Mechanisms Of Primary Hypertension
In more than 90% of cases, hypertension has no obvious cause, and is termed primary or essential. Primary hypertension is a complex genetic disease, in which the inheritance of a number of commonly occurring gene alleles (different forms of a gene that arise by mutation and code for alternative forms of a protein that may show functional differences) predisposes an individual to high arterial blood pressure (ABP), especially if appropriate environmental influences (e.g. high salt diet, psychosocial stress) are also present. It is thought that proteins coded for by hundreds of genes may affect blood pressure, with the allelic variation of each causing only a small effect on blood pressure. Given this genetic complexity, investigations into the mechanisms causing high blood pressure have mainly focused on uncovering functional rather than genetic abnormalities, often using strains of animals that are selectively bred to develop high ABP in the hope that the mechanisms causing hypertension in these are similar to those in humans. However, the recent advent of large genome-wide association studies has now begun to allow the tentative identification of genes having alternative alleles that affect blood pressure; one of these is ATP2B1, the gene coding for the plasma membrane Ca2+ ATPase (see Chapter 15).
Studies tracking cardiovascular function over decades show that human hypertension is initially associated with an increased cardiac output (CO) and heart rate, but a normal total peripheral resistance (TPR). Over a period of years, CO falls to subnormal levels, while TPR becomes permanently increased, thereby maintaining the hypertension (recall that ABP = CO × TPR). These observations imply that the factors maintaining high ABP change over time. Therefore the mechanisms that initiate high ABP (e.g. insufficient Na+ excretion, sympathetic overactivity) may then be succeeded and/or amplified by additional common secondary mechanisms (e.g. renal damage and vascular structural remodelling) which are caused by, and maintain, the initial rise in pressure. This unifying hypothesis for primary hypertension is shown in Figure 39a.
The kidney and sodium in hypertension Guyton’s model of hypertension The kidneys regulate long-term ABP by controlling the body’s Na+ content (see Chapter 29). Guyton proposed that hypertension is initiated by renal abnormalities which cause impaired or inadequate Na+ excretion (Figure 39b). The resulting Na+ retention increases blood volume, and therefore CO and ABP. These changes then promote Na+ excretion by causing pressure natriuresis (see Chapter 29). Fluid balance is therefore restored, but at the cost of a rise in ABP. Guyton further hypothesized that the rise in ABP or flow sets in train autoregulatory processes resulting in long-term vasoconstriction and/or vascular structural remodelling. This would reduce blood volume to normal levels, but by raising TPR would maintain the high ABP needed for Na+ balance.
There is extensive evidence that a renal mechanism of hypertension is important in many people. For example, a high salt diet, which should exacerbate the renal deficiency in Na+ excretion, worsens hypertension in many patients and, as shown in the Intersalt study, seems to cause a slow rise in ABP over many years in most people. It has also been shown that ABP falls when the kidneys from normotensives are transplanted into hypertensives. Moreover, hypertension occurs in Liddle syndrome, a condition in which a mutation of the mineralocorticoid-sensitive Na+ channel (ENaC) impairs renal Na+ excretion.
The natriuretic factor hypothesis De Wardener and others have proposed that the body responds to inadequate renal salt excretion by producing one or more natriuretic factors (not to be confused with atrial natriuretic peptide; see Chapter 29) which promote salt excretion by inhibiting the Na+–K+-ATPase in the nephron. Although this effect would be expected to reduce ABP, the Na+– K+-ATPase is also indirectly involved in lowering intracellular Ca2+, via regulation of both the membrane potential and Na+–Ca2+ exchange, in smooth muscle cells and neurones. Natriuretic factors would therefore cause additional responses such as vasoconstriction, increased noradrenaline release, and possibly stimulation of brain centres involved in raising ABP. These effects would increase TPR, causing sustained hypertension. In agreement with this hypothesis, ouabain-like factor and marinobufagenin, two endogenous substances that inhibit the Na+–K+-ATPase, are elevated in plasma taken from many hypertensives.
The reduced nephron number hypothesis Brenner and coworkers have proposed that many hypertensives have a congenital reduction in the number, or filtering ability, of their nephrons which would cause the inadequate Na+ excretion referred to above. Evidence suggests that this may arise from intrauterine growth retardation.
A considerable body of evidence supports the concept that an overactivity of the renin–angiotensin–aldosterone (RAA) system, which has a crucial role in regulating renal Na+ excretion, occurs in many hypertensives, and is responsible for the defect in renal Na+ excretion originally proposed by Guyton. Although renin release should be greatly suppressed by elevated ABP (as explained in Chapter 29), ∼70% of hypertensives have normal or high plasma renin activity, suggesting that their RAA system is inappropriately activated. This would cause Na+ retention due to increased effects of angiotensin II and aldosterone in the kidney (see Chapter 29), and also lead to angiotensin II-mediated vasoconstriction through- out the body. Both mechanisms would raise ABP. Primary hypertension in some individuals has also been linked to a mutation in the angiotensinogen gene, which could promote increased angiotensin II production. Most importantly, drugs that inhibit this system effectively control ABP in ∼50% of hypertensive individuals (see Chapter 38). Interestingly, the kidney is now thought to have its own renin–angiotensin system which is regulated independently of the RAA system in the rest of the body. Recent studies with mice in which the AT1 receptor was knocked out only in the kidney suggest that it is this ‘intra-renal’ renin–angiotensin system that may be of predominant importance in causing hypertension, although whether this is also true in humans is unknown.
The neurogenic model of hypertension proposes that hypertension is primarily initiated by overactivity of the sympathetic nervous system. Although the kidneys are central to controlling ABP, supporters of this concept argue that the kidneys (and in particular renin release) are themselves regulated by the sympathetic nervous system, which therefore must be the ultimate determinant of ABP. The neurogenic model is supported by evidence that sympathetic nervous activity is increased in young borderline hypertensives, by the fact that drugs such as moxonidine, which act in the brain to reduce sympathetic outflow, effectively lower ABP (see Chapter 38), and by the results of the Simplicity HTN-2 trial, which reported in 2010 that renal sympathetic denervation caused a sustained fall in blood pressure in a group of ‘resistant’ hypertensives whose blood pressure could not be controlled pharmacologically. Sympathetic overactivity is thought to occur in ∼50% of hypertensives, and could potentially be caused by a variety of factors that have been shown to stimulate areas of the brainstem that control sympathetic outflow; these include inflam- mation, hypoxia, elevated reactive oxygen species or overactivity of the RAA system.
Insulin resistance is a condition in which the body becomes less responsive to the actions of the hormone insulin, leading to a compensatory rise in plasma insulin levels. Both insulin resistance and obesity, with which it is often associated, are very common in hypertensives. There is evidence that excessive insulin can cause multiple effects on the body which could promote hypertension, including activation of the sympathetic nervous system, increased renal Na+ reabsorption and reduced endothelium-dependent vasodilatation.
Established hypertension is associated with the structural alteration of small arteries and larger arterioles. This process, termed remodelling, results in the narrowing of these vessels and an increase in the ratio of wall thickness to luminal radius. Remodelling is proposed to be an adaptive mechanism which would reduce vascular wall stress (see the Laplace/Frank law; see Chapter 18) and protect the microcirculation from increased ABP. However, it would also ‘lock in’ vascular narrowing and the resulting increase in TPR. Remodelling may also be enhanced by overactivation of the RAA and sympathetic nervous systems, which is known to promote smooth muscle cell growth.
Remodelling will increase basal TPR and also exaggerate any increase in TPR caused by vasoconstriction. In addition, studies in spontaneously hypertensive rats indicate that remodelling of renal afferent arterioles may contribute to hypertension by interfering with renal Na+ excretion (see above). This implies that remodelling would accentuate increases in ABP caused by other factors, thereby contributing to the vicious cycle illustrated in Figure 39a. In addition, remodelling of the coronary arteries as a result of hypertension may increase the risk of myocardial infarction by restricting the ability of these vessels to increase the cardiac blood supply during ischaemia.
In less than 10% of cases, high ABP is secondary to a known condition or factor. Common causes of secondary hypertension include:
· Renal parenchymal and renovascular diseases, which impair volume regulation and/or activate the RAA system
· Endocrine disturbances, often of the adrenal cortex, and associated with oversecretion of aldosterone, cortisol and/or catecholamines
- Oral contraceptives, which may raise ABP via RAA activation and hyperinsulinaemia.
Malignant or accelerated hypertension is an uncommon condition that develops quickly, involves large elevations in pressure, is often secondary to other conditions, rapidly damages the kidneys, retina, brain and heart, and if untreated causes death within 1–2 years.
Consequences of hypertension
Chronic hypertension causes changes in the arteries similar to those due to ageing. These include endothelial damage and arteriosclerosis, a thickening and increased connective tissue content of the arterial wall that reduces arterial compliance. These effects on vascular structure combine with elevated arterial pressure to promote atherosclerosis, coronary heart disease, left ventricular hypertrophy and renal damage. Hypertension is therefore an important risk factor for myocardial infarction, congestive heart failure, stroke and renal failure.