Pathophysiology of hypertension

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A diagram explaining factors affecting arterial pressure Arterial pressure diagram.png
A diagram explaining factors affecting arterial pressure

Pathophysiology is a study which explains the function of the body as it relates to diseases and conditions. The pathophysiology of hypertension is an area which attempts to explain mechanistically the causes of hypertension, which is a chronic disease characterized by elevation of blood pressure. Hypertension can be classified by cause as either essential (also known as primary or idiopathic) or secondary. About 90–95% of hypertension is essential hypertension. [1] [2] [3] [4] Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium. Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excess aldosterone, cortisol, or catecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease. [5]

Contents

Cardiac output and peripheral resistance are the two determinants of arterial pressure. [6] Cardiac output is determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries and arterioles.

Genetics

Single gene mutations can cause Mendelian forms of high blood pressure; [7] ten genes have been identified which cause these monogenic forms of hypertension. [7] [8] These mutations affect blood pressure by altering kidney salt handling. [9] [10] There is greater similarity in blood pressure within families than between families, which indicates a form of inheritance, [11] and this is not due to shared environmental factors. [12] With the aid of genetic analysis techniques, a statistically significant linkage of blood pressure to several chromosomal regions, including regions linked to familial combined hyperlipidemia, was found. [13] [14] [15] [16] [17] These findings suggest that there are many genetic loci, in the general population, each with small effects on blood pressure. Overall, however, identifiable single-gene causes of hypertension are uncommon, consistent with a multifactorial cause of essential hypertension. [2] [10] [18] [19]

Autonomic nervous system

The autonomic nervous system plays a central role in maintaining cardiovascular homeostasis via pressure, volume, and chemoreceptor signals. It does this by regulating the peripheral vasculature, and kidney function, which in turn affect cardiac output, vascular resistance, and fluid retention. Excess activity of the sympathetic nervous system increases blood pressure and contributes to hypertension. [20] [21] [22] [23] [24]

The mechanisms of increased sympathetic nervous system activity in hypertension involve alterations in baroreflex and chemoreflex pathways at both peripheral and central levels. Arterial baroreceptors are reset to a higher pressure in hypertensive patients, and this peripheral resetting reverts to normal when arterial pressure is normalized. [25] [26] [27] Furthermore, there is central resetting of the aortic baroreflex in hypertensive patients, resulting in suppression of sympathetic inhibition after activation of aortic baroreceptor nerves. This baroreflex resetting seems to be mediated, at least partly, by a central action of angiotensin II. [28] [29] [30] Additional small-molecule mediators that suppress baroreceptor activity and contribute to exaggerated sympathetic drive in hypertension include reactive oxygen species and endothelin. [31] [32] Some studies have shown that hypertensive patients manifest greater vasoconstrictor responses to infused norepinephrine than normotensive controls. [33] And that hypertensive patients do not show the normal response to increased circulating norepinephrine levels which generally induces downregulation of noradrenergic receptor, and it is believed that this abnormal response is genetically inherited. [34]

Exposure to stress increases sympathetic outflow, and repeated stress-induced vasoconstriction may result in vascular hypertrophy, leading to progressive increases in peripheral resistance and blood pressure. [2] This could partly explain the greater incidence of hypertension in lower socioeconomic groups, since they must endure greater levels of stress associated with daily living. Persons with a family history of hypertension manifest augmented vasoconstrictor and sympathetic responses to laboratory stressors, such as cold pressor testing and mental stress, that may predispose them to hypertension. This is particularly true of young African Americans. Exaggerated stress responses may contribute to the increased incidence of hypertension in this group. [35] For patients having hypertension, higher heart rate variability (HRV) is a risk factor for atrial fibrillation. [36]

Resistant hypertension can be treated by electrically stimulating the baroreflex with a pacemaker-like device. [37]

Renin–angiotensin–aldosterone system

Another system maintaining the extracellular fluid volume, peripheral resistance, and that if disturbed may lead to hypertension, is the renin–angiotensin–aldosterone system. Renin is a circulating enzyme that participates in maintaining extracellular volume and arterial vasoconstriction, therefore contributing to regulation of blood pressure. It performs this function by breaking down (hydrolysing) angiotensinogen, secreted from the liver, into the peptide angiotensin I. Angiotensin I is further cleaved by an enzyme that is located primarily but not exclusively in the pulmonary circulation bound to endothelium; that enzyme is angiotensin converting enzyme (ACE). This cleavage produces angiotensin II, the most vasoactive peptide. [38] [39] Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature of arteries, raising peripheral resistance and thereby elevating blood pressure. Angiotensin II also causes the adrenal glands to release aldosterone, which stimulates the epithelial cells of the kidneys to increase re-absorption of salt and water, leading to raised blood volume and raised blood pressure. So elevated renin levels in the blood (normally 1.98-2.46 ng/ml in the upright position) [40] leads to hypertension. [2] [41]

Recent studies claim that obesity is a risk factor for hypertension because of activation of the renin–angiotensin system (RAS) in adipose tissue, [42] [43] and also linked renin–angiotensin system with insulin resistance, and claims that anyone can cause the other. [44] Local production of angiotensin II in various tissues, including the blood vessels, heart, adrenals, and brain, is controlled by ACE and other enzymes, including the serine protease chymase. The activity of local renin–angiotensin systems and alternative pathways of angiotensin II formation may make an important contribution to remodeling of resistance vessels and the development of target organ damage (i.e. left ventricular hypertrophy, congestive heart failure, atherosclerosis, stroke, end-stage kidney disease, myocardial infarction, and arterial aneurysm) in hypertensive persons. [41]

Endothelial dysfunction

The endothelium of blood vessels produces an extensive range of substances that influence blood flow and, in turn, is affected by changes in the blood and the pressure of blood flow. For example, local nitric oxide and endothelin, which are secreted by the endothelium, are the major regulators of vascular tone and blood pressure. In patients with essential hypertension, the balance between the vasodilators and the vasoconstrictors is upset, which leads to changes in the endothelium and sets up a "vicious cycle" that contributes to the maintenance of high blood pressure. In patients with hypertension, endothelial activation and damage also lead to changes in vascular tone, vascular reactivity, and coagulation and fibrinolytic pathways. Alterations in endothelial function are a reliable indicator of target organ damage and atherosclerotic disease, as well as prognosis. [45]

Evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension. [46] [47] [48] Normally nitric oxide is an important regulator and mediator of numerous processes in the nervous, immune and cardiovascular systems, including smooth muscle relaxation thus resulting in vasodilation of the artery and increasing blood flow, suppressor of migration and proliferation of vascular smooth-muscle cells. [2] It has been suggested that angiotensin II enhances formation of the oxidant superoxide at concentrations that affect blood pressure minimally. [49]

Endothelin is a potent vasoactive peptide produced by endothelial cells that has both vasoconstrictor and vasodilator properties. Circulating endothelin levels are increased in some hypertensive patients, [50] [51] particularly African Americans and persons with hypertension. [50] [52] [53] [54]

Sodium/potassium ratio hypothesis of essential hypertension

A 2007 review article states that while excessive sodium consumption has long been recognized as contributing to the risk of hypertension, "potassium, the main intracellular cation, has usually been viewed as a minor factor in the pathogenesis of hypertension. However, abundant evidence indicates that a potassium deficit has a critical role in hypertension and its cardiovascular sequelae." The authors state that modern, western, high sodium, low potassium diets result in corresponding changes in intracellular concentration of these, the two most important cations in animal cells. This imbalance leads to contraction of vascular smooth muscle, restricting blood flow and so driving up blood pressure. The authors cite studies which show that potassium supplementation is effective in reducing hypertension. [55]

Epidemiological support for this hypothesis can be found in a 2014 meta-analysis which states that "the sodium-to-potassium ratio appears to be more strongly associated with blood pressure outcomes than either sodium or potassium alone in hypertensive adult populations.". [56]

Inflammation and adverse immune responses

Basic science discoveries have implicated the immune system as in the development of hypertension in animal models. [57] Population studies in humans have reported that higher levels of certain inflammatory cytokines are associated with greater risk of hypertension development. [58] [59] [60]

Related Research Articles

<span class="mw-page-title-main">ACE inhibitor</span> Class of medications used primarily to treat high blood pressure

Angiotensin-converting-enzyme inhibitors are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.

<span class="mw-page-title-main">Blood pressure</span> Pressure exerted by circulating blood upon the walls of arteries

Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" refers to the pressure in a brachial artery, where it is most commonly measured. Blood pressure is usually expressed in terms of the systolic pressure over diastolic pressure in the cardiac cycle. It is measured in millimeters of mercury (mmHg) above the surrounding atmospheric pressure, or in kilopascals (kPa). The difference between the systolic and diastolic pressures is known as pulse pressure, while the average pressure during a cardiac cycle is known as mean arterial pressure.

<span class="mw-page-title-main">Hypertension</span> Long-term high blood pressure in the arteries

Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major risk factor for stroke, coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, vision loss, chronic kidney disease, and dementia. Hypertension is a major cause of premature death worldwide.

<span class="mw-page-title-main">Renin</span> Aspartic protease protein and enzyme

Renin, also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the renin-angiotensin-aldosterone axis—that increases the volume of extracellular fluid and causes arterial vasoconstriction. Thus, it increases the body's mean arterial blood pressure.

<span class="mw-page-title-main">Renin–angiotensin system</span> Hormone system

The renin-angiotensin system (RAS), or renin-angiotensin-aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid, and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Angiotensin</span> Group of peptide hormones in mammals

Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the adrenal cortex to promote sodium retention by the kidneys.

<span class="mw-page-title-main">Aldosterone</span> Mineralocorticoid steroid hormone

Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays a central role in the homeostatic regulation of blood pressure, plasma sodium (Na+), and potassium (K+) levels. It does so primarily by acting on the mineralocorticoid receptors in the distal tubules and collecting ducts of the nephron. It influences the reabsorption of sodium and excretion of potassium (from and into the tubular fluids, respectively) of the kidney, thereby indirectly influencing water retention or loss, blood pressure, and blood volume. When dysregulated, aldosterone is pathogenic and contributes to the development and progression of cardiovascular and kidney disease. Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

Essential hypertension is a form of hypertension without an identifiable physiologic cause. It is the most common type affecting 85% of those with high blood pressure. The remaining 15% is accounted for by various causes of secondary hypertension. Essential hypertension tends to be familial and is likely to be the consequence of an interaction between environmental and genetic factors. Hypertension can increase the risk of cerebral, cardiac, and renal events.

<span class="mw-page-title-main">Baroreflex</span> Homeostatic mechanism in the body

The baroreflex or baroreceptor reflex is one of the body's homeostatic mechanisms that helps to maintain blood pressure at nearly constant levels. The baroreflex provides a rapid negative feedback loop in which an elevated blood pressure causes the heart rate to decrease. Decreased blood pressure decreases baroreflex activation and causes heart rate to increase and to restore blood pressure levels. Their function is to sense pressure changes by responding to change in the tension of the arterial wall. The baroreflex can begin to act in less than the duration of a cardiac cycle and thus baroreflex adjustments are key factors in dealing with postural hypotension, the tendency for blood pressure to decrease on standing due to gravity.

<span class="mw-page-title-main">Telmisartan</span> Blood pressure lowering medication

Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination telmisartan/hydrochlorothiazide, telmisartan/cilnidipine and telmisartan/amlodipine.

<span class="mw-page-title-main">Hypertensive emergency</span> Very high blood pressure and signs of organ damage

A hypertensive emergency is very high blood pressure with potentially life-threatening symptoms and signs of acute damage to one or more organ systems. It is different from a hypertensive urgency by this additional evidence for impending irreversible hypertension-mediated organ damage (HMOD). Blood pressure is often above 200/120 mmHg, however there are no universally accepted cutoff values.

<span class="mw-page-title-main">Renovascular hypertension</span> Medical condition

Renovascular hypertension is a condition in which high blood pressure is caused by the kidneys' hormonal response to narrowing of the arteries supplying the kidneys. When functioning properly this hormonal axis regulates blood pressure. Due to low local blood flow, the kidneys mistakenly increase blood pressure of the entire circulatory system. It is a form of secondary hypertension - a form of hypertension whose cause is identifiable.

<span class="mw-page-title-main">Fenoldopam</span> Antihypertensive agent, also used in hypertensive crisis

Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist. Fenoldopam is used as an antihypertensive agent. It was approved by the Food and Drug Administration (FDA) in September 1997.

<span class="mw-page-title-main">Aliskiren</span> Medication

Aliskiren is the first in a class of drugs called direct renin inhibitors. It is used for essential (primary) hypertension. While used for high blood pressure, other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.

<span class="mw-page-title-main">Salt and cardiovascular disease</span> Association between salt consumption and cardiovascular disease

Salt consumption has been extensively studied for its role in human physiology and impact on human health. Chronic, high intake of dietary salt consumption is associated with hypertension and cardiovascular disease, in addition to other adverse health outcomes. Major health and scientific organizations, such as the World Health Organization, US Centers for Disease Control and Prevention, and American Heart Association, have established high salt consumption as a major risk factor for cardiovascular diseases and stroke.

<span class="mw-page-title-main">Orthostatic hypertension</span> Medical condition

Orthostatic hypertension is a medical condition consisting of a sudden and abrupt increase in blood pressure (BP) when a person stands up. Orthostatic hypertension is diagnosed by a rise in systolic BP of 20 mmHg or more when standing. Orthostatic diastolic hypertension is a condition in which the diastolic BP raises to 98 mmHg or over in response to standing, but this definition currently lacks clear medical consensus, so is subject to change. Orthostatic hypertension involving the systolic BP is known as systolic orthostatic hypertension.

<span class="mw-page-title-main">Fimasartan</span> Chemical compound

Fimasartan is a non-peptide angiotensin II receptor antagonist (ARB) used for the treatment of hypertension and heart failure. Through oral administration, fimasartan blocks angiotensin II receptor type 1 (AT1 receptors), reducing pro-hypertensive actions of angiotensin II, such as systemic vasoconstriction and water retention by the kidneys. Concurrent administration of fimasartan with diuretic hydrochlorothiazide has shown to be safe in clinical trials. Fimasartan was approved for use in South Korea on September 9, 2010, and is available under the brand name Kanarb through Boryung Pharmaceuticals, who are presently seeking worldwide partnership.

<span class="mw-page-title-main">Hypertension and the brain</span>

Hypertension is a condition characterized by an elevated blood pressure in which the long term consequences include cardiovascular disease, kidney disease, adrenal gland tumors, vision impairment, memory loss, metabolic syndrome, stroke and dementia. It affects nearly 1 in 2 Americans and remains as a contributing cause of death in the United States. There are many genetic and environmental factors involved with the development of hypertension including genetics, diet, and stress.

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