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essential hypertension

Tuesday 28 October 2003

Mechanisms of Essential Hypertension

It is now thought that essential hypertension results from an interaction of genetic and environmental factors that affect cardiac output, peripheral resistance, or both.

Genetic factors clearly play a role in determining blood pressure levels, as shown by studies comparing blood pressure in monozygotic and dizygotic twins, studies of familial aggregation of hypertension comparing the blood pressure of biologic and adoptive siblings, and adoption studies. Moreover, several single-gene disorders cause relatively rare forms of hypertension (and hypotension) by altering net sodium reabsorption in the kidney.

The strong effect of sodium balance is emphasized by considering that the kidneys filter 170 liters of plasma containing 23 moles of salt daily; on a typical 100-mEq sodium diet, this means that 99.5% of the filtered salt must be reabsorbed. This is accomplished by an integrated system of ion channels, exchangers, and transporters. Absorption of the last 2% of sodium occurs via the epithelial Na+ channel (ENaC), highly regulated by the renin-angiotensin system in the cortical collecting tubule; this site determines net sodium balance.

Single-gene disorders cause relatively rare and severe forms of hypertension through several mechanisms.

These include:

- Gene defects in enzymes involved in aldosterone metabolism (e.g., aldosterone synthase, 11β-hydroxylase, 17α-hydroxylase). These lead to an adaptive increase in secretion of aldosterone, increased salt and water resorption, plasma volume expansion and, ultimately, hypertension.

- Mutations in proteins that affect sodium reabsorption. For example, the moderately severe form of salt-sensitive hypertension, called Liddle syndrome, is caused by mutations in an ENaC protein that lead to increased distal tubular reabsorption of sodium induced by aldosterone.

Inherited variations in blood pressure may also depend on the cumulative effects of allelic forms of several genes that affect blood pressure. For example, predisposition to essential hypertension has been associated with variations in the genes encoding components of the renin-angiotensin system: there is an association of hypertension with polymorphisms in both the angiotensinogen locus and the angiotensin II type I receptor locus.38 Genetic variants in the renin-angiotensin system may contribute to the known racial differences in blood pressure regulation.

Reduced renal sodium excretion in the presence of normal arterial pressure may well be the key initiating event in essential hypertension and, indeed, a final common pathway for the pathogenesis of hypertension. Decreased sodium excretion might lead sequentially to an increase in fluid volume, increased cardiac output, and peripheral vasoconstriction, thereby elevating blood pressure.

At the higher setting of blood pressure, enough additional sodium could be excreted by the kidneys to equal intake and prevent fluid retention. Thus, an altered but steady state of sodium excretion would be achieved ("resetting of pressure natriuresis"), but at the expense of stable increases in blood pressure.

An alternative hypothesis implicates vasoconstrictive influences (either factors that induce functional vasoconstriction or stimuli that induce direct structural changes in the vessel wall, causing increased peripheral resistance) as the primary cause of hypertension.

Moreover, chronic or repeated vasoconstrictive influences could cause structural thickening of the resistant vessels. In this model, the structural changes in the vessel wall may occur early in hypertension, preceding rather than being strictly secondary to the vasoconstriction.

Environmental factors could modify expression of the genetic determinants of increased pressure. Stress, obesity, smoking, physical inactivity, and heavy consumption of salt have all been implicated as exogenous factors in hypertension. Indeed, evidence linking the level of dietary sodium intake with the prevalence of hypertension in different population groups is particularly impressive. Moreover, in both essential and secondary hypertension, heavy sodium intake augments the condition.

To summarize, essential hypertension is a complex, multifactorial disorder. Although single gene disorders can be responsible for hypertension in unusual cases, it is unlikely that a mutation at a single gene locus is a major cause of essential hypertension in the larger population. It is more likely that essential hypertension results from the combined effect of mutations or polymorphisms at several gene loci that influence blood pressure, interacting with a variety of environmental factors.

Thus, environmental factors (e.g., stress, salt intake) affect the variables that control blood pressure in the genetically predisposed individual. Mendelian forms of hypertension and hypotension are rare but yield insights into pathways and mechanisms of blood pressure regulation, and they may help define rational targets for therapeutic intervention. Sustained hypertension requires participation of the kidney, since the kidney normally responds to hypertension by eliminating salt and water.

Susceptibility genes for essential hypertension in the larger population are currently unknown but may well include genes that govern responses to an increased renal sodium load, levels of pressor substances, reactivity of vascular SMCs to pressor agents, or SMC growth. In established hypertension, both increased blood volume and increased peripheral resistance contribute to the increased pressure.

Susceptibility loci

- 2p24-p25 (12228842)
- chromosome 1q (17236131)

Videos

- Malignant hypertension by Washington Deceit

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See also

- arterial hypertension

Reviews

- Cowley AW Jr. The genetic dissection of essential hypertension. Nat Rev Genet. 2006 Nov;7(11):829-40. PMID: 17033627

- Agarwal A, Williams GH, Fisher ND. Genetics of human hypertension. Trends Endocrinol Metab. 2005 Apr;16(3):127-33. PMID: 15808811

- Mein CA, Caulfield MJ, Dobson RJ, Munroe PB. Genetics of essential hypertension. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R169-75. PMID: 14764624

References

- Chang YP, Liu X, Kim JD, Ikeda MA, Layton MR, Weder AB, Cooper RS, Kardia SL, Rao DC, Hunt SC, Luke A, Boerwinkle E, Chakravarti A.Multiple genes for essential-hypertension susceptibility on chromosome 1q.Am J Hum Genet. 2007 Feb;80(2):253-64. PMID: 17236131