American Journal of Cardiovascular Drugs

, Volume 7, Issue 4, pp 273–288 | Cite as

Impact of Weight-Loss Medications on the Cardiovascular System

Focus on Current and Future Anti-Obesity Drugs
Review Article


Overweight and obesity have been rising dramatically worldwide and are associated with numerous comorbidities such as cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD and CVD risks have also been documented in obese children. The majority of overweight and obese patients who achieve a significant short-term weight loss do not maintain their lower bodyweight in the long term. This may be due to a lack of intensive counseling and support from a facilitating environment including dedicated healthcare professionals such as nutritionists, kinesiologists, and behavior specialists. As a result, there has been a considerable focus on the role of adjunctive therapy such as pharmacotherapy for long-term weight loss and weight maintenance. Beyond an unfavorable risk factor profile, overweight and obesity also impact upon heart structure and function. Since the beginning, the quest for weight loss drugs has encountered warnings from regulatory agencies and the withdrawal from the market of efficient but unsafe medications. Fenfluramine was withdrawn from the market because of unacceptable pulmonary and cardiac adverse effects.

Nevertheless, there is extensive research directed at the development of new anti-obesity compounds. The effect of these molecules on CVD risk factors has been studied and reported but information regarding their impact on the cardiovascular system is sparse. Thus, instead of looking at the benefit of weight loss on metabolism and risk factor management, this article discusses the impact of weight loss medications on the cardiovascular system. The potential interaction of available and potential new weight loss drugs with heart function and structure is reviewed.


  1. 1.
    Executive summary of the clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Arch Intern Med 1998; 158: 1855–67.Google Scholar
  2. 2.
    Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2006; 113: 898–918.PubMedCrossRefGoogle Scholar
  3. 3.
    From the Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services interim public health recommendations. JAMA 1997; 278: 1729–31.CrossRefGoogle Scholar
  4. 4.
    Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997; 337: 581–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Weissman NJ, Tighe JFJ, Gottdiener JS, et al. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. Sustained-Release Dexfenfluramine Study Group. N Engl J Med 1998; 339: 725–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Khan MA, Herzog CA, St Peter JV, et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med 1998; 339: 713–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 335: 609–16.PubMedCrossRefGoogle Scholar
  8. 8.
    Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995; 92: 790–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Redfield MM, Nicholson WJ, Edwards WD, et al. Valve disease associated with ergot alkaloid use: echocardiographic and pathologic correlations. Ann Intern Med 1992; 117: 50–2.PubMedGoogle Scholar
  10. 10.
    Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 2000; 57: 75–81.PubMedGoogle Scholar
  11. 11.
    Mekontso-Dessap A, Brouri F, Pascal O, et al. Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice. Circulation 2006; 113: 81–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Rajamani S, Studenik C, Lemmens-Gruber R, et al. Cardiotoxic effects of fenfluramine hydrochloride on isolated cardiac preparations and ventricular myocytes of guinea-pigs. Br J Pharmacol 2000; 129: 843–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Setola V, Hufeisen SJ, Grande-Allen KJ, et al. 3,4-methylenediox-ymethamphetamine (MDMA, ‘Ecstasy’) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol Pharmacol 2003; 63: 1223–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Ryan DH, Bray GA, Helmcke F, et al. Serial echocardiographic and clinical evaluation of valvular regurgitation before, during, and after treatment with fenfluramine or dexfenfluramine and mazindol or phentermine. Obes Res 1999; 7: 313–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Jick H, Vasilakis C, Weinrauch LA, et al. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med 1998; 339: 719–24.PubMedCrossRefGoogle Scholar
  16. 16.
    Weissman NJ, Panza JA, Tighe JF, et al. Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy: a randomized, double-blind, placebo- controlled trial. Ann Intern Med 2001; 134: 267–73.PubMedGoogle Scholar
  17. 17.
    Mast ST, Jollis JG, Ryan T, et al. The progression of fenfluramine-associated valvular heart disease assessed by echocardiography. Ann Intern Med 2001; 134: 261–6.PubMedGoogle Scholar
  18. 18.
    Cannistra LB, Cannistra AJ. Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment [letter]. N Engl J Med 1998; 339: 771.PubMedCrossRefGoogle Scholar
  19. 19.
    Gardin JM, Schumacher D, Constantine G, et al. Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/ fenfluramine. JAMA 2000; 283: 1703–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Gardin JM, Weissman NJ, Leung C, et al. Clinical and echocardiographic follow-up of patients previously treated with dexfenfluramine or phentermine/fenfluramine. JAMA 2001; 286: 2011–4.PubMedCrossRefGoogle Scholar
  21. 21.
    Palmieri V, Arnett DK, Roman MJ, et al. Appetite suppressants and valvular heart disease in a population-based sample: the HyperGEN study. Am J Med 2002; 112:710–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Davidoff R, McTiernan A, Constantine G, et al. Echocardiographic examination of women previously treated with fenfluramine: long-term follow-up of a randomized, double-blind, placebo-controlled trial. Arch Intern Med 2001; 161: 1429–36.PubMedCrossRefGoogle Scholar
  23. 23.
    Weissman NJ, Panza JA, Tighe JF, et al. Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001; 134: 267–73.PubMedGoogle Scholar
  24. 24.
    McNeely W, Goa KL. Sibutramine: a review of its contribution to the management of obesity. Drugs 1998; 56: 1093–124.PubMedCrossRefGoogle Scholar
  25. 25.
    Lechin F, van der DB, Hernandez G, et al. Neurochemical, neuroautonomic and neuropharmacological acute effects of sibutramine in healthy subjects. Neurotoxicology 2006; 27: 184–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Nisoli E, Carruba MO. A benefit-risk assessment of sibutramine in the management of obesity. Drug Saf 2003; 26: 1027–48.PubMedCrossRefGoogle Scholar
  27. 27.
    Arterburn DE, Crane PK, Veenstra DL. The efficacy and safety of sibutramine for weight loss: a systematic review. Arch Intern Med 2004; 164: 994–1003.PubMedCrossRefGoogle Scholar
  28. 28.
    James WP, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group -Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 2000; 356: 2119–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Bach DS, Rissanen AM, Mendel CM, et al. Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res 1999; 7: 363–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Zannad F, Gille B, Grentzinger A, et al. Effects of sibutramine on ventricular dimensions and heart valves in obese patients during weight reduction. Am Heart J 2002; 144: 508–15.PubMedCrossRefGoogle Scholar
  31. 31.
    Guven A, Koksal N, Cetinkaya A, et al. Effects of the sibutramine therapy on pulmonary artery pressure in obese patients. Diabetes Obes Metab 2004; 6: 50–5.PubMedCrossRefGoogle Scholar
  32. 32.
    de Simone G, Romano C, De Caprio C, et al. Effects of sibutramine-induced weight loss on cardiovascular system in obese subjects. Nutr Metab Cardiovasc Dis 2005; 15: 24–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Atkinson RL. Use of drugs in the treatment of obesity. Annu Rev Nutr 1997; 17: 383–403.PubMedCrossRefGoogle Scholar
  34. 34.
    Birkenfeld AL, Schroeder C, Boschmann M, et al. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation 2002; 106: 2459–65.PubMedCrossRefGoogle Scholar
  35. 35.
    Wooltorton E. Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. CMAJ 2002; 166: 1307–8.PubMedGoogle Scholar
  36. 36.
    Deitel M. Sibutramine warning: hypertension and cardiac arrhythmias reported [letter]. Obes Surg 2002; 12: 422.PubMedCrossRefGoogle Scholar
  37. 37.
    McMahon FG, Weinstein SP, Rowe E, et al. Sibutramine is safe and effective for weight loss in obese patients whose hypertension is well controlled with angiotensin-converting enzyme inhibitors. J Hum Hypertens 2002; 16: 5–11.PubMedCrossRefGoogle Scholar
  38. 38.
    Sramek JJ, Leibowitz MT, Weinstein SP, et al. Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial. J Hum Hypertens 2002; 16: 13–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Sayin T, Guidai M. Sibutramine: possible cause of a reversible cardiomyopathy. Int J Cardiol 2005; 99: 481–2.PubMedCrossRefGoogle Scholar
  40. 40.
    Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord 1997; 21 Suppl. 3: S12–23.PubMedGoogle Scholar
  41. 41.
    Melia AT, Koss-Twardy SG, Zhi J. The effect of orlistat, an inhibitor of dietary fat absorption, on the absorption of vitamins A and E in healthy volunteers. J Clin Pharmacol 1996; 36: 647–53.PubMedGoogle Scholar
  42. 42.
    Sharma AM, Golay A. Effect of orlistat-induced weight loss on blood pressure and heart rate in obese patients with hypertension. J Hypertens 2002; 20: 1873–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Sekuri C, Tavli T, Avsar A, et al. The acute effect of orlistat on endothelial function in young obese women. Int J Clin Pharmacol Res 2003; 23: 111–7.PubMedGoogle Scholar
  44. 44.
    Sjostrom L, Rissanen A, Andersen T, et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998; 352: 167–72.PubMedCrossRefGoogle Scholar
  45. 45.
    O’Donovan D, Horowitz M, Russo A, et al. Effects of lipase inhibition on gastric emptying of, and on the glycaemic, insulin and cardiovascular responses to, a high-fat/carbohydrate meal in type 2 diabetes. Diabetologia 2004; 47: 2208–14.PubMedCrossRefGoogle Scholar
  46. 46.
    Beck-da-Silva L, Higginson L, Fraser M, et al. Effect of Orlistat in obese patients with heart failure: a pilot study. Congest Heart Fail 2005; 11: 118–23.PubMedCrossRefGoogle Scholar
  47. 47.
    Nagele H, Petersen B, Bonacker U, et al. Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient. Eur J Clin Pharmacol 1999; 55: 667–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Colman E, Fossler M. Reduction in blood cyclosporine concentrations by orlistat. N Engl J Med 2000; 342: 1141–2.PubMedCrossRefGoogle Scholar
  49. 49.
    Le Beller C, Bezie Y, Chabatte C, et al. Co-administration of orlistat and cyclosporine in a heart transplant recipient. Transplantation 2000; 70: 1541–2.PubMedCrossRefGoogle Scholar
  50. 50.
    Senechal M, Lemieux I, Beucler I, et al. Features of the metabolic syndrome of ‘hypertriglyceridemic waist’ and transplant coronary artery disease. J Heart Lung Transplant 2005; 24: 819–26.PubMedCrossRefGoogle Scholar
  51. 51.
    Devane WA, Dysarz III FA, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605–13.PubMedGoogle Scholar
  52. 52.
    Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561–4.PubMedCrossRefGoogle Scholar
  53. 53.
    Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–5.PubMedCrossRefGoogle Scholar
  54. 54.
    Ford WR, Honan SA, White R, et al. Evidence of a novel site mediating anandamide-induced negative inotropic and coronary vasodilatator responses in rat isolated hearts. Br J Pharmacol 2002; 135: 1191–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Bonz A, Laser M, Kullmer S, et al. Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 2003; 41: 657–64.PubMedCrossRefGoogle Scholar
  56. 56.
    Batkai S, Pacher P, Jarai Z, et al. Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors. Am J Physiol Heart Circ Physiol 2004; 287: H595–600.PubMedCrossRefGoogle Scholar
  57. 57.
    Pacher P, Batkai S, Kunos G. Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 2004; 558: 647–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Randall MD, Kendall DA. Involvement of a cannabinoid in endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation. Eur J Pharmacol 1997; 335: 205–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Maccarrone M, Lorenzon T, Bari M, et al. Anandamide induces apoptosis in human cells via vanilloid receptors: evidence for a protective role of cannabinoid receptors. J Biol Chem 2000; 275: 31938–45.PubMedCrossRefGoogle Scholar
  60. 60.
    Stefano GB, Salzet M, Bilfinger TV. Long-term exposure of human blood vessels to HIV gp120, morphine, and anandamide increases endothelial adhesion of monocytes: uncoupling of nitric oxide release. J Cardiovasc Pharmacol 1998; 31: 862–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 2004; 3: 771–84.PubMedCrossRefGoogle Scholar
  62. 62.
    Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995; 232: 54–61.PubMedCrossRefGoogle Scholar
  63. 63.
    Begg M, Pacher P, Batkai S, et al. Evidence for novel cannabinoid receptors. Pharmacol Ther 2005; 106: 133–45.PubMedCrossRefGoogle Scholar
  64. 64.
    Jarai Z, Wagner JA, Varga K, et al. Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 1999; 96: 14136–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Felder CC, Glass M. Cannabinoid receptors and their endogenous agonists. Annu Rev Pharmacol Toxicol 1998; 38: 179–200.PubMedCrossRefGoogle Scholar
  67. 67.
    Hanus L, Abu-Lafi S, Fride E, et al. 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 2001; 98: 3662–5.PubMedCrossRefGoogle Scholar
  68. 68.
    Porter AC, Sauer JM, Knierman MD, et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 2002; 301: 1020–4.PubMedCrossRefGoogle Scholar
  69. 69.
    Leggett JD, Aspley S, Beckett SR, et al. Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors. Br J Pharmacol 2004; 141: 253–62.PubMedCrossRefGoogle Scholar
  70. 70.
    Underdown NJ, Hiley CR, Ford WR. Anandamide reduces infarct size in rat isolated hearts subjected to ischaemia-reperfusion by a novel cannabinoid mechanism. Br J Pharmacol 2005; 146: 809–16.PubMedCrossRefGoogle Scholar
  71. 71.
    Fimiani C, Mattocks D, Cavani F, et al. Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release. Cell Signal 1999; 11: 189–93.PubMedCrossRefGoogle Scholar
  72. 72.
    Stefano GB, Liu Y, Goligorsky MS. Cannabinoid receptors are coupled to nitric oxide release in invertebrate immunocytes, microglia, and human monocytes. J Biol Chem 1996; 271: 19238–42.PubMedCrossRefGoogle Scholar
  73. 73.
    Varga K, Lake K, Martin BR, et al. Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 1995; 278: 279–83.PubMedCrossRefGoogle Scholar
  74. 74.
    Hu CP, Li NS, Peng J, et al. Involvement of vanilloid receptors in heat stress-induced delayed protection against myocardial ischemia-reperfusion injury. Neuropeptides 2003; 37: 233–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400: 452–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Sterin-Borda L, Del Zar CF, Borda E. Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria: endogenous signal transduction pathways. Biochem Pharmacol 2005; 69: 1705–13.PubMedCrossRefGoogle Scholar
  77. 77.
    Gebremedhin D, Lange AR, Campbell WB, et al. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 1999; 276: H2085–93.PubMedGoogle Scholar
  78. 78.
    Sugiura T, Kodaka T, Kondo S, et al. Inhibition by 2-arachidonoylglycerol, a novel type of possible neuromodulator, of the depolarization-induced increase in intracellular free calcium in neuroblastoma x glioma hybrid NG108–15 cells. Biochem Biophys Res Commun 1997; 233: 207–10.PubMedCrossRefGoogle Scholar
  79. 79.
    Lamontagne D, Lepicier P, Lagneux C, et al. The endogenous cardiac cannabinoid system: a new protective mechanism against myocardial ischemia. Arch Mal Coeur Vaiss 2006; 99: 242–6.PubMedGoogle Scholar
  80. 80.
    Lagneux C, Lamontagne D. Involvement of cannabinoids in the cardioprotection induced by lipopolysaccharide. Br J Pharmacol 2001; 132: 793–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Pacher P, Batkai S, Kunos G. Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 2004; 558: 647–57.PubMedCrossRefGoogle Scholar
  82. 82.
    Bouchard JF, Lepicier P, Lamontagne D. Contribution of endocannabinoids in the endothelial protection afforded by ischemic preconditioning in the isolated rat heart. Life Sci 2003; 72: 1859–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Wang Y, Liu Y, Ito Y, et al. Simultaneous measurement of anandamide and 2-arachidonoylglycerol by polymyxin B-selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock. Anal Biochem 2001; 294: 73–82.PubMedCrossRefGoogle Scholar
  84. 84.
    Gorelick DA, Heishman SJ, Preston KL, et al. The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers. Am Heart J 2006; 151: 754.el–5.CrossRefGoogle Scholar
  85. 85.
    Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434: 782–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Hiley CR, Ford WR. Cannabinoid pharmacology in the cardiovascular system: potential protective mechanisms through lipid signalling. Biol Rev Camb Philos Soc 2004; 79: 187–205.PubMedCrossRefGoogle Scholar
  87. 87.
    Joyeux M, Arnaud C, Godin-Ribuot D, et al. Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts. Cardiovasc Res 2002; 55: 619–25.PubMedCrossRefGoogle Scholar
  88. 88.
    Krylatov AV, Ugdyzhekova DS, Bernatskaya NA, et al. Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bull Exp Biol Med 2001; 131: 523–5.PubMedCrossRefGoogle Scholar
  89. 89.
    Lepicier P, Bouchard JF, Lagneux C, et al. Endocannabinoids protect the rat isolated heart against ischaemia. Br J Pharmacol 2003; 139: 805–15.PubMedCrossRefGoogle Scholar
  90. 90.
    Liu GS, Thornton J, Van Winkle DM, et al. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation 1991; 84: 350–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Vegh A, Szekeres L, Parratt J. Preconditioning of the ischaemic myocardium: involvement of the L-arginine nitric oxide pathway. Br J Pharmacol 1992; 107: 648–52.PubMedCrossRefGoogle Scholar
  92. 92.
    Szilvassy Z, Ferdinandy P, Bor P, et al. Ventricular overdrive pacing-induced anti-ischemic effect: a conscious rabbit model of preconditioning. Am J Physiol 1994; 266: H2033–41.PubMedGoogle Scholar
  93. 93.
    Di Filippo C, Rossi F, Rossi S, et al. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/ chemokines and PMN. J Leukoc Biol 2004; 75: 453–9.PubMedCrossRefGoogle Scholar
  94. 94.
    Ribuot C, Lamontagne D, Godin-Ribuot D. Cardiac and vascular effects of cannabinoids: toward a therapeutic use? [in French]. Ann Cardiol Angeiol (Paris) 2005; 54: 89–96.CrossRefGoogle Scholar
  95. 95.
    Wagner JA, Hu K, Bauersachs J, et al. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 2001; 38: 2048–54.PubMedCrossRefGoogle Scholar
  96. 96.
    Lagneux C, Adam A, Lamontagne D. A study of the mediators involved in the protection induced by exogenous kinins in the isolated rat heart. Int Immunopharmacol 2003; 3: 1511–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Landsman RS, Burkey TH, Consroe P, et al. SR141716A is an inverse agonist at the human cannabinoid CB1 receptor. Eur J Pharmacol 1997; 334: R1–2.PubMedCrossRefGoogle Scholar
  98. 98.
    Batkai S, Pacher P, Osei-Hyiaman D, et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 2004; 110: 1996–2002.PubMedCrossRefGoogle Scholar
  99. 99.
    MacLennan SJ, Reynen PH, Kwan J, et al. Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol 1998; 124: 619–22.PubMedCrossRefGoogle Scholar
  100. 100.
    Howlett AC, Barth F, Bonner TI, et al. International Union of Pharmacology: XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002; 54: 161–202.PubMedCrossRefGoogle Scholar
  101. 101.
    Pertwee RG. Pharmacology of cannabinoid receptor ligands. Curr Med Chem 1999; 6: 635–64.PubMedGoogle Scholar
  102. 102.
    Mittleman MA, Lewis RA, Maclure M, et al. Triggering myocardial infarction by marijuana. Circulation 2001; 103: 2805–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Bachs L, Morland H. Acute cardiovascular fatalities following cannabis use. Forensic Sci Int 2001; 124: 200–3.PubMedCrossRefGoogle Scholar
  104. 104.
    Petronis KR, Anthony JC. An epidemiologic investigation of marijuana- and cocaine-related palpitations. Drug Alcohol Depend 1989; 23: 219–26.PubMedCrossRefGoogle Scholar
  105. 105.
    Kosior DA, Filipiak KJ, Stolarz P, et al. Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol 2001; 78: 183–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Singh GK. Atrial fibrillation associated with marijuana use. Pediatr Cardiol 2000; 21: 284.PubMedCrossRefGoogle Scholar
  107. 107.
    Benowitz NL, Jones RT. Prolonged delta-9-tetrahydrocannabinol ingestion: effects of sympathomimetic amines and autonomic blockades. Clin Pharmacol Ther 1977; 21: 336–42.PubMedGoogle Scholar
  108. 108.
    Pars HG, Howes JF. Potential therapeutic agents derived from the cannabinoid nucleus. Adv Drug Res 1977; 11: 97–189.PubMedGoogle Scholar
  109. 109.
    Benowitz NL, Jones RT. Cardiovascular effects of prolonged delta-9-tetrahydrocannabinol ingestion. Clin Pharmacol Ther 1975; 18: 287–97.PubMedGoogle Scholar
  110. 110.
    Kanakis Jr C, Pouget JM, Rosen KM. The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. Circulation 1976; 53: 703–7.PubMedCrossRefGoogle Scholar
  111. 111.
    Jones RT. Cardiovascular system effects of marijuana. J Clin Pharmacol 2002; 42: 58S–63S.PubMedGoogle Scholar
  112. 112.
    Kanakis C, Pouget M, Rosen KM. Lack of cardiovascular effects of delta-9-tetrahydrocannabinol in chemically denervated men. Ann Intern Med 1979; 91: 571–4.PubMedGoogle Scholar
  113. 113.
    Gash A, Karliner JS, Janowsky D, et al. Effects of smoking marihuana on left ventricular performance and plasma norepinephrine: studies in normal men. Ann Intern Med 1978; 89: 448–52.PubMedGoogle Scholar
  114. 114.
    Aronow WS, Cassidy J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. N Engl J Med 1974; 291: 65–7.PubMedCrossRefGoogle Scholar
  115. 115.
    Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365: 1389–97.PubMedCrossRefGoogle Scholar
  116. 116.
    Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 2005; 353: 2121–34.PubMedCrossRefGoogle Scholar
  117. 117.
    Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America. A randomized controlled trial. JAMA 2006; 295: 761–75.PubMedCrossRefGoogle Scholar
  118. 118.
    Scheen AJ, Finer N, Hollander P, et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006; 368: 1660–72.PubMedCrossRefGoogle Scholar
  119. 119.
    Depre C, Vanoverschelde JL, Taegtmeyer H. Glucose for the heart. Circulation 1999; 99: 578–88.PubMedCrossRefGoogle Scholar
  120. 120.
    King LM, Opie LH. Glucose and glycogen utilisation in myocardial ischemia: changes in metabolism and consequences for the myocyte. Mol Cell Biochem 1998; 180: 3–26.PubMedCrossRefGoogle Scholar
  121. 121.
    Lopaschuk GD, Belke DD, Gamble J, et al. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994; 1213: 263–76.PubMedCrossRefGoogle Scholar
  122. 122.
    Dennis SC, Gevers W, Opie LH. Protons in ischemia: where do they come from; where do they go to? J Mol Cell Cardiol 1991; 23: 1077–86.PubMedCrossRefGoogle Scholar
  123. 123.
    Liu B, Clanachan AS, Schulz R, et al. Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res 1996; 79: 940–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Tracey WR, Treadway JL, Magee WP, et al. Cardioprotective effects of ingliforib, a novel glycogen phosphorylase inhibitor. Am J Physiol Heart Circ Physiol 2004; 286: HI 177–84.Google Scholar
  125. 125.
    Efendic S, Portwood N. Overview of incretin hormones. Horm Metab Res 2004; 36: 742–6.PubMedCrossRefGoogle Scholar
  126. 126.
    Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26: 2929–40.PubMedCrossRefGoogle Scholar
  127. 127.
    Poon T, Nelson P, Shen L, et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther 2005; 7: 467–77.PubMedCrossRefGoogle Scholar
  128. 128.
    Fineman MS, Bicsak TA, Shen LZ, et al. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003; 26: 2370–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628–35.PubMedCrossRefGoogle Scholar
  130. 130.
    Kendall DM, Riddle MC, Rosenstock J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083–91.PubMedCrossRefGoogle Scholar
  131. 131.
    DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092–100.CrossRefGoogle Scholar
  132. 132.
    Barragan JM, Rodriguez RE, Blazquez E. Changes in arterial blood pressure and heart rate induced by glucagon-like peptide-l-(7–36) amide in rats. Am J Physiol 1994; 266: E459–66.PubMedGoogle Scholar
  133. 133.
    Yamamoto H, Lee CE, Marcus JN, et al. Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomie regulatory neurons. J Clin Invest 2002; 110: 43–52.PubMedGoogle Scholar
  134. 134.
    Gros R, You X, Baggio LL, et al. Cardiac function in mice lacking the glucagonlike peptide-1 receptor. Endocrinology 2003; 144: 2242–52.PubMedCrossRefGoogle Scholar
  135. 135.
    Ahren B. GLP-1 and extra-islet effects. Horm Metab Res 2004; 36: 842–5.PubMedCrossRefGoogle Scholar
  136. 136.
    Nickola MW, Wold LE, Colligan PB, et al. Leptin attenuates cardiac contraction in rat ventricular myocytes: role of NO. Hypertension 2000; 36: 501–5.PubMedCrossRefGoogle Scholar
  137. 137.
    Illiano G, Naviglio S, Pagano M, et al. Leptin affects adenylate cyclase activity in H9c2 cardiac cell line: effects of short- and long-term exposure. Am J Hypertens 2002; 15: 638–43.PubMedCrossRefGoogle Scholar
  138. 138.
    Barouch LA, Berkowitz DE, Harrison RW, et al. Disruption of leptin signaling contributes to cardiac hypertrophy independently of body weight in mice. Circulation 2003; 108: 754–9.PubMedCrossRefGoogle Scholar
  139. 139.
    Rajapurohitam V, Gan XT, Kirshenbaum LA, et al. The obesity-associated peptide leptin induces hypertrophy in neonatal rat ventricular myocytes. Circ Res 2003; 93: 277–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996; 334: 292–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Bray GA, York DA. Clinical review 90: leptin and clinical medicine: a new piece in the puzzle of obesity. J Clin Endocrinol Metab 1997; 82: 2771–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387: 903–8.PubMedCrossRefGoogle Scholar
  143. 143.
    Sader S, Nian M, Liu P. Leptin: a novel link between obesity, diabetes, cardiovascular risk, and ventricular hypertrophy. Circulation 2003; 108: 644–6.PubMedCrossRefGoogle Scholar
  144. 144.
    Sweeney G. Leptin signalling. Cell Signal 2002; 14: 655–63.PubMedCrossRefGoogle Scholar
  145. 145.
    Wold LE, Relling DP, Duan J, et al. Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/ STAT pathway. Hypertension 2002; 39: 69–74.PubMedCrossRefGoogle Scholar
  146. 146.
    Xu FP, Chen MS, Wang YZ, et al. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 2004; 110: 1269–75.PubMedCrossRefGoogle Scholar
  147. 147.
    Collins S, Daniel KW, Rohlfs EM, et al. Impaired expression and functional activity of the beta 3- and beta 1-adrenergic receptors in adipose tissue of congenitally obese (C57BL/6J ob/ob) mice. Mol Endocrinol 1994; 8: 518–27.PubMedCrossRefGoogle Scholar
  148. 148.
    Collins S, Surwit RS. The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 2001; 56: 309–28.PubMedCrossRefGoogle Scholar
  149. 149.
    Bachman ES, Dhillon H, Zhang CY, et al. BetaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 2002; 297: 843–5.PubMedCrossRefGoogle Scholar
  150. 150.
    Bristow MR, Hershberger RE, Port JD, et al. Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 1990; 82: 112–25.CrossRefGoogle Scholar
  151. 151.
    Minhas KM, Khan SA, Raju SV, et al. Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. J Physiol 2005; 565: 463–74.PubMedCrossRefGoogle Scholar
  152. 152.
    Tsutsumi K. Lipoprotein lipase and atherosclerosis. Curr Vasc Pharmacol 2003; 1: 11–7.PubMedCrossRefGoogle Scholar
  153. 153.
    Eckel RH. Lipoprotein lipase: a multifunctional enzyme relevant to common metabolic diseases. N Engl b-J Med 1989; 320: 1060–8.CrossRefGoogle Scholar
  154. 154.
    Tsutsumi K, Inoue Y, Shima A, et al. The novel compound NO-1886 increases lipoprotein lipase activity with resulting elevation of high density lipoprotein cholesterol, and long-term administration inhibits atherogenesis in the coronary arteries of rats with experimental atherosclerosis. J Clin Invest 1993; 92: 411–7.PubMedCrossRefGoogle Scholar
  155. 155.
    Kern PA, Ong JM, Saffari B, et al. The effects of weight loss on the activity and expression of adipose-tissue lipoprotein lipase in very obese humans. N Engl J Med 1990; 322: 1053–9.PubMedCrossRefGoogle Scholar
  156. 156.
    Sadur CN, Yost TJ, Eckel RH. Insulin responsiveness of adipose tissue lipoprotein lipase is delayed but preserved in obesity. J Clin Endocrinol Metab 1984; 59: 1176–82.PubMedCrossRefGoogle Scholar
  157. 157.
    Levak-Frank S, Radner H, Walsh A, et al. Muscle-specific overexpression of lipoprotein lipase causes a severe myopathy characterized by proliferation of mitochondria and peroxisomes in transgenic mice. J Clin Invest 1995; 96: 976–86.PubMedCrossRefGoogle Scholar
  158. 158.
    Jensen DR, Schlaepfer IR, Morin CL, et al. Prevention of diet-induced obesity in transgenic mice overexpressing skeletal muscle lipoprotein lipase. Am J Physiol 1997; 273: R683–9.PubMedGoogle Scholar
  159. 159.
    Kusunoki M, Hara T, Tsutsumi K, et al. The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet. Diabetologia 2000; 43: 875–80.PubMedCrossRefGoogle Scholar
  160. 160.
    Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997; 88: 131–41.PubMedCrossRefGoogle Scholar
  161. 161.
    Fan W, Boston BA, Kesterson RA, et al. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 1997; 385: 165–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Giraudo SQ, Billington CJ, Levine AS. Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands. Brain Res 1998; 809: 302–6.PubMedCrossRefGoogle Scholar
  163. 163.
    Nordheim U, Nicholson JR, Dokladny K, et al. Cardiovascular responses to melanocortin 4-receptor stimulation in conscious unrestrained normotensive rats. Peptides 2006; 27: 438–43.PubMedCrossRefGoogle Scholar
  164. 164.
    Davignon J. Prospects for drug therapy for hyperlipoproteinaemia. Diabete Metab 1995; 21: 139–46.PubMedGoogle Scholar
  165. 165.
    Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001; 81: 1097–142.PubMedGoogle Scholar
  166. 166.
    Engler H, Riesen WF. Effect of thyroid function on concentrations of lipoprotein(a). Clin Chem 1993; 39: 2466–9.PubMedGoogle Scholar
  167. 167.
    de Bruin TW, van Barlingen H, Linde-Sibenius TM, et al. Lipoprotein(a) and apolipoprotein B plasma concentrations in hypothyroid, euthyroid, and hyperthyroid subjects. J Clin Endocrinol Metab 1993; 76: 121–6.PubMedCrossRefGoogle Scholar
  168. 168.
    Lazar MA. Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993; 14: 184–93.PubMedGoogle Scholar
  169. 169.
    Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001; 344: 501–9.PubMedCrossRefGoogle Scholar
  170. 170.
    Forrest D, Vennstrom B. Functions of thyroid hormone receptors in mice. Thyroid 2000; 10: 41–52.PubMedCrossRefGoogle Scholar
  171. 171.
    Wikstrom L, Johansson C, Salto C, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 1998; 17: 455–61.PubMedCrossRefGoogle Scholar
  172. 172.
    Johansson C, Vennstrom B, Thoren P. Evidence that decreased heart rate in thyroid hormone receptor-alphal-deficient mice is an intrinsic defect. Am J Physiol 1998; 275: R640–6.PubMedGoogle Scholar
  173. 173.
    Gloss B, Trost S, Bluhm W, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology 2001; 142: 544–50.PubMedCrossRefGoogle Scholar
  174. 174.
    Schwartz HL, Strait KA, Ling NC, et al. Quantitation of rat tissue thyroid hormone binding receptor isoforms by immunoprecipitation of nuclear triiodothyronine binding capacity. J Biol Chem 1992; 267: 11794–9.PubMedGoogle Scholar
  175. 175.
    Trost SU, Swanson E, Gloss B, et al. The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 2000; 141: 3057–64.PubMedCrossRefGoogle Scholar
  176. 176.
    Ribeiro MO, Carvalho SD, Schultz JJ, et al. Thyroid hormone: sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform-specific. J Clin Invest 2001; 108: 97–105.PubMedGoogle Scholar
  177. 177.
    Weiss RE, Murata Y, Cua K, et al. Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. Endocrinology 1998; 139: 4945–52.PubMedCrossRefGoogle Scholar
  178. 178.
    Ye L, Li YL, Mellstrom K, et al. Thyroid receptor ligands: 1. Agonist ligands selective for the thyroid receptor betal. J Med Chem 2003; 46: 1580–8.PubMedCrossRefGoogle Scholar
  179. 179.
    Iossa S, Liverini G, Barletta A. Relationship between the resting metabolic rate and hepatic metabolism in rats: effect of hyperthyroidism and fasting for 24 hours. J Endocrinol 1992; 135: 45–51.PubMedCrossRefGoogle Scholar
  180. 180.
    Oppenheimer JH, Schwartz HL, Lane JT, et al. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis, and thermogenesis in the rat. J Clin Invest 1991; 87: 125–32.PubMedCrossRefGoogle Scholar
  181. 181.
    Grover GJ, Mellstrom K, Ye L, et al. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A 2003; 100: 10067–72.PubMedCrossRefGoogle Scholar
  182. 182.
    Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.PubMedCrossRefGoogle Scholar
  183. 183.
    Zhang C, Hein TW, Wang W, et al. Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. J Mol Cell Cardiol 2006; 40: 247–57.PubMedCrossRefGoogle Scholar
  184. 184.
    Zhang C, Xu X, Potter BJ, et al. TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol 2006; 26: 475–80.PubMedCrossRefGoogle Scholar
  185. 185.
    Bagi Z, Koller A, Kaley G. PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with type 2 diabetes. Am J Physiol Heart Circ Physiol 2004; 286: H742–8.PubMedCrossRefGoogle Scholar
  186. 186.
    Verges B. Clinical interest of PPARs ligands. Diabetes Metab 2004; 30: 7–12.PubMedCrossRefGoogle Scholar
  187. 187.
    Moller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001; 414: 821–7.PubMedCrossRefGoogle Scholar
  188. 188.
    Picchi A, Gao X, Belmadani S, et al. Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 2006; 99: 69–77.PubMedCrossRefGoogle Scholar
  189. 189.
    Wang X, Feuerstein GZ, Xu L, et al. Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. Mol Pharmacol 2004; 65: 890–6.PubMedCrossRefGoogle Scholar
  190. 190.
    Kalra SP, Dube MG, Pu S, et al. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr Rev 1999; 20: 68–100.PubMedCrossRefGoogle Scholar
  191. 191.
    Billington CJ, Briggs JE, Harker S, et al. Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Physiol 1994; 266: R1765–70.PubMedGoogle Scholar
  192. 192.
    Broberger C, Landry M, Wong H, et al. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 1997; 66: 393–408.PubMedCrossRefGoogle Scholar
  193. 193.
    Stricker-Krongrad A, Kozak R, Burlet C, et al. Physiological regulation of hypothalamic neuropeptide Y release in lean and obese rats. Am J Physiol 1997; 273: R2112–6.PubMedGoogle Scholar
  194. 194.
    Wilding JP, Gilbey SG, Mannan M, et al. Increased neuropeptide Y content in individual hypothalamic nuclei, but not neuropeptide Y mRNA, in diet-induced obesity in rats. J Endocrinol 1992; 132: 299–304.PubMedCrossRefGoogle Scholar
  195. 195.
    Harland D, Bennett T, Gardiner SM. Cardiovascular actions of neuropeptide Y in the hypothalamic paraventricular nucleus of conscious Long Evans and Brattleboro rats. Neurosci Lett 1988; 85: 239–43.PubMedCrossRefGoogle Scholar
  196. 196.
    van Dijk G, Bottone AE, Strubbe JH, et al. Hormonal and metabolic effects of paraventricular hypothalamic administration of neuropeptide Y during rest and feeding. Brain Res 1994; 660: 96–103.PubMedCrossRefGoogle Scholar
  197. 197.
    Van Ness JM, DeMaria JE, Overton JM. Increased NPY activity in the PVN contributes to food-restriction induced reductions in blood pressure in aortic coarctation hypertensive rats. Brain Res 1999; 821: 263–9.CrossRefGoogle Scholar
  198. 198.
    Carter DA, Vallejo M, Lightman SL. Cardiovascular effects of neuropeptide Y in the nucleus tractus solitarius of rats: relationship with noradrenaline and vasopressin. Peptides 1985; 6: 421–5.PubMedCrossRefGoogle Scholar
  199. 199.
    Michel MC, Beck-Sickinger A, Cox H, et al. XVI. International Union of Pharmacology recommendations for the nomenclature of neuropeptide Y, peptide YY, and pancreatic polypeptide receptors. Pharmacol Rev 1998; 50: 143–50.PubMedGoogle Scholar
  200. 200.
    Adrian TE, Ferri GL, Bacarese-Hamilton AJ, et al. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985; 89: 1070–7.PubMedGoogle Scholar
  201. 201.
    Pedersen-Bjergaard U, Host U, Kelbaek H, et al. Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man. Scand J Clin Lab Invest 1996; 56: 497–503.PubMedCrossRefGoogle Scholar
  202. 202.
    Keire DA, Bowers CW, Solomon TE, et al. Structure and receptor binding of PYY analogs. Peptides 2002; 23: 305–21.PubMedCrossRefGoogle Scholar
  203. 203.
    Batterham RL, Cowley MA, Small CJ, et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 2002; 418: 650–4.PubMedCrossRefGoogle Scholar
  204. 204.
    Nordheim U, Hofbauer KG. Stimulation of NPY Y2 receptors by PYY3-36 reveals divergent cardiovascular effects of endogenous NPY in rats on different dietary regimens. Am J Physiol Regul Integr Comp Physiol 2004; 286: R138–42.PubMedCrossRefGoogle Scholar
  205. 205.
    Beck B, Jhanwar-Uniyal M, Burlet A, et al. Rapid and localized alterations of neuropeptide Y in discrete hypothalamic nuclei with feeding status. Brain Res 1990; 528: 245–9.PubMedCrossRefGoogle Scholar
  206. 206.
    Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881–7.PubMedCrossRefGoogle Scholar
  207. 207.
    Kopelman PG. Hormones and obesity. Baillieres Clin Endocrinol Metab 1994; 8: 549–75.PubMedCrossRefGoogle Scholar
  208. 208.
    Jessop DS, Dallman MF, Fleming D, et al. Resistance to glucocorticoid feedback in obesity. J Clin Endocrinol Metab 2001; 86: 4109–14.PubMedCrossRefGoogle Scholar
  209. 209.
    Rebuffe-Scrive M, Bronnegard M, Nilsson A, et al. Steroid hormone receptors in human adipose tissues. J Clin Endocrinol Metab 1990; 71: 1215–9.PubMedCrossRefGoogle Scholar
  210. 210.
    Stewart PM, Tomlinson JW. Cortisol, 11 beta-hydroxysteroid dehydrogenase type 1 and central obesity. Trends Endocrinol Metab 2002; 13: 94–6.PubMedCrossRefGoogle Scholar
  211. 211.
    Seckl JR, Morton NM, Chapman KE, et al. Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. Recent Prog Horm Res 2004; 59: 359–93.PubMedCrossRefGoogle Scholar
  212. 212.
    Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 2000; 141: 560–3.PubMedCrossRefGoogle Scholar
  213. 213.
    Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science 2001; 294: 2166–70.PubMedCrossRefGoogle Scholar
  214. 214.
    Masuzaki H, Yamamoto H, Kenyon CJ, et al. Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest 2003; 112: 83–90.PubMedGoogle Scholar
  215. 215.
    Hermanowski-Vosatka A, Balkovec JM, Cheng K, et al. 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 2005; 202: 517–27.PubMedCrossRefGoogle Scholar
  216. 216.
    Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect ‘Cushing’s disease of the omentum’? Lancet 1997; 349: 1210–3.PubMedCrossRefGoogle Scholar
  217. 217.
    Rask E, Olsson T, Soderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 2001; 86: 1418–21.PubMedCrossRefGoogle Scholar
  218. 218.
    Rask E, Walker BR, Soderberg S, et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 2002; 87: 3330–6.PubMedCrossRefGoogle Scholar
  219. 219.
    Paulmyer-Lacroix O, Boullu S, Oliver C, et al. Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab 2002; 87: 2701–5.PubMedCrossRefGoogle Scholar
  220. 220.
    Tomlinson JW, Sinha B, Bujalska I, et al. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab 2002; 87: 5630–5.PubMedCrossRefGoogle Scholar
  221. 221.
    Lindsay RS, Wake DJ, Nair S, et al. Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pirna Indians and Caucasians. J Clin Endocrinol Metab 2003; 88: 2738–44.PubMedCrossRefGoogle Scholar
  222. 222.
    Walker BR, Seckl JR. 11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease. Expert Opin Ther Targets 2003; 7: 771–83.PubMedCrossRefGoogle Scholar
  223. 223.
    Alberts P, Engblom L, Edling N, et al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia 2002; 45: 1528–32.PubMedCrossRefGoogle Scholar
  224. 224.
    Alberts P, Nilsson C, Selen G, et al. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology 2003; 144: 4755–62.PubMedCrossRefGoogle Scholar
  225. 225.
    Walker BR, Connacher AA, Lindsay RM, et al. Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing1 glucocorticoid receptor activation. J Clin Endocrinol Metab 1995; 80: 3155–9.PubMedCrossRefGoogle Scholar
  226. 226.
    Andrews RC, Rooyackers O, Walker BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 285–91.PubMedCrossRefGoogle Scholar
  227. 227.
    Livingstone DE, Walker BR. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats. J Pharmacol Exp Ther 2003; 305: 167–72.PubMedCrossRefGoogle Scholar
  228. 228.
    Sandeep TC, Andrew R, Homer NZ, et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 2005; 54: 872–9.PubMedCrossRefGoogle Scholar
  229. 229.
    Hermanowski-Vosatka A, Balkovec JM, Cheng K, et al. 11beta-HSDl inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 2005; 202: 517–27.PubMedCrossRefGoogle Scholar
  230. 230.
    Nosadini R, Del Prato S, Tiengo A, et al. Insulin resistance in Cushing’s syndrome. J Clin Endocrinol Metab 1983; 57: 529–36.PubMedCrossRefGoogle Scholar
  231. 231.
    Page R, Boolell M, Kalfas A, et al. Insulin secretion, insulin sensitivity and glucose-mediated glucose disposal in Cushing’s disease: a minimal model analysis. Clin Endocrinol (Oxf) 1991; 35: 509–17.CrossRefGoogle Scholar
  232. 232.
    Faggiano A, Pivonello R, Spiezia S, et al. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 2003; 88: 2527–33.PubMedCrossRefGoogle Scholar
  233. 233.
    Glorioso N, Filigheddu F, Parpaglia PP, et al. 11beta-Hydroxysteroid dehydrogenase type 2 activity is associated with left ventricular mass in essential hypertension. Eur Heart J 2005; 26: 498–504.PubMedCrossRefGoogle Scholar
  234. 234.
    Sheppard KE. Corticosteroid receptors, 11 beta-hydroxysteroid dehydrogenase, and the heart. Vitam Horm 2003; 66: 77–112.PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Benoit Drolet
    • 1
    • 2
  • Chantale Simard
    • 1
    • 2
  • Paul Poirier
    • 1
    • 2
  1. 1.Laval HospitalInstitut universitaire de cardiologie et de pneumologieQuebec CityCanada
  2. 2.Faculty of PharmacyLaval UniversityQuebec CityCanada

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