaine’s actions in mice. Nat Neurosci 14(9):1160–1166PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Ishiguro H, Horiuchi Y, Ishikawa M, Koga M, Imai K, Suzuki Y et al (2010) Brain cannabinoid CB2 receptor in schizophrenia. Biol Psychiatry 67(10):974–982PubMedCrossRefGoogle Scholar
  25. 25.
    Stempel AV, Stumpf A, Zhang HY, Ozdogan T, Pannasch U, Theis AK et al (2016) Cannabinoid type 2 receptors mediate a cell type-specific plasticity in the hippocampus. Neuron 90(4):795–809PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215(1):89–97PubMedCrossRefGoogle Scholar
  27. 27.
    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258(5090):1946–1949PubMedCrossRefGoogle Scholar
  28. 28.
    Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR et al (1995) Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50(1):83–90PubMedCrossRefGoogle Scholar
  29. 29.
    Deutsch DG, Goligorsky MS, Schmid PC, Krebsbach RJ, Schmid HH, Das SK et al (1997) Production and physiological actions of anandamide in the vasculature of the rat kidney. J Clin Invest 100(6):1538–1546PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gauthier KM, Baewer DV, Hittner S, Hillard CJ, Nithipatikom K, Reddy DS et al (2005) Endothelium-derived 2-arachidonylglycerol: an intermediate in vasodilatory eicosanoid release in bovine coronary arteries. Am J Physiol Heart Circ Physiol 288(3):H1344–H1351PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Sugiura T, Kodaka T, Nakane S, Kishimoto S, Kondo S, Waku K (1998) Detection of an endogenous cannabimimetic molecule, 2-arachidonoylglycerol, and cannabinoid CB1 receptor mRNA in human vascular cells: is 2-arachidonoylglycerol a possible vasomodulator? Biochem Biophys Res Commun 243(3):838–843PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Szekeres M, Nadasy GL, Turu G, Soltesz-Katona E, Benyo Z, Offermanns S et al (2015) Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension. Mol Cell Endocrinol 403:46–56PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Pacher P, Batkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58(3):389–462PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wagner JA, Hu K, Bauersachs J, Karcher J, Wiesler M, Goparaju SK et al (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38(7):2048–2054PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Quercioli A, Pataky Z, Vincenti G, Makoundou V, Di Marzo V, Montecucco F et al (2011) Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 32(11):1369–1378PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Montecucco F, Matias I, Lenglet S, Petrosino S, Burger F, Pelli G et al (2009) Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis 205(2):433–441PubMedCrossRefGoogle Scholar
  37. 37.
    Lobato NS, Filgueira FP, Prakash R, Giachini FR, Ergul A, Carvalho MH et al (2013) Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats. PLoS One 8(5):e63449PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pires PW (2018) Cannabinoids during ischemic strokes: friends or foes? Am J Physiol Heart Circ Physiol 314(6):H1155–H11H6PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Randall MD, Alexander SP, Bennett T, Boyd EA, Fry JR, Gardiner SM et al (1996) An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun 229(1):114–120PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Lopez-Dyck E, Andrade-Urzua F, Elizalde A, Ferrer-Villada T, Dagnino-Acosta A, Huerta M et al (2017) ACPA and JWH-133 modulate the vascular tone of superior mesenteric arteries through cannabinoid receptors, BKCa channels, and nitric oxide dependent mechanisms. Pharmacol Rep 69(6):1131–1139PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A et al (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346(Pt 3):835–840PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Batkai S, Jarai Z, Wagner JA, Goparaju SK, Varga K, Liu J et al (2001) Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis. Nat Med 7(7):827–832PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Sanchez-Pastor E, Andrade F, Sanchez-Pastor JM, Elizalde A, Huerta M, Virgen-Ortiz A et al (2014) Cannabinoid receptor type 1 activation by arachidonylcyclopropylamide in rat aortic rings causes vasorelaxation involving calcium-activated potassium channel subunit alpha-1 and calcium channel, voltage-dependent, L type, alpha 1C subunit. Eur J Pharmacol 729:100–106PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Batkai S, Mukhopadhyay P, Harvey-White J, Kechrid R, Pacher P, Kunos G (2007) Endocannabinoids acting at CB1 receptors mediate the cardiac contractile dysfunction in vivo in cirrhotic rats. Am J Physiol Heart Circ Physiol 293(3):H1689–H1695PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bradshaw HB, Lee SH, McHugh D (2009) Orphan endogenous lipids and orphan GPCRs: a good match. Prostaglandins Other Lipid Mediat 89(3–4):131–134PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Burstein S, McQuain C, Ross A, Salmonsen R, Zurier RE (2011) Resolution of inflammation by N-arachidonoylglycine. J Cell Biochem 112(11):3227–3233PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Brown AJ (2007) Novel cannabinoid receptors. Br J Pharmacol 152(5):567–575PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH (2017) Cannabinoid receptor-related orphan G protein-coupled receptors. Adv Pharmacol 80:223–247PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Zhao P, Abood ME (2013) GPR55 and GPR35 and their relationship to cannabinoid and lysophospholipid receptors. Life Sci 92(8-9):453–457PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Montecucco F, Bondarenko AI, Lenglet S, Burger F, Piscitelli F, Carbone F et al (2016) Treatment with the GPR55 antagonist CID16020046 increases neutrophil activation in mouse atherogenesis. Thromb Haemost 116(5):987–997PubMedPubMedCentralGoogle Scholar
  51. 51.
    Oz M (2006) Receptor-independent effects of endocannabinoids on ion channels. Curr Pharm Des 12(2):227–239PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Bondarenko A, Waldeck-Weiermair M, Naghdi S, Poteser M, Malli R, Graier WF (2010) GPR55-dependent and -independent ion signalling in response to lysophosphatidylinositol in endothelial cells. Br J Pharmacol 161(2):308–320PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Bondarenko AI, Malli R, Graier WF (2011) The GPR55 agonist lysophosphatidylinositol directly activates intermediate-conductance Ca2+-activated K+ channels. Pflugers Arch 462(2):245–255PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Pertwee RG (2010) Receptors and channels targeted by synthetic cannabinoid receptor agonists and antagonists. Curr Med Chem 17(14):1360–1381PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Bednarczyk P, Koziel A, Jarmuszkiewicz W, Szewczyk A (2013) Large-conductance Ca2+-activated potassium channel in mitochondria of endothelial EA.hy926 cells. Am J Physiol Heart Circ Physiol 304(11):H1415–H1427PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Bondarenko AI, Jean-Quartier C, Malli R, Graier WF (2013) Characterization of distinct single-channel properties of Ca2+ inward currents in mitochondria. Pflugers Arch 465(7):997–1010PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ryan D, Drysdale AJ, Lafourcade C, Pertwee RG, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29(7):2053–2063PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Benard G, Massa F, Puente N, Lourenco J, Bellocchio L, Soria-Gomez E et al (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15(4):558–564PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    O’Sullivan SE, Kendall DA, Randall MD (2009) Time-dependent vascular effects of Endocannabinoids mediated by peroxisome proliferator-activated receptor gamma (PPARgamma). PPAR Res 2009:425289PubMedPubMedCentralGoogle Scholar
  60. 60.
    Niederhoffer N, Szabo B (2000) Cannabinoids cause central sympathoexcitation and bradycardia in rabbits. J Pharmacol Exp Ther 294(2):707–713PubMedPubMedCentralGoogle Scholar
  61. 61.
    Grzeda E, Schlicker E, Luczaj W, Harasim E, Baranowska-Kuczko M, Malinowska B (2015) Bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids in anaesthetized rats: role of the paraventricular nucleus. J Physiol Pharmacol 66(3):343–353PubMedPubMedCentralGoogle Scholar
  62. 62.
    Niederhoffer N, Schmid K, Szabo B (2003) The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression. Naunyn Schmiedeberg’s Arch Pharmacol 367(5):434–443CrossRefGoogle Scholar
  63. 63.
    Malinowska B, Godlewski G, Bucher B, Schlicker E (1997) Cannabinoid CB1 receptor-mediated inhibition of the neurogenic vasopressor response in the pithed rat. Naunyn Schmiedeberg’s Arch Pharmacol 356(2):197–202CrossRefGoogle Scholar
  64. 64.
    Li Q, Ma HJ, Song SL, Shi M, Li DP, Zhang Y (2012) Effects of anandamide on potassium channels in rat ventricular myocytes: a suppression of I(to) and augmentation of K(ATP) channels. Am J Phys Cell Physiol 302(6):C924–C930CrossRefGoogle Scholar
  65. 65.
    Al Kury LT, Yang KH, Thayyullathil FT, Rajesh M, Ali RM, Shuba YM et al (2014) Effects of endogenous cannabinoid anandamide on cardiac Na/Ca exchanger. Cell Calcium 171:3485–3498Google Scholar
  66. 66.
    Mukhopadhyay P, Rajesh M, Batkai S, Patel V, Kashiwaya Y, Liaudet L et al (2010) CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res 85(4):773–784PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Su JY, Vo AC (2007) 2-Arachidonylglyceryl ether and abnormal cannabidiol-induced vascular smooth muscle relaxation in rabbit pulmonary arteries via receptor-pertussis toxin sensitive G proteins-ERK1/2 signaling. Eur J Pharmacol 559(2-3):189–195PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Van den Bossche I, Vanheel B (2000) Influence of cannabinoids on the delayed rectifier in freshly dissociated smooth muscle cells of the rat aorta. Br J Pharmacol 131(1):85–93PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Breyne J, Van de Voorde J, Vanheel B (2006) Characterization of the vasorelaxation to methanandamide in rat gastric arteries. Can J Physiol Pharmacol 84(11):1121–1132PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Chataigneau T, Feletou M, Thollon C, Villeneuve N, Vilaine JP, Duhault J et al (1998) Cannabinoid CB1 receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries. Br J Pharmacol 123(5):968–974PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Rajesh M, Mukhopadhyay P, Hasko G, Huffman JW, Mackie K, Pacher P (2008) CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 153(2):347–357PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Bondarenko AI, Malli R, Graier WF (2011) The GPR55 agonist lysophosphatidylinositol acts as an intracellular messenger and bidirectionally modulates Ca2+-activated large-conductance K+ channels in endothelial cells. Pflugers Arch 461(1):177–189PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Stanley CP, Hind WH, Tufarelli C, O’Sullivan SE (2015) Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation. Cardiovasc Res 19Google Scholar
  74. 74.
    Ho WS, Zheng X, Zhang DX (2015) Role of endothelial TRPV4 channels in vascular actions of the endocannabinoid, 2-arachidonoylglycerol. Br J Pharmacol 172(22):5251–5264PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Suleimani YMA, Hiley CR (2010) Lysophosphatidylinositol (LPI) mediates vasorelaxation of the rat mesenteric resistance artery and induces calcium release in rat mesenteric artery endothelial cells. In: Proceedings of the British Pharmacological Society Winter Meeting 2010, London, 81(1)Google Scholar
  76. 76.
    Lepicier P, Bouchard JF, Lagneux C, Lamontagne D (2003) Endocannabinoids protect the rat isolated heart against ischaemia. Br J Pharmacol 139(4):805–815PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Lamontagne D, Lepicier P, Lagneux C, Bouchard JF (2006) The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia. Arch Mal Coeur Vaiss 99(3):242–246PubMedPubMedCentralGoogle Scholar
  78. 78.
    Mukhopadhyay P, Horvath B, Rajesh M, Matsumoto S, Saito K, Batkai S et al (2011) Fatty acid amide hydrolase is a key regulator of the endocannabinoid-induced myocardial tissue injury. Free Radic Biol Med 50(1):179–195PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Mo FM, Offertaler L, Kunos G (2004) Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG. Eur J Pharmacol 489(1-2):21–27PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Zhang X, Maor Y, Wang JF, Kunos G, Groopman JE (2010) Endocannabinoid-like N-arachidonoyl serine is a novel pro-angiogenic mediator. Br J Pharmacol 160(7):1583–1594PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Pisanti S, Picardi P, Prota L, Proto MC, Laezza C, McGuire PG et al (2011) Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis. Blood 117(20):5541–5550PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Mach F, Montecucco F, Steffens S (2008) Cannabinoid receptors in acute and chronic complications of atherosclerosis. Br J Pharmacol 153(2):290–298PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Weil AT, Zinberg NE, Nelsen JM (1968) Clinical and psychological effects of marihuana in man. Science 162(3859):1234–1242PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Hollister LE (1971) Actions of various marihuana derivatives in man. Pharmacol Rev 23(4):349–357PubMedPubMedCentralGoogle Scholar
  85. 85.
    Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA (1974) Cannabidiol interferes with the effects of delta 9 – tetrahydrocannabinol in man. Eur J Pharmacol 28(1):172–177PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Kiplinger GF, Manno JE (1971) Dose-response relationships to cannabis in human subjects. Pharmacol Rev 23(4):339–347PubMedPubMedCentralGoogle Scholar
  87. 87.
    Van Hoozen BE, Cross CE (1997) Marijuana. Respiratory tract effects. Clin Rev Allergy Immunol 15(3):243–269PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Gash A, Karliner JS, Janowsky D, Lake CR (1978) Effects of smoking marihuana on left ventricular performance and plasma norepinephrine: studies in normal men. Ann Intern Med 89(4):448–452PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Beaconsfield P, Ginsburg J, Rainsbury R (1972) Marihuana smoking. Cardiovascular effects in man and possible mechanisms. N Engl J Med 287(5):209–212PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Mathew RJ, Wilson WH, Tant SR (1989) Acute changes in cerebral blood flow associated with marijuana smoking. Acta Psychiatr Scand 79(2):118–128PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Mathew RJ, Wilson WH, Humphreys DF, Lowe JV, Wiethe KE (1992) Regional cerebral blood flow after marijuana smoking. J Cereb Blood Flow Metab 12(5):750–758PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    O’Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA, Ponto LB et al (2007) Effects of smoking marijuana on focal attention and brain blood flow. Hum Psychopharmacol 22(3):135–148PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Rezkalla S, Kloner RA (2018) Cardiovascular effects of marijuana. Trends Cardiovasc MedGoogle Scholar
  94. 94.
    Korantzopoulos P, Liu T, Papaioannides D, Li G, Goudevenos JA (2008) Atrial fibrillation and marijuana smoking. Int J Clin Pract 62(2):308–313PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Pacher P, Steffens S, Hasko G, Schindler TH, Kunos G (2018) Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 15(3):151–166PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Weiss JL, Watanabe AM, Lemberger L, Tamarkin NR, Cardon PV (1972) Cardiovascular effects of delta-9-tetrahydrocannabinol in man. Clin Pharmacol Ther 13(5):671–684PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Jadoon KA, Tan GD, O’Sullivan SE (2017) A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight 15:2(12)Google Scholar
  98. 98.
    Vollmer RR, Cavero I, Ertel RJ, Solomon TA, Buckley JP (1974) Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-delta 9-trans-tetrahydrocannabinol. J Pharm Pharmacol 26(3):186–192PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Kanakis C Jr, Pouget JM, Rosen KM (1976) The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. Circulation 53(4):703–707PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Malit LA, Johnstone RE, Bourke DI, Kulp RA, Klein V, Smith TC (1975) Intravenous delta9-Tetrahydrocannabinol: effects of ventilatory control and cardiovascular dynamics. Anesthesiology 42(6):666–673PubMedCrossRefGoogle Scholar
  101. 101.
    Benowitz NL, Jones RT (1975) Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther 18(3):287–297PubMedCrossRefGoogle Scholar
  102. 102.
    Gardiner SM, March JE, Kemp PA, Bennett T (2001) Regional haemodynamic responses to the cannabinoid agonist, WIN 55212-2, in conscious, normotensive rats, and in hypertensive, transgenic rats. Br J Pharmacol 133(3):445–453PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Lake KD, Compton DR, Varga K, Martin BR, Kunos G (1997) Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther 281(3):1030–1037PubMedGoogle Scholar
  104. 104.
    Varga K, Lake KD, Huangfu D, Guyenet PG, Kunos G (1996) Mechanism of the hypotensive action of anandamide in anesthetized rats. Hypertension 28(4):682–686PubMedCrossRefGoogle Scholar
  105. 105.
    Lake KD, Martin BR, Kunos G, Varga K (1997) Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29(5):1204–1210PubMedCrossRefGoogle Scholar
  106. 106.
    Malinowska B, Baranowska-Kuczko M, Schlicker E (2012) Triphasic blood pressure responses to cannabinoids: do we understand the mechanism? Br J Pharmacol 165(7):2073–2088PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Varga K, Lake K, Martin BR, Kunos G (1995) Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 278(3):279–283PubMedCrossRefGoogle Scholar
  108. 108.
    Ishac EJ, Jiang L, Lake KD, Varga K, Abood ME, Kunos G (1996) Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 118(8):2023–2028PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zakrzeska A, Schlicker E, Baranowska M, Kozlowska H, Kwolek G, Malinowska B (2010) A cannabinoid receptor, sensitive to O-1918, is involved in the delayed hypotension induced by anandamide in anaesthetized rats. Br J Pharmacol 160(3):574–584PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Malinowska B, Kwolek G, Gothert M (2001) 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 364(6):562–569CrossRefGoogle Scholar
  111. 111.
    Pacher P, Batkai S, Kunos G (2004) Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 558(Pt 2):647–657PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Krayer O (1961) The history of the Bezold-Jarisch effect. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 240:361–368PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Jarai Z, Wagner JA, Goparaju SK, Wang L, Razdan RK, Sugiura T et al (2000) Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension 35(2):679–684PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Niederhoffer N, Szabo B (1999) Effect of the cannabinoid receptor agonist WIN55212-2 on sympathetic cardiovascular regulation. Br J Pharmacol 126(2):457–466PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Gardiner SM, March JE, Kemp PA, Bennett T (2002) Complex regional haemodynamic effects of anandamide in conscious rats. Br J Pharmacol 135(8):1889–1896PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Gardiner SM, March JE, Kemp PA, Bennett T (2002) Influence of the CB(1) receptor antagonist, AM 251, on the regional haemodynamic effects of WIN-55212-2 or HU 210 in conscious rats. Br J Pharmacol 136(4):581–587PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Stanke-Labesque F, Mallaret M, Lefebvre B, Hardy G, Caron F, Bessard G (2004) 2-Arachidonoyl glycerol induces contraction of isolated rat aorta: role of cyclooxygenase-derived products. Cardiovasc Res 63(1):155–160PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Vanheel B, Van de Voorde J (2001) Regional differences in anandamide- and methanandamide-induced membrane potential changes in rat mesenteric arteries. J Pharmacol Exp Ther 296(2):322–328PubMedPubMedCentralGoogle Scholar
  119. 119.
    O’Sullivan SE, Kendall DA, Randall MD (2004) Heterogeneity in the mechanisms of vasorelaxation to anandamide in resistance and conduit rat mesenteric arteries. Br J Pharmacol 142(3):435–442PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    O’Sullivan SE, Kendall DA, Randall MD (2005) The effects of Delta9-tetrahydrocannabinol in rat mesenteric vasculature, and its interactions with the endocannabinoid anandamide. Br J Pharmacol 145(4):514–526PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Ho WS, Hiley CR (2003) Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx. Br J Pharmacol 139(3):585–597PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Harris D, McCulloch AI, Kendall DA, Randall MD (2002) Characterization of vasorelaxant responses to anandamide in the rat mesenteric arterial bed. J Physiol 539(Pt 3):893–902PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR et al (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 96(24):14136–14141PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    O’Sullivan SE, Kendall DA, Randall MD (2005) Vascular effects of delta 9-tetrahydrocannabinol (THC), anandamide and N-arachidonoyldopamine (NADA) in the rat isolated aorta. Eur J Pharmacol 507(1-3):211–221PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Herradon E, Martin MI, Lopez-Miranda V (2007) Characterization of the vasorelaxant mechanisms of the endocannabinoid anandamide in rat aorta. Br J Pharmacol 152(5):699–708PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Godlewski G, Offertaler L, Osei-Hyiaman D, Mo FM, Harvey-White J, Liu J et al (2009) The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels. J Pharmacol Exp Ther 328(1):351–361PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Bondarenko AI, Drachuk K, Panasiuk O, Sagach V, Deak AT, Malli R et al (2013) N-arachidonoyl glycine suppresses Na+/Ca2+ exchanger-mediated Ca2+ entry into endothelial cells and activates BK channels independently of G-protein coupled receptors. Br J Pharmacol 169(4):933–948PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Chemin J, Cazade M, Lory P (2014) Modulation of T-type calcium channels by bioactive lipids. Pflugers Arch 466(4):689–700PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Barbara G, Alloui A, Nargeot J, Lory P, Eschalier A, Bourinet E et al (2009) T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids. J Neurosci 29(42):13106–13114PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Yang W, Li Q, Wang SY, Gao F, Qian WJ, Li F et al (2016) Cannabinoid receptor agonists modulate calcium channels in rat retinal Muller cells. Neuroscience 313:213–224PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Patil M, Patwardhan A, Salas MM, Hargreaves KM, Akopian AN (2011) Cannabinoid receptor antagonists AM251 and AM630 activate TRPA1 in sensory neurons. Neuropharmacology 61(4):778–788PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Akopian AN, Ruparel NB, Patwardhan A, Hargreaves KM (2008) Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci 28(5):1064–1075PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Maingret F, Patel AJ, Lazdunski M, Honore E (2001) The endocannabinoid anandamide is a direct and selective blocker of the background K(+) channel TASK-1. EMBO J 20(1-2):47–54PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Veale EL, Buswell R, Clarke CE, Mathie A (2007) Identification of a region in the TASK3 two pore domain potassium channel that is critical for its blockade by methanandamide. Br J Pharmacol 152(5):778–786PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Olschewski A, Li Y, Tang B, Hanze J, Eul B, Bohle RM et al (2006) Impact of TASK-1 in human pulmonary artery smooth muscle cells. Circ Res 98(8):1072–1080PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Gardener MJ, Johnson IT, Burnham MP, Edwards G, Heagerty AM, Weston AH (2004) Functional evidence of a role for two-pore domain potassium channels in rat mesenteric and pulmonary arteries. Br J Pharmacol 142(1):192–202PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Bondarenko AI, Montecucco F, Panasiuk O, Sagach V, Sidoryak N, Brandt KJ et al (2017) GPR55 agonist lysophosphatidylinositol and lysophosphatidylcholine inhibit endothelial cell hyperpolarization via GPR-independent suppression of Na+-Ca2+ exchanger and endoplasmic reticulum Ca2+ refilling. Vasc Pharmacol 89:39–48CrossRefGoogle Scholar
  138. 138.
    Al Suleimani YM, Al Mahruqi AS (2017) The endogenous lipid N-arachidonoyl glycine is hypotensive and nitric oxide-cGMP-dependent vasorelaxant. Eur J Pharmacol 794:209–215PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Bondarenko A, Sagach V (2006) Na+-K+-ATPase is involved in the sustained ACh-induced hyperpolarization of endothelial cells from rat aorta. Br J Pharmacol 149(7):958–965PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Steffens M, Feuerstein TJ (2004) Receptor-independent depression of DA and 5-HT uptake by cannabinoids in rat neocortex--involvement of Na(+)/K(+)-ATPase. Neurochem Int 44(7):529–538PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Ellis EF, Moore SF, Willoughby KA (1995) Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin. Am J Phys 269(6 Pt 2):H1859–H1864Google Scholar
  142. 142.
    Randall MD, Kendall DA (1997) Involvement of a cannabinoid in endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation. Eur J Pharmacol 335(2-3):205–209PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Wagner JA, Varga K, Jarai Z, Kunos G (1999) Mesenteric vasodilation mediated by endothelial anandamide receptors. Hypertension 33(1 Pt 2):429–434PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Plane F, Holland M, Waldron GJ, Garland CJ, Boyle JP (1997) Evidence that anandamide and EDHF act via different mechanisms in rat isolated mesenteric arteries. Br J Pharmacol 121(8):1509–1511PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    White R, Hiley CR (1997) A comparison of EDHF-mediated and anandamide-induced relaxations in the rat isolated mesenteric artery. Br J Pharmacol 122(8):1573–1584PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Zygmunt PM, Hogestatt ED, Waldeck K, Edwards G, Kirkup AJ, Weston AH (1997) Studies on the effects of anandamide in rat hepatic artery. Br J Pharmacol 122(8):1679–1686PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Fulton D, Quilley J (1998) Evidence against anandamide as the hyperpolarizing factor mediating the nitric oxide-independent coronary vasodilator effect of bradykinin in the rat. J Pharmacol Exp Ther 286(3):1146–1151PubMedPubMedCentralGoogle Scholar
  148. 148.
    Zygmunt PM, Sorgard M, Petersson J, Johansson R, Hogestatt ED (2000) Differential actions of anandamide, potassium ions and endothelium-derived hyperpolarizing factor in guinea-pig basilar artery. Naunyn Schmiedeberg’s Arch Pharmacol 361(5):535–542CrossRefGoogle Scholar
  149. 149.
    Niederhoffer N, Szabo B (1999) Involvement of CB1 cannabinoid receptors in the EDHF-dependent vasorelaxation in rabbits. Br J Pharmacol 126(6):1383–1386PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Mulvany MJ, Halpern W (1977) Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 41(1):19–26PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Lu X, Kassab GS (2011) Assessment of endothelial function of large, medium, and small vessels: a unified myograph. Am J Physiol Heart Circ Physiol 300(1):H94–H100PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Falloon BJ, Stephens N, Tulip JR, Heagerty AM (1995) Comparison of small artery sensitivity and morphology in pressurized and wire-mounted preparations. Am J Phys 268(2 Pt 2):H670–H678Google Scholar
  153. 153.
    Pratt PF, Hillard CJ, Edgemond WS, Campbell WB (1998) N-arachidonylethanolamide relaxation of bovine coronary artery is not mediated by CB1 cannabinoid receptor. Am J Phys 274(1 Pt 2):H375–H381Google Scholar
  154. 154.
    Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK et al (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63(3):699–705PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V et al (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400(6743):452–457PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Begg M, Baydoun A, Parsons ME, Molleman A (2001) Signal transduction of cannabinoid CB1 receptors in a smooth muscle cell line. J Physiol 531(Pt 1):95–104PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    White R, Hiley CR (1998) The actions of some cannabinoid receptor ligands in the rat isolated mesenteric artery. Br J Pharmacol 125(3):533–541PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Weresa J, Pedzinska-Betiuk A, Kossakowski R, Malinowska B (2018) Cannabinoid CB1 and CB2 receptors antagonists AM251 and AM630 differentially modulate the chronotropic and inotropic effects of isoprenaline in isolated rat atria. Pharmacol Rep 71(1):82–89PubMedCrossRefGoogle Scholar
  159. 159.
    Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C et al (1994) SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett 350(2-3):240–244PubMedCrossRefGoogle Scholar
  160. 160.
    Kozlowska H, Baranowska M, Schlicker E, Kozlowski M, Laudanski J, Malinowska B (2007) Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery. J Hypertens 25(11):2240–2248PubMedCrossRefGoogle Scholar
  161. 161.
    Ho WS, Hiley CR (2003) Vasodilator actions of abnormal-cannabidiol in rat isolated small mesenteric artery. Br J Pharmacol 138(7):1320–1332PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Chaytor AT, Martin PE, Evans WH, Randall MD, Griffith TM (1999) The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication. J Physiol 520(Pt 2):539–550PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Bondarenko AI, Panasiuk O, Drachuk K, Montecucco F, Brandt KJ, Mach F (2018) The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells. Vasc Pharmacol 102:44–55CrossRefGoogle Scholar
  164. 164.
    Bukoski RD, Batkai S, Jarai Z, Wang Y, Offertaler L, Jackson WF et al (2002) CB1 receptor antagonist SR141716A inhibits Ca2+-induced relaxation in CB1 receptor-deficient mice. Hypertension 39(2):251–257PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Raffa RB, Ward SJ (2012) CB(1)-independent mechanisms of Delta(9)-THCV, AM251 and SR141716 (rimonabant). J Clin Pharm Ther 37(3):260–265PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Hoddah H, Marcantoni A, Comunanza V, Carabelli V, Carbone E (2009) L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons. Cell Calcium 46(5–6):303–312PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Carpi S, Fogli S, Romanini A, Pellegrino M, Adinolfi B, Podesta A et al (2015) AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells. Anti-Cancer Drugs 26(7):754–762PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    White R, Ho WS, Bottrill FE, Ford WR, Hiley CR (2001) Mechanisms of anandamide-induced vasorelaxation in rat isolated coronary arteries. Br J Pharmacol 134(4):921–929PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Ishioka N, Bukoski RD (1999) A role for N-arachidonylethanolamine (anandamide) as the mediator of sensory nerve-dependent Ca2+-induced relaxation. J Pharmacol Exp Ther 289(1):245–250PubMedPubMedCentralGoogle Scholar
  170. 170.
    Baranowska-Kuczko M, Kozlowska H, Kozlowski M, Schlicker E, Kloza M, Surazynski A et al (2014) Mechanisms of endothelium-dependent relaxation evoked by anandamide in isolated human pulmonary arteries. Naunyn Schmiedeberg’s Arch Pharmacol 387(5):477–486CrossRefGoogle Scholar
  171. 171.
    Baranowska-Kuczko M, MacLean MR, Kozlowska H, Malinowska B (2012) Endothelium-dependent mechanisms of the vasodilatory effect of the endocannabinoid, anandamide, in the rat pulmonary artery. Pharmacol Res 66(3):251–259PubMedCrossRefGoogle Scholar
  172. 172.
    Stanley CP, Hind WH, Tufarelli C, O’Sullivan SE (2016) The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries. Pharmacol Res 113(Pt A):356–363PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Grainger J, Boachie-Ansah G (2001) Anandamide-induced relaxation of sheep coronary arteries: the role of the vascular endothelium, arachidonic acid metabolites and potassium channels. Br J Pharmacol 134(5):1003–1012PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Ho WS, Randall MD (2007) Endothelium-dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2-arachidonoylglycerol. Br J Pharmacol 150(5):641–651PubMedPubMedCentralCrossRefGoogle Scholar
  175. 175.
    Kagota S, Yamaguchi Y, Nakamura K, Sugiura T, Waku K, Kunitomo M (2001) 2-Arachidonoylglycerol, a candidate of endothelium-derived hyperpolarizing factor. Eur J Pharmacol 415(2-3):233–238PubMedCrossRefPubMedCentralGoogle Scholar
  176. 176.
    Mechoulam R, Fride E, Ben-Shabat S, Meiri U, Horowitz M (1998) Carbachol, an acetylcholine receptor agonist, enhances production in rat aorta of 2-arachidonoyl glycerol, a hypotensive endocannabinoid. Eur J Pharmacol 362(1):R1–R3PubMedCrossRefPubMedCentralGoogle Scholar
  177. 177.
    Stanley CP, O’Sullivan SE (2014) Cyclooxygenase metabolism mediates vasorelaxation to 2-arachidonoylglycerol (2-AG) in human mesenteric arteries. Pharmacol Res 81C:74–82CrossRefGoogle Scholar
  178. 178.
    Poblete IM, Orliac ML, Briones R, Adler-Graschinsky E, Huidobro-Toro JP (2005) Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol 568(Pt 2):539–551PubMedPubMedCentralCrossRefGoogle Scholar
  179. 179.
    Al Suleimani YM, Al Mahruqi AS, Hiley CR (2015) Mechanisms of vasorelaxation induced by the cannabidiol analogue compound O-1602 in the rat small mesenteric artery. Eur J Pharmacol 765:107–114PubMedCrossRefPubMedCentralGoogle Scholar
  180. 180.
    Al Kury LT, Voitychuk OI, Yang KH, Thayyullathil FT, Doroshenko P, Ramez AM et al (2014) Effects of endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes. Br J Pharmacol 171(14):3485–3498PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P (2001) Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J 20(24):7033–7040PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Lagaud GJ, Randriamboavonjy V, Roul G, Stoclet JC, Andriantsitohaina R (1999) Mechanism of Ca2+ release and entry during contraction elicited by norepinephrine in rat resistance arteries. Am J Phys 276(1 Pt 2):H300–H308Google Scholar
  183. 183.
    Zhang J, Ren C, Chen L, Navedo MF, Antos LK, Kinsey SP et al (2010) Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure. Am J Physiol Heart Circ Physiol 298(5):H1472–H1483PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Parmar N, Ho WS (2010) N-arachidonoyl glycine, an endogenous lipid that acts as a vasorelaxant via nitric oxide and large conductance calcium-activated potassium channels. Br J Pharmacol 160(3):594–603PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Ho WS, Yeung SYM (2009) Novel G-protein-coupled receptors in rat arteries: potential targets for N-arachidonoyl glycine? Proc Br Pharmacol Soc 7(4):060PGoogle Scholar
  186. 186.
    Milman G, Maor Y, Abu-Lafi S, Horowitz M, Gallily R, Batkai S et al (2006) N-arachidonoyl L-serine, an endocannabinoid-like brain constituent with vasodilatory properties. Proc Natl Acad Sci U S A 103(7):2428–2433PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM et al (2005) Evidence for novel cannabinoid receptors. Pharmacol Ther 106(2):133–145PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Bondarenko AI (2014) Endothelial atypical cannabinoid receptor: do we have enough evidence? Br J Pharmacol 171(24):5573–5588PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    MacIntyre J, Dong A, Straiker A, Zhu J, Howlett SE, Bagher A et al (2014) Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature. Eur J Pharmacol 735C:105–114CrossRefGoogle Scholar
  190. 190.
    O’Sullivan SE, Kendall DA, Randall MD (2004) Characterisation of the vasorelaxant properties of the novel endocannabinoid N-arachidonoyl-dopamine (NADA). Br J Pharmacol 141(5):803–812PubMedPubMedCentralCrossRefGoogle Scholar
  191. 191.
    Hoi PM, Visintin C, Okuyama M, Gardiner SM, Kaup SS, Bennett T et al (2007) Vascular pharmacology of a novel cannabinoid-like compound, 3-(5-dimethylcarbamoyl-pent-1-enyl)-N-(2-hydroxy-1-methyl-ethyl)benzamide (VSN16) in the rat. Br J Pharmacol 152(5):751–764PubMedPubMedCentralCrossRefGoogle Scholar
  192. 192.
    Bol M, Leybaert L, Vanheel B (2012) Influence of methanandamide and CGRP on potassium currents in smooth muscle cells of small mesenteric arteries. Pflugers Arch 463(5):669–677PubMedCrossRefPubMedCentralGoogle Scholar
  193. 193.
    Sade H, Muraki K, Ohya S, Hatano N, Imaizumi Y (2006) Activation of large-conductance, Ca2+-activated K+ channels by cannabinoids. Am J Phys Cell Physiol 290(1):C77–C86CrossRefGoogle Scholar
  194. 194.
    Bondarenko AI, Panasiuk O, Okhai I, Montecucco F, Brandt KJ, Mach F (2017) Direct activation of Ca2+- and voltage-gated potassium channels of large conductance by anandamide in endothelial cells does not support the presence of endothelial atypical cannabinoid receptor. Eur J Pharmacol 805:14–24PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Baker D, Pryce G, Visintin C, Sisay S, Bondarenko AI, Ho WSV et al (2017) Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol 174(16):2662–2681PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Dopico AM, Bukiya AN (2014) Lipid regulation of BK channel function. Front Physiol 5:312PubMedPubMedCentralGoogle Scholar
  197. 197.
    Bukiya AN, Durdagi S, Noskov S, Rosenhouse-Dantsker A (2017) Cholesterol up-regulates neuronal G protein-gated inwardly rectifying potassium (GIRK) channel activity in the hippocampus. J Biol Chem 292(15):6135–6147PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Bukiya AN, Osborn CV, Kuntamallappanavar G, Toth PT, Baki L, Kowalsky G et al (2015) Cholesterol increases the open probability of cardiac KACh currents. Biochim Biophys Acta 1848(10 Pt A):2406–2413PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Kannan KB, Barlos D, Hauser CJ (2007) Free cholesterol alters lipid raft structure and function regulating neutrophil Ca2+ entry and respiratory burst: correlations with calcium channel raft trafficking. J Immunol 178(8):5253–5261PubMedCrossRefPubMedCentralGoogle Scholar
  200. 200.
    Morales-Lazaro SL, Rosenbaum T (2017) Multiple mechanisms of regulation of transient receptor potential ion channels by cholesterol. Curr Top Membr 80:139–161PubMedCrossRefPubMedCentralGoogle Scholar
  201. 201.
    Beech DJ, Bahnasi YM, Dedman AM, Al-Shawaf E (2009) TRPC channel lipid specificity and mechanisms of lipid regulation. Cell Calcium 45(6):583–588PubMedPubMedCentralCrossRefGoogle Scholar
  202. 202.
    Dopico AM, Bukiya AN, Singh AK (2012) Large conductance, calcium- and voltage-gated potassium (BK) channels: regulation by cholesterol. Pharmacol Ther 135(2):133–150PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    Bukiya AN, Belani JD, Rychnovsky S, Dopico AM (2011) Specificity of cholesterol and analogs to modulate BK channels points to direct sterol-channel protein interactions. J Gen Physiol 137(1):93–110PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Dainese E, Oddi S, Maccarrone M (2010) Interaction of endocannabinoid receptors with biological membranes. Curr Med Chem 17(14):1487–1499PubMedCrossRefPubMedCentralGoogle Scholar
  205. 205.
    Di Scala C, Fantini J, Yahi N, Barrantes FJ, Chahinian H (2018) Anandamide revisited: how cholesterol and ceramides control receptor-dependent and receptor-independent signal transmission pathways of a lipid neurotransmitter. Biomolecules 22:8(2)Google Scholar
  206. 206.
    Di Scala C, Mazzarino M, Yahi N, Varini K, Garmy N, Fantini J et al (2017) Anandamide-ceramide interactions in a membrane environment: molecular dynamic simulations data. Data Brief 14:163–167PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    McHugh D, Hu SS, Rimmerman N, Juknat A, Vogel Z, Walker JM et al (2010) N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci 11:44PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Yin H, Chu A, Li W, Wang B, Shelton F, Otero F et al (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem 284(18):12328–12338PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Lu VB, Puhl HL 3rd, Ikeda SR (2013) N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. Mol Pharmacol 83(1):267–282PubMedPubMedCentralCrossRefGoogle Scholar
  210. 210.
    Finlay DB, Joseph WR, Grimsey NL, Glass M (2016) GPR18 undergoes a high degree of constitutive trafficking but is unresponsive to N-arachidonoyl glycine. PeerJ 4:e1835PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    El-Remessy AB, Rajesh M, Mukhopadhyay P, Horvath B, Patel V, Al-Gayyar MM et al (2011) Cannabinoid 1 receptor activation contributes to vascular inflammation and cell death in a mouse model of diabetic retinopathy and a human retinal cell line. Diabetologia 54(6):1567–1578PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Rajesh M, Batkai S, Kechrid M, Mukhopadhyay P, Lee WS, Horvath B et al (2012) Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 61(3):716–727PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Rajesh M, Mukhopadhyay P, Hasko G, Liaudet L, Mackie K, Pacher P (2010) Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol 160(3):688–700PubMedPubMedCentralCrossRefGoogle Scholar
  214. 214.
    Mach F, Steffens S (2008) The role of the endocannabinoid system in atherosclerosis. J Neuroendocrinol 20(Suppl 1):53–57PubMedCrossRefPubMedCentralGoogle Scholar
  215. 215.
    Lepicier P, Lagneux C, Sirois MG, Lamontagne D (2007) Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts. Life Sci 81(17-18):1373–1380PubMedCrossRefPubMedCentralGoogle Scholar
  216. 216.
    Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M et al (2009) CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol 46(5):612–620PubMedCrossRefGoogle Scholar
  217. 217.
    Hajrasouliha AR, Tavakoli S, Ghasemi M, Jabehdar-Maralani P, Sadeghipour H, Ebrahimi F et al (2008) Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur J Pharmacol 579(1-3):246–252PubMedCrossRefGoogle Scholar
  218. 218.
    Gonzalez C, Herradon E, Abalo R, Vera G, Perez-Nievas BG, Leza JC et al (2011) Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia-reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS. Diabetes Metab Res Rev 27(4):331–340PubMedCrossRefGoogle Scholar
  219. 219.
    Choi IY, Ju C, Anthony Jalin AM, Lee DI, Prather PL, Kim WK (2013) Activation of cannabinoid CB2 receptor-mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182(3):928–939PubMedCrossRefGoogle Scholar
  220. 220.
    Yu SJ, Reiner D, Shen H, Wu KJ, Liu QR, Wang Y (2015) Time-dependent protection of CB2 receptor agonist in stroke. PLoS One 10(7):e0132487PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Batkai S et al (2010) Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy. Free Radic Biol Med 48(3):457–467PubMedCrossRefGoogle Scholar
  222. 222.
    Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C et al (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434(7034):782–786PubMedCrossRefGoogle Scholar
  223. 223.
    Montecucco F, Di Marzo V, da Silva RF, Vuilleumier N, Capettini L, Lenglet S et al (2012) The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 33(7):846–856PubMedCrossRefGoogle Scholar
  224. 224.
    Zhao Y, Yuan Z, Liu Y, Xue J, Tian Y, Liu W et al (2010) Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol 55(3):292–298PubMedCrossRefGoogle Scholar
  225. 225.
    Mukhopadhyay P, Baggelaar M, Erdelyi K, Cao Z, Cinar R, Fezza F et al (2016) The novel, orally available and peripherally restricted selective cannabinoid CB2 receptor agonist LEI-101 prevents cisplatin-induced nephrotoxicity. Br J Pharmacol 173(3):446–458PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Ramirez SH, Hasko J, Skuba A, Fan S, Dykstra H, McCormick R et al (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32(12):4004–4016PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Steffens S, Mach F (2006) Towards a therapeutic use of selective CB2 cannabinoid receptor ligands for atherosclerosis. Futur Cardiol 2(1):49–53CrossRefGoogle Scholar
  228. 228.
    Pacher P, Mechoulam R (2011) Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 50(2):193–211PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Meletta R, Slavik R, Mu L, Rancic Z, Borel N, Schibli R et al (2017) Cannabinoid receptor type 2 (CB2) as one of the candidate genes in human carotid plaque imaging: evaluation of the novel radiotracer [11C]RS-016 targeting CB2 in atherosclerosis. Nucl Med Biol 47:31–43PubMedCrossRefGoogle Scholar
  230. 230.
    Rajesh M, Pan H, Mukhopadhyay P, Batkai S, Osei-Hyiaman D, Hasko G et al (2007) Cannabinoid-2 receptor agonist HU-308 protects against hepatic ischemia/reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis. J Leukoc Biol 82(6):1382–1389PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Biernacki M, Malinowska B, Timoszuk M, Toczek M, Jastrzab A, Remiszewski P et al (2018) Hypertension and chronic inhibition of endocannabinoid degradation modify the endocannabinoid system and redox balance in rat heart and plasma. Prostaglandins Other Lipid Mediat 138:54–63PubMedCrossRefPubMedCentralGoogle Scholar
  232. 232.
    Fernandez-Rodriguez CM, Romero J, Petros TJ, Bradshaw H, Gasalla JM, Gutierrez ML et al (2004) Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis. Liver Int 24(5):477–483PubMedCrossRefPubMedCentralGoogle Scholar
  233. 233.
    Domenicali M, Ros J, Fernández-Varo G, Cejudo-Martín P, Crespo M, Morales-Ruiz M et al (2005) Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats: role of cannabinoid and vanilloid receptors. Gut 54(4):522–527PubMedPubMedCentralCrossRefGoogle Scholar
  234. 234.
    Yang Y, Lin H, Huang Y, Lee T, Hou M, Wang Y et al (2007) Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis. Liver Int 27(8):1045–1055PubMedCrossRefPubMedCentralGoogle Scholar
  235. 235.
    Ho WS, Gardiner SM (2009) Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats. Br J Pharmacol 156(1):94–104PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Wheal AJ, Bennett T, Randall MD, Gardiner SM (2007) Cardiovascular effects of cannabinoids in conscious spontaneously hypertensive rats. Br J Pharmacol 152(5):717–724PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Varma DR, Goldbaum D (1975) Effect of delta9-tetrahydrocannabinol on experimental hypertension in rats. J Pharm Pharmacol 27(10):790–791PubMedCrossRefPubMedCentralGoogle Scholar
  238. 238.
    Wheal AJ, Jadoon K, Randall MD, O’Sullivan SE (2017) In vivo cannabidiol treatment improves endothelium-dependent vasorelaxation in mesenteric arteries of Zucker diabetic fatty rats. Front Pharmacol 8:248PubMedPubMedCentralCrossRefGoogle Scholar
  239. 239.
    Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K et al (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36(5):1077–1082PubMedCrossRefPubMedCentralGoogle Scholar
  240. 240.
    Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M et al (2007) Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 102(5):1488–1496PubMedCrossRefPubMedCentralGoogle Scholar
  241. 241.
    Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M et al (2008) Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism. Neuropharmacology 55(8):1280–1286PubMedCrossRefPubMedCentralGoogle Scholar
  242. 242.
    Rajesh M, Mukhopadhyay P, Batkai S, Patel V, Saito K, Matsumoto S et al (2011) Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol 56(25):2115–2125CrossRefGoogle Scholar
  243. 243.
    Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Drel VR et al (2007) Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circ Physiol 293(1):H610–H619PubMedPubMedCentralCrossRefGoogle Scholar
  244. 244.
    Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150(5):613–623CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Circulatory Physiology DepartmentBogomoletz Institute of Physiology National Academy of Sciences of UkraineKievUkraine

Personalised recommendations