Pathogenesis of Essential Hypertension
The pathogenesis of essential hypertension is multifactorial and highly complex. Multiple factors modulate blood pressure (BP) for adequate tissue perfusion; these include the following:
Circulating blood volume
Blood vessel elasticity
Over the course of its natural history, essential hypertension progresses from occasional to established hypertension. After a long, invariable, asymptomatic period, persistent hypertension develops into complicated hypertension, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident.
The progression of essential hypertension begins with prehypertension in persons aged 10-30 years (by increased cardiac output) and then advances to early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent), then to established hypertension in persons aged 30-50 years, and finally to complicated hypertension in persons aged 40-60 years.
Factors Influencing BP Regulation
Regulation of normal blood pressure (BP) is a complex process. Arterial BP is a product of cardiac output and peripheral vascular resistance. The factors affecting cardiac output include sodium intake, renal function, and mineralocorticoids; the inotropic effects occur via extracellular fluid volume augmentation and an increase in heart rate and contractility.
Peripheral vascular resistance is dependent upon the sympathetic nervous system, humoral factors, and local autoregulation. The sympathetic nervous system produces its effects via the vasoconstrictor alpha effect or the vasodilator beta effect. Recent studies with bilateral radiofrequency renal nerve ablation have shown a significant reduction of blood pressure in drug-resistant patients.  Similar reductions in blood pressure have shown bilateral carotid artery stimulation in the same populations. 
These studies confirm the important role of the sympathetic nervous system in the pathogenesis of hypertension. The humoral actions on peripheral resistance are also influenced by other mediators, such as vasoconstrictors (eg, angiotensin, catecholamines) or vasodilators (eg, prostaglandins, kinins).
Blood viscosity, vascular wall shear conditions (rate and stress), and blood flow velocity (mean and pulsatile components) have potential relevance with regard to the regulation of BP in humans by vascular and endothelial function. Circulating blood volume is regulated by renal salt and water handling, a phenomenon that plays a particularly important role in salt-sensitive hypertension.
Autoregulation of BP
Autoregulation of BP occurs by way of intravascular volume contraction and expansion regulated by the kidney, as well as via transfer of transcapillary fluid. Through the mechanism of pressure natriuresis, salt and water balance is achieved at heightened systemic pressure, as proposed by Guyton. Interactions between cardiac output and peripheral resistance are autoregulated to maintain a set BP in an individual. For example, constriction of the arterioles elevates arterial pressure by increasing total peripheral resistance, whereas venular constriction leads to redistribution of the peripheral intravascular volume to the central circulation, thereby increasing preload and cardiac output.
Vasoreactivity and the role of the vascular endothelium
The vasoreactivity of the vascular bed, an important phenomenon mediating changes of hypertension, is influenced by the activity of vasoactive factors, reactivity of the smooth muscle cells, and structural changes in the vessel wall and vessel caliber, expressed by a lumen-to-wall ratio.
The vascular endothelium is considered to be a vital organ, in which synthesis of various vasodilating and constricting mediators occurs. The interaction of autocrine and paracrine factors takes place in the vascular endothelium, leading to growth and remodeling of the vessel wall and to the hemodynamic regulation of BP.
Numerous hormonal, humoral vasoactive, and growth and regulating peptides are produced in the vascular endothelium. These mediators include angiotensin II, bradykinin, endothelin, nitric oxide, and several other growth factors. Endothelin is a potent vasoconstrictor and growth factor that likely plays a major role in the pathogenesis of hypertension. Angiotensin II is a potent vasoconstrictor synthesized from angiotensin I with the help of an angiotensin-converting enzyme (ACE).
Another vasoactive substance manufactured in the endothelium is nitric oxide. Nitric oxide is an extremely potent vasodilator that influences local autoregulation and other vital organ functions. Additionally, several growth factors are manufactured in the vascular endothelium; each of these plays an important role in atherogenesis and target organ damage. These factors include platelet-derived growth factor, fibroblast growth factor, insulin growth factor, and many others.
Etiology of Essential Hypertension
A possible etiology of essential hypertension has been proposed in which multiple factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, may interact to produce hypertension.
Patients who develop hypertension are known to develop a systemic hypertensive response secondary to vasoconstrictive stimuli. Alterations in structural and physical properties of resistance arteries, as well as changes in endothelial function, are probably responsible for this abnormal behavior of vasculature. Furthermore, vascular remodeling occurs over the years as hypertension evolves, thereby maintaining increased vascular resistance irrespective of the initial hemodynamic pattern.
Changes in vascular wall thickness affect the amplification of peripheral vascular resistance in hypertensive patients and result in the reflection of waves back to the aorta, increasing systolic BP.
One form of essential hypertension, termed high-output hypertension, results from decreased peripheral vascular resistance and concomitant cardiac stimulation by adrenergic hyperactivity and altered calcium homeostasis. A second mechanism manifests with normal or reduced cardiac output and elevated systemic vascular resistance (SVR) due to increased vasoreactivity. Another (and overlapping) mechanism is increased salt and water reabsorption (salt sensitivity) by the kidney, which increases circulating blood volume.
Hypertensive Emergencies and Target Organ Damage
The pathophysiology of hypertensive emergencies is not well understood. Failure of normal autoregulation and an abrupt rise in systemic vascular resistance (SVR) are typically initial steps in the disease process. Increases in SVR are thought to occur from the release of humoral vasoconstrictors from the wall of a stressed vessel. The increased pressure within the vessel then starts a cycle of endothelial damage, local intravascular activation of the clotting cascade, fibrinoid necrosis of small blood vessels, and the release of more vasoconstrictors. If the process is not stopped, a cycle of further vascular injury, tissue ischemia, and autoregulatory dysfunction ensues. [3, 4]
Single-organ involvement is found in approximately 83% of patients presenting with hypertensive emergencies. Two-organ involvement is found in 14% of patients, and multiorgan involvement (>3 organ systems) is found in approximately 3% of patients presenting with a hypertensive emergency. 
Hypertension and cardiovascular disease
During hypertensive emergencies, the left ventricle is unable to compensate for an acute rise in SVR. This leads to left ventricular failure and pulmonary edema or myocardial ischemia.
Chronic hypertension causes increased arterial stiffness, increased systolic blood pressure (BP), and widened pulse pressures. These factors decrease coronary perfusion pressures, increase myocardial oxygen consumption, and lead to left ventricular hypertrophy (LVH).  In LVH, the myocardium undergoes structural changes in response to increased afterload. Cardiac myocytes respond by hypertrophy, allowing the heart to pump more strongly against the elevated pressure. However, the contractile function of the left ventricle remains normal until later stages. Eventually, LVH lessens the chamber lumen, limiting diastolic filling and stroke volume. The left ventricular diastolic function is markedly compromised in long-standing hypertension.
The mechanisms of diastolic dysfunction apparently include an aberration in the passive relaxation of the left ventricle during diastole. Over time, fibrosis may occur, further contributing to the poor compliance of the ventricle. As the left ventricle does not relax during early diastole, left ventricular end-diastolic pressure increases, further increasing left atrial pressure in late diastole. The exact determinants of left ventricular diastolic dysfunction have not been well studied; possibly, the abnormality is governed by abnormal calcium kinetics.
Cardiac involvement in hypertension manifests as LVH, left atrial enlargement, aortic root dilatation, atrial and ventricular arrhythmias, systolic and diastolic heart failure, and ischemic heart disease. LVH is associated with an increased risk of premature death and morbidity. A higher frequency of cardiac atrial and ventricular dysrhythmias and sudden cardiac death may exist. Possibly, increased coronary arteriolar resistance leads to reduced blood flow to the hypertrophied myocardium, resulting in angina despite clean coronary arteries. Hypertension, along with reduced oxygen supply and other risk factors, accelerates the process of atherogenesis, thereby further reducing oxygen delivery to the myocardium.
Hypertension and cerebrovascular disease
Cerebral autoregulation is the inherent ability of the cerebral vasculature to maintain a constant cerebral blood flow (CBF) across a wide range of perfusion pressures. Rapid rises in BP can cause hyperperfusion and increased CBF, which can lead to increased intracranial pressure and cerebral edema.  Patients with chronic hypertension can tolerate higher mean arterial pressures before they suffer disruption of their autoregulatory system. However, such patients also have increased cerebrovascular resistance and are more prone to cerebral ischemia when flow decreases, especially if BP is decreased into normotensive ranges.
Hypertension and renal disease
Hypertension is commonly observed in patients with kidney disease, with chronic hypertension causing pathologic changes to the small arteries of the kidney. As hypertensive damage occurs, the renal arteries develop endothelial dysfunction and impaired vasodilation, which alter renal autoregulation. When the renal autoregulatory system is disrupted, the intraglomerular pressure starts to vary directly with the systemic arterial pressure, thus offering no protection to the kidney during BP fluctuations. During a hypertensive crisis, this can lead to acute renal ischemia.
Volume expansion is the main cause of hypertension in patients with glomerular disease (nephrotic and nephritic syndrome). Hypertension in patients with vascular disease is the result of the activation of the renin-angiotensin system, which is often secondary to ischemia. The combination of volume expansion and the activation of the renin-angiotensin system is believed to be the main factor behind hypertension in patients with chronic renal failure.
The renin-angiotensin system
The activities of the renin-angiotensin system influence the progression of renal disease. Angiotensin II acts on the afferent and efferent arterioles, but more so on the efferent arterioles, leading to increased intraglomerular pressure and, in turn, to microalbuminuria. Reducing intraglomerular pressure using an ACE inhibitor has been shown to be beneficial in patients with diabetic nephropathy, even if they are not hypertensive. The beneficial effect of ACE inhibitors on the progression of renal insufficiency in patients who are nondiabetic is less clear. The benefit of ACE inhibitors is greater in patients with more pronounced proteinuria.
The term renovascular hypertension (RVHT) denotes the causal relationship between anatomically evident arterial occlusive disease and elevated BP. RVHT is the clinical consequence of renin-angiotensin-aldosterone activation. As demonstrated by Goldblatt, renal artery occlusion creates ischemia, which triggers the release of renin and a secondary elevation in BP. Hyperreninemia promotes conversion of angiotensin I to angiotensin II, causing severe vasoconstriction and aldosterone release.
The ensuing cascade of events varies, depending on the presence of a functioning contralateral kidney. In the setting of 2 kidneys, aldosterone-mediated sodium and water retention is handled properly by the nonstenotic kidney, precluding volume from contributing to the angiotensin II–mediated hypertension. By contrast, a solitary, ischemic kidney has little or no capacity for sodium and water excretion; hence, volume plays an additive role in the hypertension.
Hypertension and end-stage renal disease
Despite widespread treatment of hypertension in the United States, the incidence of end-stage renal disease continues to rise. The explanation for this rise may be concomitant diabetes mellitus, the progressive nature of hypertensive renal disease despite therapy, or a failure to reduce BP to a protective level. A reduction in renal blood flow in conjunction with elevated afferent glomerular arteriolar resistance increases glomerular hydrostatic pressure secondary to efferent glomerular arteriolar constriction. The result is glomerular hyperfiltration, followed by development of glomerulosclerosis and further impairment of renal function.
Hypertension and ocular changes
The pathophysiologic effects of hypertensive ocular changes can be divided into acute changes from malignant hypertension and chronic changes from long-term, systemic hypertension.
Optic changes that can result from malignant hypertension include the development of the following acute retinal lesions:
Focal intraretinal periarteriolar transudates
Inner retinal ischemic spots (cotton-wool spots)
Chronic hypertensive retinal changes include the following:
Arteriolosclerosis - Localized or generalized narrowing of vessels
Copper wiring and silver wiring of arterioles as a result of arteriolosclerosis
Arteriovenous (AV) nicking as a result of arteriolosclerosis
Nerve fiber layer losses
Increased vascular tortuosity
Remodeling changes due to capillary nonperfusion, such as shunt vessels and microaneurysms
Hypertension and metabolic syndrome
The metabolic syndrome is an assemblage of metabolic risk factors that directly promote the development of atherosclerotic cardiovascular disease. [8, 9] Dyslipidemia, hypertension, and hyperglycemia are the most widely recognized metabolic risk factors. The combination of these risk factors leads to a prothrombotic, proinflammatory state in humans and identifies individuals who are at elevated risk for atherosclerotic cardiovascular disease.
Hypertensive patients who are obese have a sympathetic overdrive, higher cardiac output, and a rise in peripheral vascular resistance due to reduced endothelium-dependent vasodilation. Plasma aldosterone and endothelin are increased, the increase in cardiac output manifests secondary to increased preload, and the end-diastolic volume and pressure are elevated, leading to left ventricular dilatation. Left ventricular wall thickening occurs secondary to increased afterload, heightening the risk of congestive heart failure. The concomitant diabetes that is often present in patients who are obese produces a devastating effect on the kidneys and leads to a much higher incidence of renal failure. Obstructive sleep apnea confers additional risk of resistant hypertension.