Preventing and Treating Hypertension with Diet (Part 4)

Pathophysiological Mechanisms of Hypertension

heartacheThe enormous medical and health economic relevance of hypertension has led to an intensified research of the causes and mechanisms of elevated blood pressure. However, the relationship between diet and blood pressure is still not fully understood. A definite cause of hypertension can be named in only about five percent of patients1)Touyz RM. New insights into mechanisms of hypertension. Curr Opin Nephrol Hypertens. 2012;21(2):119-121. doi:10.1097/MNH.0b013e328350a50f. This points to the tremendous complexity of the pathogenesis of hypertension. As a matter of fact, multiple factors contribute to the development of this chronic disease. They can be assigned to different domains and levels such as genetics, psychology, physiology, and the environment.

This chapter deals with the pathophysiological mechanisms of hypertension and how nutrition, constituting the most relevant environmental factor, is able to influence them. An understanding of the association between diet and blood pressure provides the basis for preventive and therapeutic approaches to influence the development and the progress of hypertension.

The Interaction Between Cardiac Output and Vascular Resistance

Blood pressure is essential for the blood supply of all organs. It is built up by the contraction of the heart muscle and the ejection of blood into the aorta and the subsequent vessels, which have an influence on blood pressure by altering their diameter. Simply said, there are only two basic physiological mechanisms that affect blood pressure: cardiac output (CO) (stroke volume x heart rate) and vascular resistance. However, these two parameters are, in turn, influenced by numerous complex biological factors. The central and autonomic (mainly sympathetic) nervous system, the kidney via the renin-angiotensin-aldosterone system (RAAS), sodium retaining hormones, vasoconstrictors and vasodilators, as well as vascular growth factors, such as TGF-β, mediate between the cardiac and vascular components of the blood pressure system2)James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.2844273)Takamura Y, Shimokawa H, Zhao H, Igarashi H, Egashira K, Takeshita A. Important role of endothelium-derived hyperpolarizing factor in shear stress–induced endothelium-dependent relaxations in the rat mesenteric artery. J Cardiovasc Pharmacol. 1999;34(3):381-3874)Davies PF. Endothelial transcriptome profiles in vivo in complex arterial Flow fields. Ann Biomed Eng. 2008;36(4):563-570. doi:10.1007/s10439-007-9400-0. The following paragraphs will describe the pathophysiological mechanisms and their interaction with dietary factors in more detail.

Cardiac Output

Which Factors Influence Cardiac Output?

Cardiac output is the product of stroke volume and heart rate. Stroke volume is influenced by the contractility of the heart muscle, its inotropy, and the filling level of the ventricle. The extent to which the heart muscle contracts depends, among other things, on the central and sympathetic nervous system. Its filling volume is influenced by venous return, as well as by general blood volume. The latter is substantially regulated by the kidneys5)Dunn A, Lo V, Donnelly S. The role of the kidney in blood volume regulation: the kidney as a regulator of the hematocrit. Am J Med Sci. 2007;334(1):65-71. doi:10.1097/MAJ.0b013e318095a4ae. The kidneys have the ability to control blood pressure via the excretion of sodium and water, hence regulating extracellular and blood volume6)Lohmeier TE. The sympathetic nervous system and long-term blood pressure regulation. Am J Hypertens. 2001;14(6 Pt 2):147S-154S. The sensitivity of this pressure natriuresis can be influenced by the renin-angiotensin-aldosterone system (RAAS). The RAAS is a hormonal system that regulates blood pressure via vascular tone and fluid and electrolyte balance. When renal blood flow is reduced, for example in the case of low blood pressure, kidney cells secrete renin into the circulation. Renin then converts angiotensinogen, released by the liver, to angiotensin I. The angiotensin-converting enzyme (ACE) derived from vascular endothelial cells then transforms angiotensin I into angiotensin II, a potent vasoconstrictive peptide. Angiotensin II also enhances the secretion of aldosterone from the adrenal cortex that leads to an increased reabsorption of sodium and water into the blood, subsequently increasing blood pressure. As blood pressure or blood sodium increases, RAAS is suppressed, which leads to increased excretion of sodium and water by the kidney7)Yang T, Xu C. Physiology and Pathophysiology of the Intrarenal Renin-Angiotensin System: An Update. J Am Soc Nephrol. 2017;28(4):1040-1049. doi:10.1681/ASN.20160707348)Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59(3):251-287. doi:10.1124/pr.59.3.3. The RAAS is the point of attack for many standard anti-hypertensive medications, such as e.g. ACE inhibitors, aldosterone or AT1-receptor antagonists.

The interactions between the kidney and blood pressure are very complex and cannot be described in detail here. However, we will have a look at the connecting points between kidney physiology, blood pressure and diet later on.

How Can Diet Influence Cardiac Output?

Environmental factors, including nutrition, can regulate cardiac output and thus blood pressure through their influence on blood volume. In addition, there are also dietary modulators of the sympathetic and parasympathetic nervous system, which can affect stroke volume, heart rate, and inotropy of the heart muscle.

Weight Loss

One of the factors influencing blood volume is weight loss due to food intake below the body’s demand. It is assumed that weight loss reduces blood volume by inhibition of the natriuretic peptides system which causes vasodilatation and natriuresis9)Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42(5):878-884. doi:10.1161/01.HYP.0000094221.86888.AE. In addition, activity of the sympathetic nervous system decreases, and a potential hyperinsulinemia is alleviated, resulting in decreased sodium reabsorption by the kidneys, which also affects intravascular volume, but this mechanism is not fully understood yet10)Ferrari P, Weidmann P. Insulin, insulin sensitivity and hypertension. J Hypertens. 1990;8(6):491-500.

Many studies have shown that losing weight through a low-calorie diet and/or increasing physical activity leads to a reduction in blood pressure in obese or overweight subjects11)Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to prevent and treat hypertension: a scientific statement from the American Heart Association. Hypertension. 2006;47(2):296-308. doi:10.1161/01.HYP.0000202568.01167.B6. A meta-analysis of randomized controlled trials found a reduction in systolic and diastolic blood pressure of 1 mm Hg per lost kg of body weight12)Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction on blood pressure: a meta-analysis of randomized controlled trials. Hypertension. 2003;42(5):878-884. doi:10.1161/01.HYP.0000094221.86888.AE. A systematic review found a reduction in systolic and diastolic blood pressure by 6.0 and 4.6 mm Hg, respectively, associated with a weight loss of 10 kg13)Aucott L, Poobalan A, Smith WCS, Avenell A, Jung R, Broom J. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes: a systematic review. Hypertension. 2005;45(6):1035-1041. doi:10.1161/01.HYP.0000165680.59733.d4.

Salt Intake

The underlying mechanism of the hypertensive effect of sodium is as yet poorly understood14)Elijovich F, Weinberger MH, Anderson CAM, et al. Salt Sensitivity of Blood Pressure: A Scientific Statement From the American Heart Association. Hypertension. 2016;68(3):e7-e46. doi:10.1161/HYP.0000000000000047. According to the classical view, it is assumed that an increased salt intake leads to an accumulation of sodium in the extracellular space, which causes an increase in the extracellular volume with a consecutive increase in blood pressure15)Guyton AC. Blood pressure control–special role of the kidneys and body fluids. Science. 1991;252(5014):1813-1816.

However, recent studies claim the opposite, stating that the accumulation of sodium is ​not accompanied by a corresponding water accumulation, presumably because the skin is capable of an osmotically inactive sodium storage, as shown in animal experiments and a small study in humans16)Choi HY, Park HC, Ha SK. Salt Sensitivity and Hypertension: A Paradigm Shift from Kidney Malfunction to Vascular Endothelial Dysfunction. Electrolyte Blood Press. 2015;13(1):7-16. doi:10.5049/EBP.2015.13.1.7.

Hence, an excess of salt seems to increase blood pressure rather by influencing the parameter of vascular resistance. The phenomenon of salt sensitivity observed in many trials seems to be related not only to renal malfunction, but also to the endothelial dysfunction17)Choi HY, Park HC, Ha SK. Salt Sensitivity and Hypertension: A Paradigm Shift from Kidney Malfunction to Vascular Endothelial Dysfunction. Electrolyte Blood Press. 2015;13(1):7-16. doi:10.5049/EBP.2015.13.1.7. The latter parameter will be discussed in the corresponding section below.

Calcium Intake

Calcium is not only involved in the mechanism of peripheral vascular resistance (see below), but also in the regulation of blood volume. Ionized calcium presumably reduces renin secretion through interaction with the calcium-sensing receptor and thus acts indirectly as a natriuretic and diuretic peptide18)Pörsti I, Mäkynen H. Dietary calcium intake: effects on central blood pressure control. Semin Nephrol. 1995;15(6):550-56319)Maillard MP, Tedjani A, Perregaux C, Burnier M. Calcium-sensing receptors modulate renin release in vivo and in vitro in the rat. J Hypertens. 2009;27(10):1980-1987. doi:10.1097/HJH.0b013e32832f0d22.

Sugar Intake

Interestingly, carbohydrate intake also has a direct impact on blood pressure. Experimental studies on humans show that fructose especially has an acute effect on blood pressure. Compared to a drink containing 60 g of glucose, a drink with the same amount of fructose increased the blood pressure of healthy volunteers by an average of 6.2 mm Hg, whereas the glucose drink had no effect on blood pressure20)Brown CM, Dulloo AG, Yepuri G, Montani J-P. Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol Regul Integr Comp Physiol. 2008;294(3):R730-737. doi:10.1152/ajpregu.00680.2007. Similarly, Perez-Pozo et al.21)Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010;34(3):454-461. doi:10.1038/ijo.2009.259 found that 200 g of fructose daily significantly increased systolic and diastolic blood pressure in 74 healthy men over two weeks. Studies using animal models and also those on humans show that a high intake of sugar, especially fructose, leads to an acute and chronic increase in serum uric acid22)Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA. 2010;304(20):2270-2278. doi:10.1001/jama.2010.1638. This, in turn, causes activation of the RAAS, which elevates blood volume and hereby blood pressure23)Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010;34(3):454-461. doi:10.1038/ijo.2009.259. Furthermore, fructose directly promotes intestinal uptake and renal reabsorption of sodium24)Singh AK, Amlal H, Haas PJ, et al. Fructose-induced hypertension: essential role of chloride and fructose absorbing transporters PAT1 and Glut5. Kidney Int. 2008;74(4):438-447. doi:10.1038/ki.2008.18425)Barone S, Fussell SL, Singh AK, et al. Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem. 2009;284(8):5056-5066. doi:10.1074/jbc.M80812820026)Soleimani M. Dietary fructose, salt absorption and hypertension in metabolic syndrome: towards a new paradigm. Acta Physiol (Oxf). 2011;201(1):55-62. doi:10.1111/j.1748-1716.2010.02167.x27)Queiroz-Leite GD, Crajoinas RO, Neri EA, et al. Fructose acutely stimulates NHE3 activity in kidney proximal tubule. Kidney Blood Press Res. 2012;36(1):320-334. doi:10.1159/00034339028)Cabral PD, Hong NJ, Hye Khan MA, et al. Fructose stimulates Na/H exchange activity and sensitizes the proximal tubule to angiotensin II. Hypertension. 2014;63(3):e68-73. doi:10.1161/HYPERTENSIONAHA.113.02564.

Dietary Influences on the Central and Autonomic Nervous System

The amount and composition of food have a depressing or stimulating effect on the central and autonomic nervous system, such as the amino acid theanine, which can be found in green or black tea, or alkaloids such as theophylline or caffeine. Caffeine is considered sympathomimetic because it increases the activity of the sympathetic nervous system29)Corti R, Binggeli C, Sudano I, et al. Coffee acutely increases sympathetic nerve activity and blood pressure independently of caffeine content: role of habitual versus nonhabitual drinking. Circulation. 2002;106(23):2935-2940 as well as the amount of circulating catecholamines, and it increases plasma renin activity30)Robertson D, Frölich JC, Carr RK, et al. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med. 1978;298(4):181-186. doi:10.1056/NEJM197801262980403. Blood pressure is also increased by caffeine or coffee consumption, but after about three to five days of regular coffee consumption, this effect is subject to habituation31)Ammon HP, Bieck PR, Mandalaz D, Verspohl EJ. Adaptation of blood pressure to continuous heavy coffee drinking in young volunteers. A double-blind crossover study. Br J Clin Pharmacol. 1983;15(6):701-706. Caffeine also increases the inotropy of the heart muscle32)Chaban R, Kornberger A, Branski N, et al. In-vitro examination of the positive inotropic effect of caffeine and taurine, the two most frequent active ingredients of energy drinks. BMC Cardiovasc Disord. 2017;17. doi:10.1186/s12872-017-0625-z, as shown in an in vitro experiment. The haemodynamic cause of caffeine increasing blood pressure is gender specific: In men, increased vascular resistance is responsible for the increase; in women caffeine primarily increases stroke volume and cardiac output33)Hartley TR, Lovallo WR, Whitsett TL. Cardiovascular effects of caffeine in men and women. Am J Cardiol. 2004;93(8):1022-1026. doi:10.1016/j.amjcard.2003.12.057. However, the complex interactions of caffeine as a substance in coffee and other foods are not yet well understood, and, therefore, isolated effects of caffeine cannot be equated with caffeinated foods or drinks. This also applies to other diet related CNS modulators. Here, further research focusing on the long-term effects on blood pressure is needed.

Although various nutritional mechanisms have an effect on cardiac output as a modulator of blood pressure, the potential of diet to influence blood pressure through altering peripheral vascular resistance is probably more relevant. This will be discussed below.

What Influences Vascular Resistance?

Presumably the most significant factor in the development of hypertension is peripheral arterial vascular resistance. Some authors go as far as to characterize arterial hypertension as a “vasculopathy”34)Touyz RM. New insights into mechanisms of hypertension. Curr Opin Nephrol Hypertens. 2012;21(2):119-121. doi:10.1097/MNH.0b013e328350a50f, p. 119 or a “hemodynamic marker of injured endothelium and vascular smooth muscle”35)Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol. 2014;6(2):38-66. doi:10.4330/wjc.v6.i2.38, p. 752.

In fact, the common feature of all forms of hypertension is endothelial dysfunction. The vascular endothelium is responsible for vascular tone and regulation of oxidative stress by releasing the vasodilators nitric oxide (NO; via the endothelial NO synthase (eNOS)) and prostacyclin, and the vasoconstrictor endothelin, and it controls local angiotensin II activity. It also modulates leukocyte and platelet adhesion and transmigration of leukocytes36)Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285-1295. doi:10.1161/CIRCULATIONAHA.106.652859.

In the context of endothelial dysfunction, the above-mentioned functions get out of balance: The vasoconstrictors outweigh the vasodilators, because there is a reduced bioavailability of NO, especially due to a reduced synthesis and an increased degradation37)Förstermann U, Münzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113(13):1708-1714. doi:10.1161/CIRCULATIONAHA.105.602532. The cause of endothelial dysfunction is primarily due to three main pathophysiological damage patterns: increased oxidative stress by free oxygen and nitrogen radicals (ROS and RNS), which directly degrade NO, an inflammatory process driven by CRP as well as various cytokines and chemokines, and autoimmune vascular dysfunction, which is maintained by immune cells.

Due to the complex interactions of the various factors, it is often difficult to define “the” initial cause of blood pressure elevation, even more so in the individual patient with essential hypertension. It is still unclear whether endothelial dysfunction is the cause or consequence of hypertension38)Bernatova I. Endothelial dysfunction in experimental models of arterial hypertension: cause or consequence? Biomed Res Int. 2014;2014:598271. doi:10.1155/2014/598271. In fact, vascular changes are actually an attempt by the body to regulate various types of damage, but they manifest as a maladaptive process. Once endothelial damage has occurred, endothelial dysfunction and hypertension seem to maintain a bidirectional process.

The vascular damages can be of a biomechanical nature. Here again the cardiac output comes into play indirectly, but also of biohumoral or biochemical nature. The last two include in particular metabolic, endocrine, toxic, infectious, and, of course, nutrition-related factors.

Similar to the process of cardiac remodeling resulting from hypertension (e.g. left ventricular hypertrophy), not discussed here, the vessels are characterized by a structural remodeling in the sense of increased stiffness and a reduced flexibility and elasticity39)Mayet J, Hughes A. Cardiac and vascular pathophysiology in hypertension. Heart. 2003;89(9):1104-1109. Initially, this is probably a physiological attempt of adaptation to the already existing high blood pressure. After some time, however, the structural changes contribute to the maintenance of hypertension, as they increase vascular resistance. At the cellular level, adding to the dysfunction of the endothelial cells, the process further shows as pathological growth and apoptosis of smooth vascular muscle, as fibrosis, hypercontractility, and calcification. Thus, endothelial dysfunction is also considered an initial step in the development of atherosclerosis40)Gimbrone MA, García-Cardeña G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016;118(4):620-636. doi:10.1161/CIRCRESAHA.115.306301.

At the molecular level, there is an altered signal transduction cascade that is i.a. stimulated by angiotensin II, aldosterone, and endothelin-141)Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci. 2007;112(8):417-428. doi:10.1042/CS2006034242)Rautureau Y, Paradis P, Schiffrin EL. Cross-talk between aldosterone and angiotensin signaling in vascular smooth muscle cells. Steroids. 2011;76(9):834-839. doi:10.1016/j.steroids.2011.02.01543)Kohan DE, Rossi NF, Inscho EW, Pollock DM. Regulation of blood pressure and salt homeostasis by endothelin. Physiol Rev. 2011;91(1):1-77. doi:10.1152/physrev.00060.2009.

Studies show that even the normotensive offspring of hypertensive parents initially has functional and then structural microvascular damages, although blood pressure is still normal. Endothelial dysfunction, impaired vasodilation, diastolic dysfunction, and various cardiac structural changes are already present in these subjects44)Eftekhari A, Mathiassen ON, Buus NH, Gotzsche O, Mulvany MJ, Christensen KL. Disproportionally impaired microvascular structure in essential hypertension. J Hypertens. 2011;29(5):896-905. doi:10.1097/HJH.0b013e3283447a1c45)Giannattasio C, Cattaneo BM, Mangoni AA, et al. Cardiac and vascular structural changes in normotensive subjects with parental hypertension. J Hypertens. 1995;13(2):259-264.

Genetic and epigenetic research shows that most of the single-nucleotide polymorphisms (SNPs) related to hypertension and cardiovascular disease are associated with oxidative stress, inflammation, and immune dysfunction. An analysis of a microarray of genetic polymorphisms showed most of them (31 of 49) to be up-regulated supporting an inflammatory environment46)Harrap SB. Blood pressure genetics: time to focus. J Am Soc Hypertens. 2009;3(4):231-237. doi:10.1016/j.jash.2009.06.001.

Oxidative Stress

As already mentioned above, oxidative stress is an important endothelial damage factor. Oxidative stress in the form of radical oxygen (ROS) and nitrogen species (RNS) is caused by a wide variety of metabolic processes. The most prominent ROS is the so-called superoxide, and its production is stimulated by activation of the angiotensin II/angiotensin II type I receptor (AT1R) and the NADPH oxidase by Angiotensin II. Superoxide neutralizes NO, the most important vasodilative factor47)Yan Chen, Kim Dongsoo, Aizawa Toru, Berk Bradford C. Functional Interplay Between Angiotensin II and Nitric Oxide. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23(1):26-36. doi:10.1161/01.ATV.0000046231.17365.9D. In addition, ROS damage the endothelial cells directly. This process is enhanced in hypertensive patients by a reduced antioxidant reserve, i.e. an imbalance between oxidative and antioxidant substances. Hypertensive patients also show an increased formation of ROS and an exacerbated stress response48)Russo C, Olivieri O, Girelli D, et al. Anti-oxidant status and lipid peroxidation in patients with essential hypertension. J Hypertens. 1998;16(9):1267-127149)Tse WY, Maxwell SR, Thomason H, et al. Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage. J Hum Hypertens. 1994;8(11):843-849.

Additionally, oxidative stress also indirectly affects the sympathetic nervous system through interaction with the rostral ventrolateral medulla and thus cardiac output and arterial vasoconstriction, which may also increase blood pressure through these mechanisms50)Nishihara M, Hirooka Y, Matsukawa R, Kishi T, Sunagawa K. Oxidative stress in the rostral ventrolateral medulla modulates excitatory and inhibitory inputs in spontaneously hypertensive rats. J Hypertens. 2012;30(1):97-106. doi:10.1097/HJH.0b013e32834e1df451)Konno S, Hirooka Y, Kishi T, Sunagawa K. Sympathoinhibitory effects of telmisartan through the reduction of oxidative stress in the rostral ventrolateral medulla of obesity-induced hypertensive rats. J Hypertens. 2012;30(10):1992-1999. doi:10.1097/HJH.0b013e328357fa98.

Inflammatory Processes

Inflammatory processes of different etiology have an influence on the NO bioavailability. For example, NO and its producing enzyme, eNOS, are inhibited by CRP, the “classic” acute-phase protein52)Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002;106(12):1439-1441. Angiotensin II induces vasoconstriction and inflammation via upregulation of cytokines and chemokines. Combined with increased oxidative stress, this leads to an increase in blood pressure53)Ghanem FA, Movahed A. Inflammation in high blood pressure: a clinician perspective. J Am Soc Hypertens. 2007;1(2):113-119. doi:10.1016/j.jash.2007.01.004.

Autoimmune Vascular Dysfunction

The immune system, both the innate and the adaptive one, is also involved in the pathogenesis of hypertension, i.a. by stimulating the production of cytokines and the autonomic nervous system54)Luft FC. Neural regulation of the immune system modulates hypertension-induced target-organ damage. J Am Soc Hypertens. 2012;6(1):23-26. doi:10.1016/j.jash.2011.09.006. Angiotensin II directly activates immune cells and also promotes cell infiltration into the organs55)Muller DN, Kvakan H, Luft FC. Immune-related effects in hypertension and target-organ damage. Curr Opin Nephrol Hypertens. 2011;20(2):113-117. doi:10.1097/MNH.0b013e3283436f88. Angiotensin II can cause hyperaldosteronism, and aldosterone has been recognized as an immune stimulant56)Herrada AA, Campino C, Amador CA, Michea LF, Fardella CE, Kalergis AM. Aldosterone as a modulator of immunity: implications in the organ damage. J Hypertens. 2011;29(9):1684-1692. doi:10.1097/HJH.0b013e32834a4c75.

How Can Nutrition Influence Endothelial Function?

Our diet provides numerous bioactive substances that can influence the amount of oxidative stress, inflammatory processes, and the activation of our immune system. In addition, some nutritional components also act directly on the RAAS system, which, in turn, affects the endothelium. The autonomic nervous system is also a mechanism of action that can be modulated through nutrition. Last but not least, nutrition also supplies the endothelial cells with either essential substrates, such as electrolytes or fatty acids, or, on the other hand, harmful substances.

Sodium, Potassium and Magnesium

The hypertensive effect of sodium is presumably mediated not so much by blood volume (see above), but rather by its effect on the endothelium and, thereby, on vascular resistance. Due to its influence on the plasma membrane and the cytoskeleton, sodium leads to altered morphology and function in terms of rigidity of the endothelial cells, and it reduces NO production57)Oberleithner H, Riethmüller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci USA. 2007;104(41):16281-16286. doi:10.1073/pnas.0707791104. In addition, it increases oxidative stress and TGF-β production. The effect is enhanced by the presence of aldosterone58)Kanbay M, Chen Y, Solak Y, Sanders PW. Mechanisms and consequences of salt sensitivity and dietary salt intake. Curr Opin Nephrol Hypertens. 2011;20(1):37-43. doi:10.1097/MNH.0b013e32834122f1. These changes also occur independently of increased blood pressure and can be partially compensated by the intake of potassium59)Kanbay M, Chen Y, Solak Y, Sanders PW. Mechanisms and consequences of salt sensitivity and dietary salt intake. Curr Opin Nephrol Hypertens. 2011;20(1):37-43. doi:10.1097/MNH.0b013e32834122f1. CRP also enhances the effect of aldosterone and thus the effect of sodium on the vascular endothelium, which constitutes another association with inflammatory processes60)Kusche-Vihrog K, Urbanova K, Blanqué A, et al. C-reactive protein makes human endothelium stiff and tight. Hypertension. 2011;57(2):231-237. doi:10.1161/HYPERTENSIONAHA.110.163444.

Potassium has natriuretic and vasodilatory properties, it increases baroreflex sensitivity, reduces oxidative stress via several pathways, and decreases TGF-β production61)Gu D, He J, Wu X, Duan X, Whelton PK. Effect of potassium supplementation on blood pressure in Chinese: a randomized, placebo-controlled trial. J Hypertens. 2001;19(7):1325-133162)Houston MC. The importance of potassium in managing hypertension. Curr Hypertens Rep. 2011;13(4):309-317. doi:10.1007/s11906-011-0197-8.

Magnesium is assumed to work synergistically with low serum sodium and high serum potassium levels in lowering blood pressure63)Laurant P, Touyz RM. Physiological and pathophysiological role of magnesium in the cardiovascular system: implications in hypertension. J Hypertens. 2000;18(9):1177-1191. Magnesium competes with sodium for the binding sites of vascular smooth muscle cells and, thus, acts analogous to calcium channel blockers as a direct vasodilator. It also increases NO, generally improves endothelial function, and reduces CRP and oxidative stress64)Song Y, Liu S. Magnesium for cardiovascular health: time for intervention. Am J Clin Nutr. 2012;95(2):269-270. doi:10.3945/ajcn.111.03110465)Cunha AR, Umbelino B, Correia ML, Neves MF. Magnesium and vascular changes in hypertension. Int J Hypertens. 2012;2012:754250. doi:10.1155/2012/754250.


Fructose not only increases sodium reabsorption, which increases blood volume (see above), but also leads to endothelial dysfunction if consumed excessively. The reason for this is probably mainly due to insulin resistance resulting in hyperinsulinemia, which leads to an increased production of endothelin-1. Together with factors such as angiotensin II and thromboxane A2, the activity of eNOS and enzymatic NO production is reduced66)Klein AV, Kiat H. The mechanisms underlying fructose-induced hypertension: a review. J Hypertens. 2015;33(5):912-920. doi:10.1097/HJH.0000000000000551. In addition, excessive sugar intake increases serum uric acid concentration, which stimulates the RAAS67)Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA. 2010;304(20):2270-2278. doi:10.1001/jama.2010.163868)Feig DI, Rodriguez-Iturbe B, Nakagawa T, Johnson RJ. Nephron number, uric acid, and renal microvascular disease in the pathogenesis of essential hypertension. Hypertension. 2006;48(1):25-26. doi:10.1161/01.HYP.0000223447.53155.d569)Feig DI, Kang D-H, Johnson RJ. Uric Acid and Cardiovascular Risk. N Engl J Med. 2008;359(17):1811-1821. doi:10.1056/NEJMra080088570)Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010;34(3):454-461. doi:10.1038/ijo.2009.259. Uric acid promotes CRP secretion and the formation of ROS, which also exerts endothelium-damaging effects71)Kang D-H, Ha S-K. Uric Acid Puzzle: Dual Role as Anti-oxidantand Pro-oxidant. Electrolyte Blood Press. 2014;12(1):1-6. doi:10.5049/EBP.2014.12.1.1. In a rat model, Katakam and colleagues72)Katakam PV, Ujhelyi MR, Hoenig ME, Miller AW. Endothelial dysfunction precedes hypertension in diet-induced insulin resistance. Am J Physiol. 1998;275(3):R788-792. doi:10.1152/ajpregu.1998.275.3.R788 showed that hyperinsulinemia occurs after three days of fructose feeding, followed by endothelial dysfunction after 18 days, and hypertension after 28 days. However, the interaction of these factors is not fully understood.

Furthermore, hyperinsulinaemia is thought to cause enhance sympathetic nervous system activity leading to an increased release of catecholamines and thus increased vasoconstriction and other endothelial damage73)Tran LT, Yuen VG, McNeill JH. The fructose-fed rat: a review on the mechanisms of fructose-induced insulin resistance and hypertension. Mol Cell Biochem. 2009;332(1-2):145-159. doi:10.1007/s11010-009-0184-474)Klein AV, Kiat H. The mechanisms underlying fructose-induced hypertension: a review. J Hypertens. 2015;33(5):912-920. doi:10.1097/HJH.0000000000000551.

Fatty Acids

Unsaturated fatty acids, both monounsaturated and polyunsaturated, reduce the formation of thromboxane-275)Ferrara LA, Raimondi AS, d’Episcopo L, Guida L, Dello Russo A, Marotta T. Olive oil and reduced need for antihypertensive medications. Arch Intern Med. 2000;160(6):837-842, which acts as a vasoconstrictor.

Omega-3 fatty acids from cold-water fish, flaxseed, and nuts lower blood pressure in observational, epidemiological, and prospective clinical trials.

Omega-3 fatty acids promote the formation of NO through up-regulation and activation of eNOS, improve endothelial dysfunction, affect the autonomic nervous system by increasing vagal tone, reduce insulin resistance, stimulate vasodilatory prostanoids, and reduce ACE activity76)Cicero AFG, Ertek S, Borghi C. Omega-3 polyunsaturated fatty acids: their potential role in blood pressure prevention and management. Curr Vasc Pharmacol. 2009;7(3):330-337.. Arachidonic acid (an omega-6 fatty acid) is a precursor of proaggregatory and vasoconstrictive eicosanoids, such as e.g. thromboxane A2. Omega-3 fatty acids reduce the synthesis of these eicosanoids. The ratio of omega-6 to omega-3 fatty acids in the diet is, therefore, probably more relevant than the absolute intake of omega-3 fatty acids. According to some authors, a ratio of about 1: 1 is desirable77)Boudreau MD, Chanmugam PS, Hart SB, Lee SH, Hwang DH. Lack of dose response by dietary n-3 fatty acids at a constant ratio of n-3 to n-6 fatty acids in suppressing eicosanoid biosynthesis from arachidonic acid. Am J Clin Nutr. 1991;54(1):111-117. doi:10.1093/ajcn/54.1.11178)Marventano S, Kolacz P, Castellano S, et al. A review of recent evidence in human studies of n-3 and n-6 PUFA intake on cardiovascular disease, cancer, and depressive disorders: does the ratio really matter? Int J Food Sci Nutr. 2015;66(6):611-622. doi:10.3109/09637486.2015.1077790.

So-called oxylipins derived from polyunsaturated fatty acids regulate vascular tone and inflammation. For example, oxylipins produced from arachidonic acid or linoleic acid have been associated with vasoconstriction, inflammation, and oxidative stress. Other oxylipins such as epoxyeicosatrienoic acids exert vasodilating effects by inhibiting soluble epoxide hydrolase (sEH). The sEH has been a pharmacological target in animal studies to develop new antihypertensive medication79)Caligiuri SPB, Aukema HM, Ravandi A, Guzman R, Dibrov E, Pierce GN. Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase. Hypertension. 2014;64(1):53-59. doi:10.1161/HYPERTENSIONAHA.114.03179. Interestingly, a randomized clinical trial in which patients with peripheral arterial disease (75% hypertensive) were supplied with 30 g of milled flaxseed/d for 6 months found that the consumption of flaxseed could lower systolic blood pressure by 7.07 mm Hg (95% CI: 1.5, 14.4 mm Hg) in those participants with a decrease in sEH-derived oxylipins. Participants with an increase in those oxylipins showed an increase in systolic blood pressure as well (+ 3.17 mm Hg (95% CI: 4.78, 11.13)). The authors of this trial suggest that it is the a-linolenic acid in flaxseed that exhibits antihypertensive effects via the described pathway80)Caligiuri SPB, Aukema HM, Ravandi A, Guzman R, Dibrov E, Pierce GN. Flaxseed Consumption Reduces Blood Pressure in Patients With Hypertension by Altering Circulating Oxylipins via an α-Linolenic Acid–Induced Inhibition of Soluble Epoxide Hydrolase. Hypertension. 2014;64(1):53-59. doi:10.1161/HYPERTENSIONAHA.114.03179.

Omega-9 fatty acids, in particular the monounsaturated fatty acid oleic acid contained in olive oil as part of a Mediterranean diet, are associated with a reduction of blood pressure81)Psaltopoulou T, Naska A, Orfanos P, Trichopoulos D, Mountokalakis T, Trichopoulou A. Olive oil, the Mediterranean diet, and arterial blood pressure: the Greek European Prospective Investigation into Cancer and Nutrition (EPIC) study. Am J Clin Nutr. 2004;80(4):1012-1018. doi:10.1093/ajcn/80.4.1012. However, it is unclear if the effects of olive oil are rather based on the content of antioxidant polyphenols (see above), and not on its fatty acids.


The underlying mechanism for the hypotensive effect of protein intake is not yet understood. It is assumed that this effect can be ascribed to certain amino acids that have an influence on NO production and thus promote vasodilation. For example, L-arginine and endogenous methylarginine are the precursor molecules for the production of NO by eNOS82)Rajapakse NW, Mattson DL. Role of L-arginine in nitric oxide production in health and hypertension. Clin Exp Pharmacol Physiol. 2009;36(3):249-255. doi:10.1111/j.1440-1681.2008.05123.x. In fact, studies on hypertensive and normotensive individuals show a hypotensive effect after oral administration of L-arginine (oral or parenteral)83)Ast J, Jablecka A, Bogdanski P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit. 2010;16(5):CR266-271. A meta-analysis of 11 RCTs, in which 4 to 24 grams of L-arginine were administered daily, found an average blood pressure reduction of 5.39/2.66 mm Hg (95% CI: −8.54, −2.25; −3.77, −1.54)84)Dong J-Y, Qin L-Q, Zhang Z, et al. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J. 2011;162(6):959-965. doi:10.1016/j.ahj.2011.09.012.

Multiple studies provide evidence that the consumption of dairy products is inversely associated with risk of hypertension85)Schwingshackl L, Schwedhelm C, Hoffmann G, et al. Food Groups and Risk of Hypertension: A Systematic Review and Dose-Response Meta-Analysis of Prospective Studies. Adv Nutr. 2017;8(6):793-803. doi:10.3945/an.117.017178, which is believed to be due to the content of certain peptides86)Jauhiainen T, Korpela R. Milk peptides and blood pressure. J Nutr. 2007;137(3 Suppl 2):825S-9S. doi:10.1093/jn/137.3.825S. Interventional studies have shown that daily administration of specially fermented milk (150 ml) over 21 weeks reduced hypertensive subjects’ blood pressure by an average of 6.7 ± 3.0 mm Hg systolic and 3.6 ± 1.9 mm Hg diastolic more when compared to the control group. The milk of the intervention group contained two bioactive peptides with the properties of an ACE inhibitor during the fermentation process87)Seppo L, Jauhiainen T, Poussa T, Korpela R. A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr. 2003;77(2):326-330. doi:10.1093/ajcn/77.2.326.


Dietary fiber also exerts hypotensive effects, as shown in studies88)Whelton SP, Hyre AD, Pedersen B, Yi Y, Whelton PK, He J. Effect of dietary fiber intake on blood pressure: a meta-analysis of randomized, controlled clinical trials. J Hypertens. 2005;23(3):475-481. So far, the underlying mechanism is not well understood. It is known that fiber can attenuate the body’s insulin response to food. As explained earlier regarding sugar intake, hyperinsulinaemia leads to reduced NO bioavailability via various pathways, which ultimately increases peripheral vascular resistance and thus blood pressure89)Klein AV, Kiat H. The mechanisms underlying fructose-induced hypertension: a review. J Hypertens. 2015;33(5):912-920. doi:10.1097/HJH.0000000000000551.


Antioxidants include both antioxidant vitamins such as vitamin C and E as well as polyphenols and other radical scavengers.

Vitamin C increases NO, improves endothelial function and arterial compliance, regulates the autonomic nervous system, and reduces oxidative stress90)Plantinga Y, Ghiadoni L, Magagna A, et al. Supplementation with vitamins C and E improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertens. 2007;20(4):392-397. doi:10.1016/j.amjhyper.2006.09.02191)Simon JA. Vitamin C and cardiovascular disease: a review. J Am Coll Nutr. 1992;11(2):107-125.

Concerning vitamin E, the evidence seems to be disappointing: Most of the studies did not show any reduction in blood pressure when tocopherols or tocotrienols were supplemented92)Houston M. The role of nutrition and nutraceutical supplements in the treatment of hypertension. World J Cardiol. 2014;6(2):38-66. doi:10.4330/wjc.v6.i2.38. The administration of alpha-tocopherol even led to a significant increase in blood pressure by 7.0/5.3 mm Hg in patients with type-2 diabetes and drug-controlled hypertension93)Ward NC, Wu JHY, Clarke MW, et al. The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. J Hypertens. 2007;25(1):227-234. doi:10.1097/01.hjh.0000254373.96111.43. This effect can probably be explained by the interaction of tocopherol with cytochrome P450, as it reduces the antihypertensive effect of the medication.

Flavonoids belong to the group of polyphenols and have an antioxidant effect. More than 4,000 different flavonoids have been identified so far in various foods such as fruits, vegetables, red wine, tea, cocoa, and other plant products94)Moline J, Bukharovich IF, Wolff MS, Phillips R. Dietary flavonoids and hypertension: is there a link? Med Hypotheses. 2000;55(4):306-309. doi:10.1054/mehy.2000.1057. They are “radical scavengers” that prevent lipid peroxidation and have antihypertensive effects by reducing oxidative stress and preventing endothelial dysfunction95)Hooper L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2012;95(3):740-751. doi:10.3945/ajcn.111.023457.

Other Phytochemicals

It is believed that the most important element of a diet high in vegetables is the nitrate content96)Webb Andrew J., Patel Nakul, Loukogeorgakis Stavros, et al. Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite. Hypertension. 2008;51(3):784-790. doi:10.1161/HYPERTENSIONAHA.107.103523. Nitrate was previously considered to be a food and water pollutant. Today, it is understood as a kind of nutrient that can lower blood pressure and improve cardiovascular health. However, the efficacy of nitrate supplementation is not fully understood, as there are also studies that cannot demonstrate a significant effect on blood pressure97)Bondonno CP, Liu AH, Croft KD, et al. Absence of an effect of high nitrate intake from beetroot juice on blood pressure in treated hypertensive individuals: a randomized controlled trial. Am J Clin Nutr. 2015;102(2):368-375. doi:10.3945/ajcn.114.10118898)Gilchrist M, Winyard PG, Aizawa K, Anning C, Shore A, Benjamin N. Effect of dietary nitrate on blood pressure, endothelial function, and insulin sensitivity in type 2 diabetes. Free Radic Biol Med. 2013;60:89-97. doi:10.1016/j.freeradbiomed.2013.01.024. Here, the intake antihypertensive medication, possibly non-documented antibiotics, but also a lessened efficacy of nitrate under the condition of older age and higher cardiovascular risk might play a role99)Lara J, Ashor AW, Oggioni C, Ahluwalia A, Mathers JC, Siervo M. Effects of inorganic nitrate and beetroot supplementation on endothelial function: a systematic review and meta-analysis. Eur J Nutr. 2016;55(2):451-459. doi:10.1007/s00394-015-0872-7.

Nitrate in the diet contributes to the formation of nitric oxide (NO), thereby complementing the physiological pathway of endothelial cells that synthesize NO from the oxidation of L-arginine by the eNOS. As a result, NO has a vasodilating effect.


As numerous and interrelated the pathophysiological mechanisms of hypertension are, as numerous are the pathways dietary factors are acting on. By looking at the biochemical and physiological levels, the great opportunities of influencing blood pressure through diet become apparent. However, only clinical trials are able to reveal if the physiological exertion of influence can be translated to the clinical level, that is, if diet is efficient in preventing and treating hypertension. We will look at the evidence regarding interventional studies in the next part of our hypertension series.

This article is part of the series “Preventing and Treating Hypertension with Diet“.