The role of uric acid in the pathogenesis of hypertension in the young

Abstract

Uric acid has been suspected to be a risk factor for hypertension since the 1870s. Numerous epidemiological studies demonstrate an association between uric acid and both incident and prevalent hypertension in diverse populations. Studies in elderly patients have had more variable results, raising the possibility that uric acid may be more significant to hypertension in the young. Animal models support a two-phase mechanism for the development of hyperuricemic hypertension. Initially, uric acid induces vasoconstriction by activation of the renin-angiotensin system and reduction of circulating nitric oxide, which can be reversed by lowering uric acid. Over time, uric acid uptake into vascular smooth muscle cells causes cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis, causing sodium-sensitive hypertension. Consistent with the animal model data, small clinical trials performed in adolescents with newly diagnosed essential hypertension demonstrate that at least in certain young patients, reduction of serum uric acid can mitigate blood pressure elevation. While more research is clearly necessary, the available data suggest that uric acid is likely causative in some cases of early-onset hypertension.

Figure 1

Animal model data suggest that hyperuricemia leads to hypertension in a stepwise fashion. The effects of uric acid on the blood vessel are shown. The first phase is direct, uric acid–dependent activation of the renin‐angiotensin system and down‐regulation of the nitric oxide (NO) production, leading to vasoconstriction. At this stage, uric acid reduction results in vascular relaxation and improved blood pressure. The second phase, which develops over time, is uric acid–mediated arteriolosclerosis. Uric acid uptake into vascular smooth muscle cells causes the activation and elaboration of production of growth factor (PDGF) and monocyte chemoattractant protein‐1 (MCP‐1). This results in the autocrine stimulation of vascular smooth muscle cell proliferation, vascular wall thickening, loss of vascular compliance, and a shift in pressure natriuresis. This process is not reversed by the late reduction of uric acid and causes permanent sodium‐sensitive hypertension.

Figure 2

Number of research articles published per year, 1970–2011, on the topic of the role of uric acid in hypertension. Articles were identified on PubMed using search terms uric acid, urate, hypertension, cardiovascular disease, fructose, sweetened beverages, xanthine oxidase inhibitors, allopurinol, uricosurics and probenecid. Reviews were excluded and abstracts were reviewed for relevance.

Figure 3

Serum uric acid is plotted against systolic blood pressure for children with normal blood pressure and children with primary hypertension. Data do not include individuals with secondary hypertension or white‐coat hypertension. The solid and dotted lines represent the best fit and 95% confidence intervals, respectively, and demonstrate the linear relation between uric acid and systolic blood pressure.⁵⁴