User:Madhero88/Pathophysiology of hypertension

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The pathophysiology of hypertension is an area of active research, attempting to explain causes of hypertension, which is usually a chronic disease characterized by elevation of blood pressure to various degrees. Hypertension can be classified as either essential or secondary. Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition. About 90-95% of hypertension is essential hypertension.[1][2][3][4] While secondary hypertension indicates that the high blood pressure is a result of another underlying condition, such as kidney disease or tumours (adrenal adenoma or pheochromocytoma). Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure and arterial aneurysm, and is a leading cause of chronic renal failure.[5]

Most mechanisms leading to secondary hypertension are well understood, while pathophysiology of essential hypertension remains an area of active research, with many theories and different links to many risk factors.

A diagram explaining factors affecting arterial pressure

Cardiac output and peripheral resistance are the two determinants of arterial pressure. and so blood pressure is normally dependent on the balance between cardiac output and peripheral resistance.[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 (lumen diameter 100–400 m) and arterioles.


Genetics[edit]

Evidence for genetic influence on blood pressure comes from various sources.[7] Its proved that there is greater similarity in blood pressure within families than between families, which indicates a form of inheritance.[8] And it was proved that wasnt due to shared environmental factors.[9] Single gene mutations is proved to cause Mendelian forms of high and low blood pressure.[10] almost 10 genes have been identified to cause this forms of hypertension.[10][11]These mutations affect blood pressure by altering renal salt handling.[12] Recently and with the aid of newly developed genetic analysis techniques researchers found statistically significant linkage of blood pressure to several chromosomal regions, including regions linked to familial combined hyperlipidemia.[13][14][15][16][17] These findings suggest that there are many genetic loci, each with small effects on blood pressure in the general population. Overall, however, identifiable single-gene causes of hypertension are uncommon, consistent with a multifactorial cause of essential hypertension.[2][7][18][19]

The best studied monogenic cause of hypertension is the Liddle syndrome, a rare but clinically important disorder in which constitutive activation of the epithelial sodium channel predisposes to severe, treatment-resistant hypertension.[20] Epithelial sodium channel activation resulting in inappropriate sodium retention at the renal collecting duct level. Patients with the Liddle syndrome typically present with volume-dependent, low renin, and low aldosterone, and hypertension. Screenings of general hypertensive populations indicate that the Liddle syndrome is rare and does not contribute substantially to the development of hypertension in the general population.[21]

Vascular volume[edit]

Vascular volume is a primary determinant of arterial pressure over the long term. Although the extracellular fluid space is composed of vascular and interstitial spaces, in general, alterations in total extracellular fluid volume are associated with proportional changes of blood volume. Sodium is predominantly an extracellular ion and is a primary determinant of the extracellular fluid volume. When NaCl intake exceeds the capacity of the kidney to excrete sodium, vascular volume initially expands and cardiac output increases. so the initial elevation of blood pressure in response to vascular volume expansion is related to an increase of cardiac output; however, over time, peripheral resistance increases and cardiac output reverts toward normal. As arterial pressure increases in response to a high NaCl intake, urinary sodium excretion increases and sodium balance is maintained at the expense of an increase in arterial pressure. The is due to a phenomenon called pressure-natriuresis(pressure induced diuresis), which may involve a subtle increase of glomerular filtration rate, decreased absorbing capacity of the renal tubules, and possibly hormonal factors such as atrial natriuretic factor. and as expected individuals with an impaired capacity to excrete sodium, require greater increases of arterial pressure to achieve natriuresis and sodium balance. So this can explain why patients with decreased capacity of the kidney to excrete sodium, due to either intrinsic renal disease or to increased production of a salt-retaining hormone (mineralocorticoid ie. aldosterone) resulting in increased renal tubular reabsorption of sodium will end up with NaCl(salt)-dependent hypertension.

Renin-angiotensin-aldosterone system[edit]

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, Thus it contributing to regulation of the blood pressure, it performs this function through breaking down (hydrolyzes) 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) producing angiotensin II, the most vasoactive peptide.[22][23]Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature of arteries and thereby raises the peripheral resistance, and so elevates blood pressure. Angiotensin II also acts on the adrenal glands too and releases 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 elevation of renin level in the blood, which is normally in adult human is 1.98-24.6 ng/L in the upright position.[24] will lead to hypertension.

Autonomic nervous system[edit]

Also the autonomic nervous system, plays a central role in maintaining the cardiovascular homeostasis via pressure, volume, and chemoreceptor signals. Done by altering peripheral vasculature, and kidneys, causing increased cardiac output, increased vascular resistance, and fluid retention. Disorder of the system, as in case of sympathetic nervous system overactivity, increases blood pressure and contributes to the development and maintenance of hypertension.[25][26] In addition, autonomic imbalance (ie. increased sympathetic tone accompanied by reduced parasympathetic tone) has been associated with many metabolic and hemodynamic abnormalities that result in increased cardiovascular morbidity and mortality.[27][25]

The mechanisms of increased sympathetic nervous system activity in hypertension are complex and 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.[8][28][29] 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.[30][31] Additional small-molecule mediators that suppress baroreceptor activity and contribute to exaggerated sympathetic drive in hypertension include reactive oxygen species and endothelin.[32][33] Some studies shown that hypertensive patients manifest greater vasoconstrictor responses to infused norepinephrine than normotensive controls.[34] And that hypertensive patients doesn't show the normal response to increased circulating norepinephrine levels which generally induces downregulation of noradrenergic receptor, and its believed that this abnormal response is genetically inherited.[35]

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.[36]

Endothelial dysfunction[edit]

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.[37]

References[edit]

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