EFFECT OF BETA BLOCKER ON VASCULAR FUNCTION IN SYSTEMIC HYPERTENSION
Main Article Content
Keywords
Hypertensive vasculature, Beta-blockers, Vascular dysfunction, Endothelial function, Arterial stiffness, Vasodilating beta-blockers
Abstract
The contribution of beta-blockers in the management of hypertension has been overhauled and is currently used as a secondary treatment with results trials on the traditional methods such as atenolol. This paradigm shift is due to a vascular-centric concept of hypertension in which successful therapy is necessary to reverse endothelial dysfunction, vascular remodeling, and arterial stiffness, which are the underlying causes of cardiovascular risk. The conventional, beta-blockers that decrease blood pressure by decreasing cardiac output merely fail to increase these vascular parameters and may negatively influence central hemodynamics and metabolism, which explains why they are inferior in stroke prevention. More importantly, the beta-blocker group is a pharmacologically heterogeneous group. Some third-generation vasodilating beta-blockers (e.g., nebivol, carvedilol) have different mechanisms, one of nitric oxide potentiation, a1-adrenergic inhibition, and antioxidant effects, directly aimed at vascular pathophysiology. It has been shown that these agents enhance endothelial performance and decrease the arterial stiffness in a better way in comparison with the traditional beta-blockers with a better metabolic and hemodynamic profile. As such, blanket declassification of all beta-blockers is no longer relevant. The individualized, pathophysiology-oriented approach is justified. Beta-blockers that dilate the vas are a logical choice in patients with hypertension who have a high sympathetic tone, metabolic syndrome, or particular comorbidities, and a therapeutic objective of obtaining vascular protection. Guidelines and clinical practice in the future ought to make a differentiation between the subclasses of beta-blockers, taking advantage of their distinct vascular advantages.
References
Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016 Aug 9;134(6):441-50.
Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015 Mar 13;116(6):1007-21.
Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease – a 30th anniversary update. Acta Physiol (Oxf). 2017 Jan;219(1):22-96.
Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res. 2011 Jun;34(6):665-73.
Lacolley P, Regnault V, Segers P, Laurent S. Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease. Physiol Rev. 2017 Oct 1;97(4):1555-617.
Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation. 2003 Jun 10;107(22):2864-9.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39(33):3021-104.
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248.
Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. 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 Sep 10-16;366(9489):895-906.
Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005 Oct 29;366(9496):1545-53.
Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006 Jun 6;174(12):1737-42.
Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. 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 Mar 7;113(9):1213-25.
Kampus P, Serg M, Kals J, Zagura M, Muda P, Karu K, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension. 2011 Jun;57(6):1122-8.
Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995 Mar;272(3):1067-71.
Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001 Jul 24;104(5):511-4.
Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol. 2003 Aug 1;92(3):344-8.
Weber MA, Bakris GL, Hester A, Weir MR, Hua TA, Zappe D, et al. Systolic blood pressure and cardiovascular outcomes during treatment of hypertension with amlodipine either alone or in combination with perindopril: the Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. J Am Coll Cardiol. 2010 Jun 29;55(26):2983-92.
Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014 May 23;114(11):1804-14.
Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010 Apr;90(2):513-57.
Flack JM, Nasser SA. The role of vasodilating β-blockers in patients with hypertension and the cardiometabolic syndrome. Am J Med. 2010 Jun;123(6 Suppl 1):S21-6.
Frishman WH. β-Adrenergic receptor blockers in hypertension: alive and well. Prog Cardiovasc Dis. 2016 Sep-Oct;59(3):247-52.
Brixius K, Bundkirchen A, Bölck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol. 2001 Jul;133(5):1330-8.
Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5;362(9377):7-13.
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55.
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007 Jun;28(12):1462-536.
Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2017 Jan 20;1(1):CD002003.
Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens. 2015 Jul;33(7):1321-41.
Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004 Nov 6;364(9446):1684-9.
Fenton C, Keating GM, Lyseng-Williamson KA. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66(10):1389-409.
Pedersen ME, Cockcroft JR. The vasodilatory beta-blockers. Curr Hypertens Rep. 2007 Aug;9(4):269-77.
Van Bortel LM, Bulpitt CJ, Fici F. Quality of life and antihypertensive effect with nebivolol and losartan. Am J Hypertens. 2005 Nov;18(11):1060-6.
Mahmud A, Feely J. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am J Hypertens. 2008 Jun;21(6):663-7.
Agabiti-Rosei E, Porteri E, Rizzoni D. Arterial stiffness, hypertension, and rational use of nebivolol. Vasc Health Risk Manag. 2009;5(1):353-60.
Jünger C, Kilter H. [Vasodilating beta-blockers in cardiovascular therapy]. Dtsch Med Wochenschr. 2007 Dec;132(49):2626-30. German.
Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009 Oct 6;54(16):1491-9.
Broeders MA, Doevendans PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, et al. Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production. Circulation. 2000 Aug 29;102(9):677-84.
Dawes M, Brett SE, Chowienczyk PJ, Mant TG, Ritter JM. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol. 1999 Dec;48(6):460-3.
Ritter JM. Nebivolol: endothelium-mediated vasodilating effect. J Cardiovasc Pharmacol. 2001 Dec;38 Suppl 3:S13-6.
Cockcroft JR. Nebivolol: a review. Expert Opin Pharmacother. 2004 Nov;5(11):893-9.
Ignarro LJ. Different pharmacological properties of two enantiomers in a unique beta-blocker, nebivolol. Cardiovasc Ther. 2008 Summer;26(2):115-34.
Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frérart F, et al. Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation. 2005 Aug 16;112(8):1198-205.
de Groot AA, Mathy MJ, van Zwieten PA, Peters SL. Antioxidant activity of nebivolol in the rat aorta. J Cardiovasc Pharmacol. 2004 Jun;43(6):803-8.
Feuerstein GZ, Ruffolo RR Jr. Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur Heart J. 1995 Sep;16 Suppl F:38-42.
Yue TL, Cheng HY, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992 Oct;263(1):92-8.
Ruffolo RR Jr, Gellai M, Hieble JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. Eur J Clin Pharmacol. 1990;38 Suppl 2:S82-8.
Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.
McMurray J, Køber L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005 Feb 1;45(4):525-30.
Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004 Nov 10;292(19):2227-36.
Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens. 1996 Apr;14(4):489-94.
Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med. 1997 Jun 15;126(12):955-9.
Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008 Feb;26(2):351-6.
Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail. 2003 Oct;5(5):621-7.
Van Nueten L, Taylor FR, Robertson JI. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomised trial. J Hum Hypertens. 1998 Feb;12(2):135-40.
Van Bortel LM, Breed JG, Joosten J, Kragten JA, Lustermans FA, Mooij JM. Nebivolol in hypertension: a double-blind placebo-controlled multicenter study assessing its antihypertensive efficacy and impact on quality of life. J Cardiovasc Pharmacol. 1993 May;21(5):856-62.
Lacourcière Y, Poirier L, Lefebvre J, Archambault F, Cléroux J. Comparative effects of a new cardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteins. J Clin Pharmacol. 1992 Jun;32(7):660-6.
Rosei EA, Rizzoni D. Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics. Drugs. 2007;67(8):1097-107.
Celik T, Iyisoy A, Kursaklioglu H, Kardesoglu E, Kilic S, Turhan H, et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients. J Hypertens. 2006 Mar;24(3):591-6.
Poirier L, Cléroux J, Nadeau A, Lacourcière Y. Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens. 2001 Aug;19(8):1429-35.
Rizos EC, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Effects of nebivolol and atenolol on blood pressure and lipid profile in hypertensive patients. Vasc Health Risk Manag. 2008;4(6):1309-16.
Kishi T, Hirooka Y, Sunagawa K. Sympathoinhibition by nebivolol in the paraventricular nucleus in spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2012 May;59(5):500-7.
Münzel T, Daiber A, Gori T. More answers to the still unresolved question of nitrate tolerance. Eur Heart J. 2013 Sep;34(34):2666-73.
Gkaliagkousi E, Ferro A. Nitric oxide signalling in the regulation of cardiovascular and platelet function. Front Biosci (Landmark Ed). 2011 Jan 1;16(5):1873-97.
Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009 Mar;61(1):62-97.
Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006 Apr 4;113(13):1708-14.
Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, immunity, and hypertension. Hypertension. 2011 Feb;57(2):132-40.
Schiffrin EL. The immune system: role in hypertension. Can J Cardiol. 2013 May;29(5):543-8.
Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012 Feb;59(2):367-74.
Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001 Sep;38(3 Pt 2):581-7.
Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010 Feb 2;121(4):505-11.
Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation. 2002 Mar 19;105(10):1202-7.
Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006 Nov;27(21):2588-605.
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar 30;55(13):1318-27.
O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005 Jul;46(1):200-4.
Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43.
Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995 Nov 1;26(5):1235-41.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007 Mar 13;115(10):1285-95.
Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial dysfunction: therapeutic approach. Curr Vasc Pharmacol. 2012 May;10(3):42-60.
Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs. 2002;62(2):265-84.
Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol. 2009 Jan;157(4):527-36.
Bruno RM, Ghiadoni L, Seravalle G, Dell'oro R, Taddei S, Grassi G. Sympathetic regulation of vascular function in health and disease. Front Physiol. 2012 Jun 6;3:284.
Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol. 2014 Oct 20;177(3):1020-5.
Esler M. The 2009 Carl Ludwig Lecture: Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol (1985). 2010 Mar;108(3):227-37.
Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015 Mar 13;116(6):1007-21.
Vanhoutte PM, Shimokawa H, Feletou M, Tang EH. Endothelial dysfunction and vascular disease – a 30th anniversary update. Acta Physiol (Oxf). 2017 Jan;219(1):22-96.
Schulz E, Gori T, Münzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res. 2011 Jun;34(6):665-73.
Lacolley P, Regnault V, Segers P, Laurent S. Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease. Physiol Rev. 2017 Oct 1;97(4):1555-617.
Safar ME, Levy BI, Struijker-Boudier H. Current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. Circulation. 2003 Jun 10;107(22):2864-9.
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39(33):3021-104.
Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248.
Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. 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 Sep 10-16;366(9489):895-906.
Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. 2005 Oct 29;366(9496):1545-53.
Khan N, McAlister FA. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ. 2006 Jun 6;174(12):1737-42.
Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. 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 Mar 7;113(9):1213-25.
Kampus P, Serg M, Kals J, Zagura M, Muda P, Karu K, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall thickness. Hypertension. 2011 Jun;57(6):1122-8.
Cockcroft JR, Chowienczyk PJ, Brett SE, Chen CP, Dupont AG, Van Nueten L, et al. Nebivolol vasodilates human forearm vasculature: evidence for an L-arginine/NO-dependent mechanism. J Pharmacol Exp Ther. 1995 Mar;272(3):1067-71.
Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001 Jul 24;104(5):511-4.
Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol. 2003 Aug 1;92(3):344-8.
Weber MA, Bakris GL, Hester A, Weir MR, Hua TA, Zappe D, et al. Systolic blood pressure and cardiovascular outcomes during treatment of hypertension with amlodipine either alone or in combination with perindopril: the Avoiding Cardiovascular Events Through COMbination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial. J Am Coll Cardiol. 2010 Jun 29;55(26):2983-92.
Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014 May 23;114(11):1804-14.
Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010 Apr;90(2):513-57.
Flack JM, Nasser SA. The role of vasodilating β-blockers in patients with hypertension and the cardiometabolic syndrome. Am J Med. 2010 Jun;123(6 Suppl 1):S21-6.
Frishman WH. β-Adrenergic receptor blockers in hypertension: alive and well. Prog Cardiovasc Dis. 2016 Sep-Oct;59(3):247-52.
Brixius K, Bundkirchen A, Bölck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. Br J Pharmacol. 2001 Jul;133(5):1330-8.
Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet. 2003 Jul 5;362(9377):7-13.
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999 Jun 12;353(9169):2001-7.
Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55.
Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2007 Jun;28(12):1462-536.
Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. Cochrane Database Syst Rev. 2017 Jan 20;1(1):CD002003.
Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering on outcome incidence in hypertension: 5. Head-to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. J Hypertens. 2015 Jul;33(7):1321-41.
Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004 Nov 6;364(9446):1684-9.
Fenton C, Keating GM, Lyseng-Williamson KA. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66(10):1389-409.
Pedersen ME, Cockcroft JR. The vasodilatory beta-blockers. Curr Hypertens Rep. 2007 Aug;9(4):269-77.
Van Bortel LM, Bulpitt CJ, Fici F. Quality of life and antihypertensive effect with nebivolol and losartan. Am J Hypertens. 2005 Nov;18(11):1060-6.
Mahmud A, Feely J. Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection. Am J Hypertens. 2008 Jun;21(6):663-7.
Agabiti-Rosei E, Porteri E, Rizzoni D. Arterial stiffness, hypertension, and rational use of nebivolol. Vasc Health Risk Manag. 2009;5(1):353-60.
Jünger C, Kilter H. [Vasodilating beta-blockers in cardiovascular therapy]. Dtsch Med Wochenschr. 2007 Dec;132(49):2626-30. German.
Münzel T, Gori T. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. J Am Coll Cardiol. 2009 Oct 6;54(16):1491-9.
Broeders MA, Doevendans PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, et al. Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release: endothelial beta(2)-adrenergic receptor-mediated nitric oxide production. Circulation. 2000 Aug 29;102(9):677-84.
Dawes M, Brett SE, Chowienczyk PJ, Mant TG, Ritter JM. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol. 1999 Dec;48(6):460-3.
Ritter JM. Nebivolol: endothelium-mediated vasodilating effect. J Cardiovasc Pharmacol. 2001 Dec;38 Suppl 3:S13-6.
Cockcroft JR. Nebivolol: a review. Expert Opin Pharmacother. 2004 Nov;5(11):893-9.
Ignarro LJ. Different pharmacological properties of two enantiomers in a unique beta-blocker, nebivolol. Cardiovasc Ther. 2008 Summer;26(2):115-34.
Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frérart F, et al. Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation. 2005 Aug 16;112(8):1198-205.
de Groot AA, Mathy MJ, van Zwieten PA, Peters SL. Antioxidant activity of nebivolol in the rat aorta. J Cardiovasc Pharmacol. 2004 Jun;43(6):803-8.
Feuerstein GZ, Ruffolo RR Jr. Carvedilol, a novel multiple action antihypertensive agent with antioxidant activity and the potential for myocardial and vascular protection. Eur Heart J. 1995 Sep;16 Suppl F:38-42.
Yue TL, Cheng HY, Lysko PG, McKenna PJ, Feuerstein R, Gu JL, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther. 1992 Oct;263(1):92-8.
Ruffolo RR Jr, Gellai M, Hieble JP, Willette RN, Nichols AJ. The pharmacology of carvedilol. Eur J Clin Pharmacol. 1990;38 Suppl 2:S82-8.
Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.
McMurray J, Køber L, Robertson M, Dargie H, Colucci W, Lopez-Sendon J, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005 Feb 1;45(4):525-30.
Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004 Nov 10;292(19):2227-36.
Jacob S, Rett K, Wicklmayr M, Agrawal B, Augustin HJ, Dietze GJ. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens. 1996 Apr;14(4):489-94.
Giugliano D, Acampora R, Marfella R, De Rosa N, Ziccardi P, Ragone R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med. 1997 Jun 15;126(12):955-9.
Dhakam Z, Yasmin, McEniery CM, Burton T, Brown MJ, Wilkinson IB. A comparison of atenolol and nebivolol in isolated systolic hypertension. J Hypertens. 2008 Feb;26(2):351-6.
Nodari S, Metra M, Dei Cas L. Beta-blocker treatment of patients with diastolic heart failure and arterial hypertension. A prospective, randomized, comparison of the long-term effects of atenolol vs. nebivolol. Eur J Heart Fail. 2003 Oct;5(5):621-7.
Van Nueten L, Taylor FR, Robertson JI. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomised trial. J Hum Hypertens. 1998 Feb;12(2):135-40.
Van Bortel LM, Breed JG, Joosten J, Kragten JA, Lustermans FA, Mooij JM. Nebivolol in hypertension: a double-blind placebo-controlled multicenter study assessing its antihypertensive efficacy and impact on quality of life. J Cardiovasc Pharmacol. 1993 May;21(5):856-62.
Lacourcière Y, Poirier L, Lefebvre J, Archambault F, Cléroux J. Comparative effects of a new cardioselective beta-blocker nebivolol and nifedipine sustained-release on 24-hour ambulatory blood pressure and plasma lipoproteins. J Clin Pharmacol. 1992 Jun;32(7):660-6.
Rosei EA, Rizzoni D. Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics. Drugs. 2007;67(8):1097-107.
Celik T, Iyisoy A, Kursaklioglu H, Kardesoglu E, Kilic S, Turhan H, et al. Comparative effects of nebivolol and metoprolol on oxidative stress, insulin resistance, plasma adiponectin and soluble P-selectin levels in hypertensive patients. J Hypertens. 2006 Mar;24(3):591-6.
Poirier L, Cléroux J, Nadeau A, Lacourcière Y. Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens. 2001 Aug;19(8):1429-35.
Rizos EC, Liberopoulos EN, Mikhailidis DP, Elisaf MS. Effects of nebivolol and atenolol on blood pressure and lipid profile in hypertensive patients. Vasc Health Risk Manag. 2008;4(6):1309-16.
Kishi T, Hirooka Y, Sunagawa K. Sympathoinhibition by nebivolol in the paraventricular nucleus in spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2012 May;59(5):500-7.
Münzel T, Daiber A, Gori T. More answers to the still unresolved question of nitrate tolerance. Eur Heart J. 2013 Sep;34(34):2666-73.
Gkaliagkousi E, Ferro A. Nitric oxide signalling in the regulation of cardiovascular and platelet function. Front Biosci (Landmark Ed). 2011 Jan 1;16(5):1873-97.
Toda N, Ayajiki K, Okamura T. Cerebral blood flow regulation by nitric oxide: recent advances. Pharmacol Rev. 2009 Mar;61(1):62-97.
Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006 Apr 4;113(13):1708-14.
Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, et al. Inflammation, immunity, and hypertension. Hypertension. 2011 Feb;57(2):132-40.
Schiffrin EL. The immune system: role in hypertension. Can J Cardiol. 2013 May;29(5):543-8.
Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012 Feb;59(2):367-74.
Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension. 2001 Sep;38(3 Pt 2):581-7.
Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010 Feb 2;121(4):505-11.
Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation. 2002 Mar 19;105(10):1202-7.
Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006 Nov;27(21):2588-605.
Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar 30;55(13):1318-27.
O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005 Jul;46(1):200-4.
Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43.
Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995 Nov 1;26(5):1235-41.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002 Jan 16;39(2):257-65.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007 Mar 13;115(10):1285-95.
Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial dysfunction: therapeutic approach. Curr Vasc Pharmacol. 2012 May;10(3):42-60.
Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs. 2002;62(2):265-84.
Versari D, Daghini E, Virdis A, Ghiadoni L, Taddei S. Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol. 2009 Jan;157(4):527-36.
Bruno RM, Ghiadoni L, Seravalle G, Dell'oro R, Taddei S, Grassi G. Sympathetic regulation of vascular function in health and disease. Front Physiol. 2012 Jun 6;3:284.
Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol. 2014 Oct 20;177(3):1020-5.
Esler M. The 2009 Carl Ludwig Lecture: Pathophysiology of the human sympathetic nervous system in cardiovascular diseases: the transition from mechanisms to medical management. J Appl Physiol (1985). 2010 Mar;108(3):227-37.
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Feb 14, 2026
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Penumala Deadeepya. (2026). EFFECT OF BETA BLOCKER ON VASCULAR FUNCTION IN SYSTEMIC HYPERTENSION. Journal of Population Therapeutics and Clinical Pharmacology, 33(2), 267-281. https://doi.org/10.53555/zxzrbc45
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Author Biography
Penumala Deadeepya
Intern, Konaseema Institute of Medical Sciences and Research Foundation
How to Cite
Penumala Deadeepya. (2026). EFFECT OF BETA BLOCKER ON VASCULAR FUNCTION IN SYSTEMIC HYPERTENSION. Journal of Population Therapeutics and Clinical Pharmacology, 33(2), 267-281. https://doi.org/10.53555/zxzrbc45
