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The latest generation of beta-blockers: New pharmacologic properties

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Abstract

β-Blockers have generally demonstrated smaller reductions in cardiovascular events, compared with other antihypertensive classes, despite similar reductions in blood pressure. This may be due to the ineffectiveness of traditional β-blockers, such as atenolol, in reducing central aortic pressure, a strong, independent predictor of cardiovascular outcome. However, the β-blocker class is heterogeneous, and some newer β-blockers, which exhibit vasodilatory effects independent of β-blockade, provide beneficial effects on arterial stiffness and endothelial dysfunction, which may lead to reductions in central aortic pressure and improvements in clinical outcomes. For example, the vasodilating β-blocker nebivolol was shown to improve forearm blood flow and arterial stiffness and, in a large clinical study, to significantly reduce morbidity and mortality, independent of left ventricular ejection fraction, among patients with chronic heart failure. Further research is warranted to investigate any potential differences between traditional and newer vasodilating β-blockers on cardiovascular outcomes.

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References and Recommended Reading

  1. Egan BM, Basile J, Chilton RJ, Cohen JD: Cardioprotection: the role of beta-blocker therapy. J Clin Hypertens (Greenwich) 2005, 7:409–416. A comprehensive review of the role of β-blockers in the management of cardiovascular disease.

    CAS  Google Scholar 

  2. Hollenberg NK: The role of beta-blockers as a cornerstone of cardiovascular therapy. Am J Hypertens 2005, 18(Suppl 1):165S-168S.

    Article  PubMed  CAS  Google Scholar 

  3. Bristow MR: Beta-adrenergic receptor blockade in chronic heart failure. Circulation 2000, 101:558–569.

    PubMed  CAS  Google Scholar 

  4. Hebert PR, Moser M, Mayer J, et al.: Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med 1993, 153:578–581.

    Article  PubMed  CAS  Google Scholar 

  5. Cockcroft JR, Dollery CT: The diuretic dilemma. In The Handbook of Hypertension, vol. 13: The Management of Hypertension. Edited by Bühler FR, Laragh JH. Amsterdam: Elsevier; 1990:202–216.

    Google Scholar 

  6. MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992, 304:405–412.

    Article  Google Scholar 

  7. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002, 288:2981–2997.

    Article  Google Scholar 

  8. Blood Pressure Lowering Treatment Trialists’ Collaboration: Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000, 356:1955–1964.

    Article  Google Scholar 

  9. Staessen JA, Wang J-G, Thijs L: Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001, 358:1305–1315.

    Article  PubMed  CAS  Google Scholar 

  10. Blood Pressure Lowering Treatment Trialists’ Collaboration: Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectivelydesigned overviews of randomised trials. Lancet 2003, 362:1527–1535.

    Article  CAS  Google Scholar 

  11. Lindholm LH, Carlberg B, Samuelsson O: Should betablockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005, 366:1545–1553. A meta-analysis evaluating the cardioprotective properties of the β-blocker class and, in particular, of the traditional β-blocker atenolol.

    Article  PubMed  CAS  Google Scholar 

  12. Carlberg B, Samuelsson O, Lindholm LH: Atenolol in hypertension: Is it a wise choice? Lancet 2004, 364:1684–1689.

    Article  PubMed  CAS  Google Scholar 

  13. Dahlöf B, Devereux RB, Kjeldsen SE, et al.: for the LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet 2002, 359:995–1003.

    Article  PubMed  Google Scholar 

  14. Dahlöf B, Sever PS, Poulter NR, et al.: for the ASCOT Investigators: Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005, 366:895–906. This trial showed that an ACE inhibitor/CCB combination was superior to a β-blocker/diuretic combination in preventing cardiovascular events in hypertensive patients.

    Article  PubMed  CAS  Google Scholar 

  15. Beevers DG: The end of beta-blockers for uncomplicated hypertension? Lancet 2005, 366:1510–1512.

    Article  PubMed  Google Scholar 

  16. O’Rourke MF, Brunner HR: Introduction to arterial compliance and function. J Hypertens Suppl 1992, 10:S3-S5.

    Article  PubMed  CAS  Google Scholar 

  17. O’Rourke MF, Kelly RP: Wave reflection in the systemic circulation and its implications in ventricular function. J Hypertens 1993, 11:327–337.

    Article  PubMed  CAS  Google Scholar 

  18. Nichols WW: Clinical measurement of arterial stiffness obtained from non-invasive pressure waveforms. Am J Hypertens 2005, 18(Suppl 1):S3-S10. A comprehensive review of the importance of arterial stiffness and central aortic pressure in the assessment of cardiovascular risk in the hypertensive patient.

    Article  Google Scholar 

  19. Wilkinson IB, Cockcroft JR: Cholesterol, endothelial function and cardiovascular disease. Curr Opin Lipidol 1998, 9:237–242.

    Article  PubMed  CAS  Google Scholar 

  20. Polonia J, Barbosa L, Silva JA, Maldonado J: Different influences on central and peripheral pulse pressure, aortic wave reflections and pulse wave velocity of three different types of antihypertensive drugs. Rev Port Cardiol 2003, 22:1485–1492.

    PubMed  Google Scholar 

  21. Morgan T, Lauri J, Bertram D, Anderson A: Effect of different antihypertensive drug classes on central aortic pressure. Am J Hypertens 2004, 17:118–123.

    Article  PubMed  CAS  Google Scholar 

  22. Hirata K, Vlachopoulos C, Adji A, O’Rourke MF: Benefits from angiotensin-converting enzyme inhibitor ‘beyond blood pressure lowering’: beyond blood pressure or beyond the brachial artery? J Hypertens 2005, 23:551–556.

    Article  PubMed  CAS  Google Scholar 

  23. Chen C-H, Ting C-T, Lin S-J, et al.: Different effects of fosinopril and atenolol on wave reflections in hypertensive patients. Hypertension 1995, 25:1034–1041.

    PubMed  CAS  Google Scholar 

  24. Dhakam Z, McEniery CM, Yasmin, et al.: Atenolol and eprosartan: differential effects on central blood pressure and aortic pulse wave velocity. Am J Hypertens 2006, 19:214–219.

    Article  PubMed  CAS  Google Scholar 

  25. Asmar RG, London GM, O’Rourke ME, Safar ME, for the REASON Project coordinators and investigators: Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension 2001, 38:922–926.

    PubMed  CAS  Google Scholar 

  26. Resnick LM, Lester MH: Differential effects of antihypertensive drug therapy on arterial compliance. Am J Hypertens 2002, 15:1096–1100.

    Article  PubMed  CAS  Google Scholar 

  27. Cockcroft JR, Brown MJ: Losartan for cardiovascular disease in patients with and without diabetes in the LIFE study. Lancet 2002, 359:2202–2204.

    Article  PubMed  CAS  Google Scholar 

  28. The CAFE Investigators, for the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) Investigators: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 2006, 113:1213–1225. This substudy of the ASCOT trial showed an association between the effects of antihypertensive regimens on central aortic pressure and the risks in clinical outcomes.

    Article  CAS  Google Scholar 

  29. Wilkinson IB, McEniery CM, Cockcroft JR: Atenolol and cardiovascular risk: an issue close to the heart. Lancet 2006, 367:627–629.

    Article  PubMed  Google Scholar 

  30. Kelly R, Daley J, Avolio A, O’Rourke M: Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension 1989, 14:14–21.

    PubMed  CAS  Google Scholar 

  31. Schächinger V, Britten MB, Zeiher AM: Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000, 101:1899–1906.

    PubMed  Google Scholar 

  32. Al Suwaidi J, Hamasaki S, Higano ST, et al.: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000, 101:948–954.

    Google Scholar 

  33. Chowienczyk PJ, Watts GF, Cockcroft JR, Ritter JM: Impaired endothelium-dependent vasodilation of forearm resistance vessels in hypercholesterolaemia. Lancet 1992, 20:490–491.

    Google Scholar 

  34. Calver A, Collier J, Vallance P: Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes. J Clin Invest 1992, 90:2548–2554.

    PubMed  CAS  Google Scholar 

  35. Celermajer DS, Sorensen KE, Georgakopoulos D, et al.: Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993, 88:2149–2155.

    PubMed  CAS  Google Scholar 

  36. Wilkinson IB, Prasad K, Hall IR, Thomas A: Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia. J Am Coll Cardiol 2002, 39:1005–1011.

    Article  PubMed  Google Scholar 

  37. Wilkinson IB, MacCallum H, Rooijmans DF, et al.: Increased augmentation index and systolic stress in type 1 diabetes mellitus. Q J Med 2000, 93:441–448.

    CAS  Google Scholar 

  38. Ceravolo R, Maio R, Pujia A, et al.: Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol 2003, 41:1753–1758.

    Article  PubMed  CAS  Google Scholar 

  39. Wilkinson IB, Qasem A, McEniery CM, et al.: Nitric oxide regulates local arterial distensibility in vivo. Circulation 2002, 105:213–217.

    Article  PubMed  CAS  Google Scholar 

  40. Schmitt M, Avolio A, Qasem A, et al.: Basal NO locally modulates human iliac artery function in vivo. Hypertension 2005, 46:227–231.

    Article  PubMed  CAS  Google Scholar 

  41. Wilkinson IB, Franklin SS, Cockcroft JR: Nitric oxide and the regulation of large artery stiffness: from physiology to pharmacology. Hypertension 2004, 44:112–116. A comprehensive discussion of the role of endothelium-derived NO in regulating arterial stiffness.

    Article  PubMed  CAS  Google Scholar 

  42. Levy D, Larson MG, Vasan RS, et al.: The progression from hypertension to congestive heart failure. JAMA 1996, 275:1557–1562.

    Article  PubMed  CAS  Google Scholar 

  43. Chae CU, Pfeffer MA, Glynn RJ, et al.: Increased pulse pressure and risk of heart failure in the elderly. JAMA 1999, 281:634–639.

    Article  PubMed  CAS  Google Scholar 

  44. Domanski MJ, Mitchell GF, Norman JE, et al.: Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction. J Am Coll Cardiol 1999, 33:951–958.

    Article  PubMed  CAS  Google Scholar 

  45. Sutton-Tyrrell K, Najjar SS, Boudreau RM, et al.: for the Health ABC Study: Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005, 111:3384–3390.

    Article  PubMed  Google Scholar 

  46. Roman MJ, Ganan A, Saba PS, et al.: Impact of arterial stiffening on left ventricular structure. Hypertension 2000, 36:489–494.

    PubMed  CAS  Google Scholar 

  47. Mitchell GF, Tardif J-C, Arnold JM, et al.: Pulsatile hemodynamics in congestive heart failure. Hypertension 2001, 38:1433–1439.

    PubMed  CAS  Google Scholar 

  48. Mottram PM, Haluska BA, Leano R, et al.: Relation of arterial stiffness to diastolic dysfunction in hypertensive heart disease. Heart 2005, 91:1551–1556.

    Article  PubMed  CAS  Google Scholar 

  49. Kawaguchi M, Hay I, Fetics B, Kass DA: Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 2003, 107:714–720.

    Article  PubMed  Google Scholar 

  50. Ramsey MW, Goodfellow J, Jones CJ, et al.: Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995, 92:3212–3219.

    PubMed  CAS  Google Scholar 

  51. Nakamura M, Sugawara S, Arakawa N, et al.: Reduced vascular compliance is associated with impaired endothelium-dependent dilatation in the brachial artery of patients with congestive heart failure. J Card Fail 2004, 10:36–42.

    Article  PubMed  CAS  Google Scholar 

  52. Cheung YF, Chan GCF, Ha SY: Arterial stiffness and endothelial function in patients with β-thalassemia major. Circulation 2002, 106:2561–2566.

    Article  PubMed  CAS  Google Scholar 

  53. MacCarthy PA, Shah AM: Impaired endotheliumdependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy. Circulation 2000, 101:1854–1860.

    PubMed  CAS  Google Scholar 

  54. Fischer D, Rossa S, Landmesser U, et al.: Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death. Eur Heart J 2005, 26:65–69.

    Article  PubMed  CAS  Google Scholar 

  55. Paulus WJ, Bronzwaer JGF: Nitric oxide’s role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol 2004, 287:H8-H13.

    Article  PubMed  CAS  Google Scholar 

  56. Janssens S, Pokreisz P, Schoonjans L, et al.: Cardiomyocytespecific overexpression of nitric oxide synthase 3 improves left ventricular performance and reduces compensatory hypertrophy after myocardial infarction. Circ Res 2004, 94:1256–1262.

    Article  PubMed  CAS  Google Scholar 

  57. Cotton JM, Kearney MT, MacCarthy PA, et al.: Effects of nitric oxide synthase inhibition on basal function and the force-frequency relationship in the normal and failing human heart in vivo. Circulation 2001, 104:2318–2323.

    PubMed  CAS  Google Scholar 

  58. Loke KE, McConnell PI, Tuzman JM, et al.: Endogenous endothelial nitric oxide synthase-derived nitric oxide is a physiological regulator of myocardial oxygen consumption. Circ Res 1999, 84:840–845.

    PubMed  CAS  Google Scholar 

  59. Giugliano D, Marfella R, Acampora R, et al.: Effects of perindopril and carvedilol on endothelium-dependent vascular functions in patients with diabetes and hypertension. Diabetes Care 1998, 21:631–636.

    Article  PubMed  CAS  Google Scholar 

  60. Ma X-L, Gao F, Nelson AH, et al.: Oxidative inactivation of nitric oxide and endothelial dysfunction in stroke-prone spontaneous hypertensive rats. J Pharmacol Exp Ther 2001, 298:879–885.

    PubMed  CAS  Google Scholar 

  61. Lopez BL, Christopher TA, Yue TL, et al.: Carvedilol, a new beta-adrenoreceptor blocker antihypertensive drug, protects against free-radical-induced endothelial dysfunction. Pharmacology 1995, 51:165–173.

    Article  PubMed  CAS  Google Scholar 

  62. Yoshioka T, Iwamoto N, Tsukahara F, et al.: Anti-NO action of carvedilol in cell-free system and in vascular endothelial cells. Br J Pharmacol 2000, 129:1530–1535.

    Article  PubMed  CAS  Google Scholar 

  63. Bowman AJ, Chen CP L-H, Ford GA: Nitric oxide mediated venodilator effects of nebivolol. Br J Clin Pharmacol 1994, 38:199–204.

    PubMed  CAS  Google Scholar 

  64. Cockcroft JR, Chowienczyk PJ, Brett SE, et al.: Nebivolol vasodilates human forearm vasculature: evidence for Larginine/ NO-dependent mechanism. J Pharmacol Exp Ther 1995, 274:1067–1071.

    PubMed  CAS  Google Scholar 

  65. Dawes M, Brett SE, Chowienczyk PJ, et al.: The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol 1999, 48:460–463.

    Article  PubMed  CAS  Google Scholar 

  66. Tzemos N, Lim PO, MacDonald TM: Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation 2001, 104:511–514.

    PubMed  CAS  Google Scholar 

  67. Ritter JM: Nebivolol: endothelium-mediated vasodilating effect. J Cardiovasc Pharmacol 2001, 38(Suppl):S13-S16.

    PubMed  CAS  Google Scholar 

  68. Pauwels PJ, Gommeren W, Van Lommen G, et al.: The receptor binding profile of the new antihypertensive agent nebivolol and its stereoisomers compared with various betaadrenergic blockers. Mol Pharmacol 1988, 34:843–851.

    PubMed  CAS  Google Scholar 

  69. Prichard BN, Cruickshank JM, Graham BR: Beta-adrenergic blocking drugs in the treatment of hypertension. Blood Press 2001, 10:366–386.

    Article  PubMed  CAS  Google Scholar 

  70. Bakris GL, Fonseca V, Katholi RE, et al.: for the GEMINI Investigators: Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA 2004, 292:2227–2236. This randomized controlled trial showed the lack of adverse metabolic effects with the vasodilating β-blocker carvedilol compared with a traditional β-blocker.

    Article  PubMed  CAS  Google Scholar 

  71. Poirier L, Cléroux J, Nadeau A, Lacourcière Y: Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens 2001, 19:1429–1435.

    Article  PubMed  CAS  Google Scholar 

  72. McEniery CM, Schmitt M, Qasem A, et al.: Nebivolol increases arterial distensibility in vivo. Hypertension 2004, 44:305–310. This trial showed the beneficial effects of the vasodilating β-blocker nebivolol on arterial stiffness, compared with the traditional β-blocker atenolol.

    Article  PubMed  CAS  Google Scholar 

  73. Packer M, Bristow MR, Cohn JN, et al.; for the U.S. Carvedilol Heart Failure Study Group: The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996, 334:1349–1355.

    Article  PubMed  CAS  Google Scholar 

  74. Packer M, Coats AJ, Fowler MB, et al.; for the Carvedilol Prospective Randomized Cumulative Survival Study Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001, 344:1651–1658.

    Article  PubMed  CAS  Google Scholar 

  75. MERIT-HF Study Group: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERITHF). Lancet 1999, 353:2001–2007.

    Article  Google Scholar 

  76. CIBIS-II Investigators and Committees: The Cardiac Insufficiency Bisoprolol Study (CIBIS-II): a randomised trial. Lancet 1999, 353:9–13.

    Article  Google Scholar 

  77. Kitzman DW, Gardin JM, Gottdiener JS, Boineau AA: for the CHS: Importance of heart failure with preserved systolic function in patients >65 years of age. Am J Cardiol 2001, 87:413–419.

    Article  PubMed  CAS  Google Scholar 

  78. Flather MD, Shibata MC, Coats AJS, et al.; on behalf of the SENIORS Investigators: Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005, 26:215–225. This large-scale trial extended the benefits of β-blockade in the treatment of chronic heart failure to older patients with a high incidence of diastolic dysfunction, a population more representative of the heart-failure population occurring in the general community.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to John R. Cockcroft MD, FRCP.

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Pedersen, M.E., Cockcroft, J.R. The latest generation of beta-blockers: New pharmacologic properties. Current Science Inc 8, 279–286 (2006). https://doi.org/10.1007/s11906-006-0065-0

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