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 

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