The number of well-controlled hypertensives is unacceptably low worldwide. Respecting the circadian variation of blood pressure, nontraditional antihypertensives, and treatment in early stages of hypertension are potential ways to improve hypertension therapy. First, prominent variations in circadian rhythm are characteristic for blood pressure. The revolutionary MAPEC (Ambulatory Blood Pressure Monitoring and Cardiovascular Events) study, in 3000 adult hypertensives investigates, whether chronotherapy influences the cardiovascular prognosis beyond blood pressure reduction per se. Second, melatonin, statins and aliskiren are hopeful drugs for hypertension treatment. Melatonin, through its scavenging and antioxidant effects, preservation of NO availability, sympatholytic effect or specific melatonin receptor activation exerts antihypertensive and anti-remodeling effects and may be useful especially in patients with nondipping nighttime blood pressure pattern or with nocturnal hypertension and in hypertensives with left ventricular hypertrophy (LVH). Owing to its multifunctional physiological actions, this indolamine may offer cardiovascular protection far beyond its hemodynamic benefit. Statins exert several pleiotropic effects through inhibition of small guanosine triphosphate-binding proteins such as Ras and Rho. Remarkably, statins reduce blood pressure in hypertensive patients and more importantly they attenuate LVH. Addition of statins should be considered for high-risk hypertensives, for hypertensives with LVH, and possibly for high-risk prehypertensive patients. The direct renin inhibitor, aliskiren, inhibits catalytic activity of renin molecules in circulation and in the kidney, thus lowering angiotensin II levels. Furthermore, aliskiren by modifying the prorenin conformation may prevent prorenin activation. At present, aliskiren should be considered in hypertensive patients not sufficiently controlled or intolerant to other inhibitors of renin-angiotensin system. Third, TROPHY (Trial of Preventing Hypertension) is the first pharmacological intervention for prehypertensive patients revealing that treatment with angiotensin II type 1 receptor blocker attenuates hypertension development and thus decreases the risk of cardiovascular events.

3rd Clinic of Medicine School of Medicine Comenius University Bratislava Slovak Republic

Department of Pathophysiology Comenius University Bratislava Slovak Republic

Institute of Normal and Pathological Physiology Slovak Academy of Sciences Bratislava Slovak Republic

Institute of Physiology and Center of Cardiovascular Research Academy of Sciences of the Czech Republic Prague Czech Republic

See more in PubMed

Chobanian AV, Bakris GL, Black HR et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003; 289:2560-2572.

Mancia G, De Backer G, Dominiczak A et al. 2007 guidelines for the management of 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). J Hypertens 2007; 25:1105-1187.

Reiter RJ, Tan DX, Korkmaz A et al. Light at night chronodisruption, melatonin suppression, and cancer risk: a review. Crit Rev Oncog 2007; 13:303-328.

Reiter RJ, Tan DX, Korkmaz A. The circadian melatonin rhythm and its modulation: possible impact on hypertension. J Hypertens 2009; 27(Suppl. 5):S17-S20.

Hermida RC, Ayala DE, Calvo C et al. Chronotherapy of hypertension: administration-time-dependent effects of treatment on the circadian pattern of blood pressure. Adv Drug Deliv Rev 2007; 59:923-939.

Hermida RC, Ayala DE, Fernandez JR et al. Modeling the circadian variability of ambulatorily monitored blood pressure by multiple-component analysis. Chronobiol Int 2002; 19:461-481.

Patel PV, Wong JL, Arora R. The morning blood pressure surge: therapeutic implications. J Clin Hypertens (Greenwich) 2008; 10:140-145.

White WB. Relating cardiovascular risk to out-of-office blood pressure and the importance of controlling blood pressure 24 hours a day. Am J Med 2008; 121:S2-S7.

Williams B. The year in hypertension. J Am Coll Cardiol 2006; 48:1698-1711.

Li Y, Staessen JA, Lu L et al. Is isolated nocturnal hypertension a novel clinical entity? Findings from a Chinese population study. Hypertension 2007; 50:333-339.

Li LH, Li Y, Huang QF et al. Isolated nocturnal hypertension and arterial stiffness in a Chinese population. Blood Press Monit 2008; 13:157-159.

Kawano Y, Horio T, Matayoshi T et al. Masked hypertension: subtypes and target organ damage. Clin Exp Hypertens 2008; 30:289-296.

Reiter RJ, Gultekin F, Manchester LC et al. Light pollution, melatonin supression and cancer growth. J Pineal Res 2006; 40:357-358.

Reiter RJ, Tan DX, Manchester LC et al. Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 2007; 52:11-28.

Erren TC, Reiter RJ. Defining chronodisruption. J Pineal Res 2009; 46:245-247.

Hermida RC, Ayala DE, Fernandéz JR et al. Chronotherapy improves blood pressure control and reverts the nondipper pattern in patients with resistant hypertension. Hypertension 2008; 51:69-76.

Hermida RC, Ayla DE, Mojón A et al. Chronotherapy with nifedipine GITS in hypertensive patients: improved efficacy and safety with bedtime dosing. Am J Hypertens 2008; 21:948-954.

Hermida RC, Ayla DE, Calvo C. Optimal timing for antihypertensive dosing: focus on valsartan. Ther Clin Risk Manag 2007; 3:119-131.

Guzik P, Wykretowicz A, Krauze T et al. Add-on therapy with a nighttime dose of doxazosin in patients with uncontrolled hypertension: effects on autonomic modulation of the cardiovascular system. Hypertens Res 2008; 31:443-453.

Calvo C, Hermida RC, Ayla DE et al. Chronotherapy with torasemide in hypertensive patients: increased efficacy and therapeutic coverage with bedtime administration. Med Clin(Barc) 2006; 127:721-729.

Blaivas AJ. Timing antihypertensives to reduce nocturnal blood pressure in CKD: the importance of choosing the right dip. Am J Kidney Dis 2008; 51:1069-1070.

Hermida RC for the MAPEC Study Investigators. Ambulatory blood pressure monitoring in the prediction of cardiovascular events and effects of chronotherapy: rationale and design of the MAPEC study. Chronobiol Int 2007; 24:749-775.

Peschke E. Melatonin, endocrine pancreas and diabetes. J Pineal Res 2008; 44:26-40.

Jan JE, Wasdell MB, Freeman RD, Bax M. Evidence supporting the use of melatonin in short gestation infants. J Pineal Res 2007; 42:22-27.

Herichova I, Zeman M, Stebelova K et al. Effect of streptozotocin-induced diabetes on daily expression of per2 and dbp in the heart and liver and melatonin rhythm in pineal gland of Wistar rat. Mol Cell Biochem 2005; 270:223-229.

Buijs RM, Kalsbeek A. Hypothalamic integration of central and peripheral clocks. Nat Rev Neurosci 2001; 2:521-526.

Scheer FA, Van Montfrans GA, Van Someren EJ et al. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 2004; 43:192-197.

Holmes SW, Sudgen D. The effect of melatonin on pinealectomy-induced hypertension in the rat. Br J Pharmacol 1976; 56:360P-361P.

Zanoboni A, Forni A, Zanoboni-Muciacia W et al. Effect of pinealectomy on arterial blood pressure and food and water intake in the rat. J Endocrinol Invest 1978; 1:125-130.

Brown GM, Bar-Or A, Grossi D et al. Urinary 6-sulphatoxymelatonin, an index of pineal function in the rat. J Pineal Res 1991; 10:141-147.

Cunnane SC, Manku MS, Oka M et al. Enhanced vascular reactivity to various vasoconstrictor agents following pinealectomy in the rat: role of melatonin. Can J Physiol Pharmacol 1980; 58:287-293.

Jonas M, Garfinkel D, Zisapel N et al. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press 2003; 12:19-24.

Zeman M, Dulkova K, Bada V et al. Plasma melatonin concentrations in hypertensive patients with the dipping and non-dipping blood pressure profile. Life Sci 2005; 76:1795-1803.

Arangino S, Cagnacci A, Angiolucci M et al. Effects of melatonin on vascular reactivity, catecholamine levels, and blood pressure in healthy men. Am J Cardiol 1999; 83:1417-1419.

Simko F, Pechanova O, Pelouch V et al. The effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodeling in spontaneously hypertensive rats. J Hypertens 2009; 27(Suppl. 5):S5-S10.

Paulis L, Pechanova O, Zicha J et al. The effect of melatonin on left ventricular hypertrophy and fibrosis in L-NAME-induced hypertension. J Hypertens 2009; 27(Suppl. 5):S11-S16.

Leibowitz A, Peleg E, Sharabi Y et al. The role of melatonin in the pathogenesis of hypertension in rats with metabolic syndrome. Am J Hypertens 2008; 21:348-351.

Xia CM, Shao CH, Xin L et al. Effects of melatonin on blood pressure in stress-induced hypertension in rats. Clin Exp Pharmacol Physiol 2008; 35:1258-1264.

Cagnacci A, Cannoletta M, Renzi A et al. Prolonged melatonin administration decreases nocturnal blood pressure in women. Am J Hypertens 2005; 18:1614-1618.

Grossman E, Laudon M, Yalcin R et al. Melatonin reduces night blood pressure in patients with nocturnal hypertension. Am J Med 2006; 119:898-902.

Cavallo A, Daniels SR, Dolan LM et al. Blood pressure-lowering effect of melatonin in type 1 diabetes. J Pineal Res 2004; 36:262-266.

Reiter RJ, Tan DX, Terron MP et al. Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochim Pol 2007; 54:1-9.

Peyrot F, Ducrocq C. Potential role of tryptophan derivates in stress responses characterized by the generation of reactive oxygen and nitrogen species. J Pineal Res 2008; 45:235-246.

Simko F, Paulis L. Melatonin as a potential antihypertensive treatment. J Pin Res 2007; 42:319-322.

Paulis L, Simko F. Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind. Physiol Res 2007; 56:671-684.

Ghosh G, De K, Maity K et al. Melatonin protects against oxidative damage and restores expression of GLUT4 gene in the hyperthyroid rat heart. J Pineal Res 2007; 42:71-82.

Regrigny O, Delagrange P, Scalbert E et al. Melatonin increases pial artery tone and decreases the lower limit of cerebral blood flow autoregulation. Fundam Clin Pharmacol 2001; 15:233-238.

Reiter RJ, Tan DX, Maldonado MD. Melatonin as an antioxidant: physiology versus pharmacology. J Pineal Res 2005; 39:215-216.

Tengattini S, Reiter RJ, Tan DX et al. Cardiovascular diseases: protective effects of melatonin. J Pineal Res 2008; 44:16-25.

Simko F, Paulis L. Chronotherapy beyond blood pressure reduction? J Pineal Res 2008; 45:227-228.

Kedziora-Kornatowska K, Szewczyk-Golec K, Czuczejko J et al. Antioxidative effects of melatonin administration in elderly primary essential hypertension patients. J Pineal Res 2008; 45:312-317.

Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998; 351:1755-1762.

Williams B. Recent hypertension trials. Implications and controversies. J Am Coll Cardiol 2005; 45:813-827.

Sever P, Dahlöf P, Poulter N et al. Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial. Eur Heart J 2006; 27:2982-2988.

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart diseases: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-1389.

Shepherd J, Cobbe SM, Ford I et al. for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333:1301-1307.

Sever PS, Dahlof B, Poulter NR et al. ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomized controlled trial. Lancet 2003; 361:1149-1158.

Brown JH, Del Re DP, Sussman MA. The Rac and Rho hall of fame: a decade of hypertrophic signaling hits. Circ Res 2006; 31:730-742.

Simko F. Statins: a perspective for left ventricular hypertrophy treatment. Eur J Clin Invest 2007; 37:681-691.

Simko F, Matuskova J, Luptak I et al. Effect of simvastatin on remodeling of the left ventricle and aorta in L-NAME-induced hypertension. Life Sci 2004; 74:1211-1224.

Dechend R, Fiebeler A, Park JK et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor. Circulation 2001; 104:576-581.

Loch D, Levick S, Hoey A et al. Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats. J Cardiovasc Pharmacol 2006; 47:396-404.

Borghi C, Veronesi M, Prandin MG et al. Statins and blood pressure regulation. Curr Hypertens Rep 2001; 3:281-288.

Borghi C, Dormi A, Veronesi M et al. Use of lipid-lowering drugs and blood pressure control in patients with arterial hypertension. J Clin Hypertens 2002; 4:277-285.

Pelat T, Balligand JL. Statins and hypertension. Semin Vasc Med 2004; 4:367-375.

Blanco-Colio LM, Osende JI, Martin-Ventura JL et al. Statins in hypertensive patients: potential explanations for the ASCOT-LLA study results. Drugs 2004; 64(Suppl 2):61-67.

Tonolo G, Melis MG, Formato M et al. Additive effects of simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients. Eur J Clin Invest 2000; 30:980-987.

Endres M. Statins: potential new indications in inflammatory conditions. Atheroscler Suppl 2006; 7:31-35.

Nickenig G, Bäumer AT, Temur Y et al. Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men. Circulation 1999; 100:2131-2134.

Glorioso N, Troffa C, Filigheddu F et al. Effect of the HMG-CoA reductase inhibitors on blood pressure in patients with essential hypertension and primary hypercholesterolemia. Hypertension 1999; 34:1281-1286.

Simko F. Pathophysiological principles of the relation between myocardial hypertrophy of the left ventricle and its regression. Physiol Res 1994; 43:259-266.

Simko F. Left ventricular hypertrophy regression as a process with variable biological implications. Can J Cardiol 1996; 12:507-551.

Simko F. Physiologic and pathologic myocardial hypertrophy: physiologic and pathologic regression of hypertrophy? Med Hypotheses 2002; 58:11-14.

Feldstein CA. Statins as antihypertensives. Recent Pat Cardiovasc Drug Discov 2008; 3:92-97.

Messerli FH, Williams B, Ritz E. Essential hypertension. Lancet 2007; 370:591-603.

Dzau VJ. Theodore Cooper lecture: tissue angiotensin and pathobiology of vascular disease: a unifying hypothesis. Hypertension 2001; 37:1047-1052.

Bader M, Ganten D. Uptade on tissue renin-angiotensin systems. J Mol Med 2008; 86:615-621.

Smith WH, Ball SG. ACE inhibitors in heart failure: an update. Basic Res Cardiol 2000; 95(Suppl 1):I8-I14.

Simko F, Simko J. Heart failure and angiotensin converting enzyme inhibition: problems and perspectives. Physiol Res 1999; 48:1-8.

Simko F, Simko J, Fabryova M. ACE-inhibition and angiotensin II receptor blockers in chronic heart failure: pathophysiological consideration of the unresolved battle. Cadiovasc Drug Ther 2003; 17:287-290.

Müller DN, Derer W, Dechend R. Aliskiren - mode of action and preclinical data. J Mol Med 2008; 86:659-662.

Stanton A. Now that we have a direct renin inhibitor, what should we do with it? Curr Hypertens Rep 2008; 10:194-200.

Rashid H. Direct renin inhibition: an evaluation of the safety and tolerability of aliskiren. Curr Med Res Opin 2008; 24:2627-2637.

Oh BH, Mitchell J, Herron JR et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007; 49:1157-1163.

Westermann D, Schmieder R, Schultheiss HP et al. Renin inhibitors, clinical experience. J Mol Med 2008; 86:691-695.

Azizi M. Direct renin inhibition: clinical pharmacology. J Mol Med 2008; 86:647-654.

Triller DM, Evang SD, Tadrous M et al. First renin inhibitor, aliskiren, for the treatment of hypertension. Pharm World Sci 2008; 30:741-749.

Gaddam KK, Oparil S. Renin inhibition: should it supplant ACE inhibitors and ARBS in high risk patients? Curr Opin Nephrol Hypertens 2008; 17:484-490.

Menard J, Guyene TT, Peyrard S et al. Conformational changes in prorenin during renin inhibition in vitro and in vivo. J Hypertens 2006; 24:529-534.

Danser AH, Batenburg WW, Van Esch JHM et al. Prorenin anno 2008. J Mol Med 2008; 86:655-658.

Paulis L, Simko F. LA419, a novel nitric oxide donor, prevents cardiac remodeling via the endothelial nitric oxide synthase pathway. NO donors as a means of antiremodeling. Hypertension 2007; 50:1009-1011.

Simko F. Is NO the king? Pathophysiological benefit with uncertain clinical impact [editorial]. Physiol Res, 2007; 56(Suppl 2):S1-S6.

Brown MJ. Aliskiren. Circulation 2008; 118:773-784.

Turnbull F, Neal B, Pfeffer M et al. Blood pressure dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens 2007; 25:951-958.

Kaplan NM, Opie LH. Controversies in cardiology 2. Controversies in hypertension. Lancet 2006; 367:168-176.

Julius S, Schork MA. Borderline hypertension - a critical review. J Chronic Dis 1971; 23:723-754.

Julius S, Nesbitt SD, Egan BM et al. Trial of Preventing Hypertension [TROPHY] Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med 2006; 354:1685-1697.

Julius S. Should the results of TROPHY affect the JNC 7 definition of prehypertension? Curr Hypertens Rep 2007; 9:202-205.

Folkow B. Physiological aspects of primary hypertension. Physiol Rev 1982; 62:347-504.

Panza JA, Casino PR, Kilcoyne CM et al. Role of endothelium derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993; 87:1468-1474.

Kjeldsen SE, Narkiewicz K, Hedner T. An American TROPHY in the prevention of hypertension. Blood Press 2006; 15:132-134.

Nesbitt SD. Perspectives on prehypertension. J Cardiometab Syndr 2006; 1:364-365.

Korkmaz A, Reiter RJ, Topal T et al. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 2009; 15:43-50.

Tan DX, Manchester LC, Terron MP et al. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res 2007; 42:28-42.

Pechanova O, Zicha J, Paulis J et al. The effect of N-acetylcysteine and melatonin in adult spontaneously hypertensive rats with established hypertension. Eur J Pharmacol 2007; 561:129-136.

Carrillo-Vico A, Guerrero JM, Lardone PJ et al. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27:189-200.

Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez M et al. Elevated levels of oxidised low-density lipoprotein and impaired nocturnal synthesis of melatonin in patients with myocardial infarctions. Atherosclerosis 2005; 180:101-105.

Escames G, Acuna-Castroviejo D, Lopez LC et al. Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. J Pharm Pharmacol 2006; 58:1153-1165.

Zeman M, Szantoova K, Stebelova K et al. Effect of rhythmic melatonin administration on clock gene expression in the suprachiasmatic nucleus and the heart of hypertensive TGR(mRen2)27 rats. J Hypertens 2009; 27(Suppl. 5):S21-S26.

Lactacystin-induced kidney fibrosis: Protection by melatonin and captopril

Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension