J Clin Hypertens. 2018;20:557–559. wileyonlinelibrary.com/journal/jch
©2018 Wiley Periodicals, Inc.
Hyperuricemia and high blood pressure at rest and during
exercise: Guilty or innocent? The jury is still out
Giuseppe Mulè MD | Emilio Nardi MD | Luigi Lattuca MD | Santina Cottone MD
Unit of Nephrology and Hypertension, Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), European Society of Hypertension Excellence
Center, University of Palermo, Palermo, Italy
Giuseppe Mulè, MD, Unit of Nephrology and Hypertension, Dipartimento Biomedico di Medicina Interna e Specialistica (DIBIMIS), European Society of
Hypertension Excellence Center, University of Palermo, Palermo, Italy.
Uric acid (UA) is generated as part of the normal turnover of nucleic
acid. Purine bases and their nucleotides are captured by the liver
and converted into xanthines, metabolized by UA, or recycled by
salvage pathways or de novo synthesis.
UA formation by xanthine
occurs via hypoxanthine by the action of xanthine oxidase (XO), an
enzyme present in the peroxisomes of most cells, which is an im-
portant source of reactive oxygen species involved in various forms
of ischemic and other types of vascular injuries and chronic heart
In humans, higher primates, and in a particular species of
dog (Dalmatians), UA is the final product of the purine catabolism.
In most other mammals, the enzyme uricase further oxidizes UA to
allantoin, reducing serum uric acid (SUA).
UA circulates in plasma predominantly in the form of a mon-
ovalent sodium salt (urate).
Hyperuricemia (HU) is commonly ob-
served in hypertensive patients, especially in those with metabolic
syndrome (MetS), where it may be a marker of insulin resistance as
well as of renal dysfunction and diuretic use.
Moreover, a signif-
icant association between SUA and the intrarenal resistance index
measured by duplex ultrasound has been described,
HU in patients with essential hypertension (EH) reflected intrarenal
The concept that UA may be involved in hypertension is not a
new one. In fact, in the paper published in 1879 that originally de-
scribed EH, Frederick Mohamed noted that people with high blood
pressure (BP) had a greater chance of coming from “gouty” families
or themselves suffering from gout.
This lead him to suggest that
UA might be one of the causes of hypertension. Picking up on this
and based on his own observations a decade later, Haig proposed
low purine diets as a means to prevent hypertension and vascular
Nathan Smith Davis said whilst delivering the presidential
address to the American Medical Association in 1897, “High arterial
tension in gout is due in part to uric acid or other toxic substances
in the blood.
In spite of these anecdotal initial observations, the field lay
dormant for many years. HU was simply associated with gout and
nephrolithiasis and UA regarded as an inert molecule, which serum
levels were in part increased as the consequence of the metabolic
and hemodynamic abnormalities having as a common feature insulin
resistance (Figure 1). However, in the past 2 decades a growing body
of evidence changes this perspective suggesting that, rather than
being an “innocent bystander,” UA per se may be a “guilty party,”
being causally related to cardiometabolic and renal disorders, with
the focus of many studies being hypertension.
The first direct evidence that high UA may lead to hypertension
was provided by the development of an experimental model of mild
HU, in which rats were made unable to metabolize UA to allantoin
by means of oxonic acid (OA), a uricase inhibitor that reproduces the
enzyme deficiency that the human species developed during evolu-
In these rats, hypertension is caused by progressive renal
injury via crystalline- independent mechanisms, including induction
of oxidative stress, inhibition of nitric oxide and activation of the
renin angiotensin system (RAS), and development of microvascular
renal disease with histology that is similar to arteriolosclerosis, the
classic lesion of EH.
Finally, UA promotes proliferation of vascular
smooth muscle cells and stimulates synthesis by the same cells of
the monocyte chemoattractant protein- 1, which is known to play
a key role in promoting macrophage infiltration in atherosclerotic
In this animal model, hypertension developed in 2 phases.
Initially, the hypertension could be directly reversed by reducing UA
levels with either XO inhibitors or uricosuric agents. Hypertension
during this phase was chiefly mediated by uric acid- dependent acti-
vation of the RAS and could be observed even in the presence of a
low- salt diet.
However, over time the rats developed significant
renal microvascular disease and tubulointerstitial inflammation and
the hypertension became salt sensitive and no longer renin and UA