The association between elevated uric acid (UA) concentrations and cardiovascular
disease is well established in epidemiology, but the possibility that UA plays a specific
role in the pathophysiology of cardiovascular disease remains a matter of debate.
Although there are putative mechanisms by which UA could injure the cardiovascular
system, it also has a number of properties that might be considered as protective. Most
notably, its role as a radical-scavenging antioxidant might be expected to mitigate the
effects of increased oxidative stress, which is characteristic of most risk factors for
cardiovascular disease and is an important precipitant of endothelial dysfunction. The aim
of the studies described in this thesis was to examine the effects of UA on endothelial
function and investigate whether UA has the potential to reverse endothelial dysfunction
induced by low-density lipoprotein (LDL).
Mesenteric arteries were isolated from Wistar-Kyoto rats and the responses to a
vasoconstrictor (PE, phenylephrine) and endothelium-dependent (ACh, acetylcholine)
and -independent (SNP, sodium nitroprusside) vasodilators examined using perfusion
myography. This model was considered advantageous because it enabled the
measurement of pharmacological responses in the presence of different luminal solutions
in an experimental environment that most closely mimics the conditions found in vivo.
Luminal perfusion with L-NAME and/or indomethacin demonstrated that nitric oxide
synthase (NOS) -derived nitric oxide (NO) was the major vasodilator released by the
endothelium in response to ACh in this experimental model.
Exposure of the vascular lumen to increasing concentrations of UA (200, 400, 600pM) or
vehicle solution had no effect upon the responses to PE, ACh or SNP. This implied that,
in this model, acute exposure to elevated UA does not impair endothelial function. In
contrast, when the lumen was perfused with increasing concentrations of LDL (250, 500
and lOOOμg/ml), maximal vasodilatation towards resting diameter in response to ACh
was reduced to 42.6, 33.6 and 21.7% respectively. The failure of the NOS inhibitor LNAME to further impair vasodilatation implied that major effect of LDL was to abolish
endothelium-dependent NO-mediated vasodilatation. Supplementing the perfusing LDL
solution with ImM L-arginine restored endothelium-dependent responses, implying that
the LDL-induced endothelial dysfunction was in part explained by a disruption of Larginine metabolism. Supplementation with the extracellular O₂ scavenger, superoxide
dismutase (SOD), did not prevent the deleterious action of LDL.
Supplementation of 250μg/ml LDL with increasing concentrations of UA (200, 400,
600μM) partially reversed the inhibition of maximal vasodilatation towards resting
diameter in response to ACh to 62.2, 69.5 and 74.4% respectively. No such improvement
could be achieved in the presence of L-NAME. The beneficial effect of 400μM UA upon
LDL-induced endothelial dysfunction contrasted with the lack of effect of two other
water-soluble antioxidants, ascorbic acid (AA) and glutathione (GSH), at the same
The experiments then focused on investigating the potential mechanism by which UA
prevented LDL-induced endothelial dysfunction. Isolated rings of thoracic aorta from
Wistar-Kyoto rats were mounted in a wire myograph and exposed to ACh in the presence
of varying concentrations of UA and 250pg/ml LDL. The superfusate was then
transferred to endothelium-denuded rings and caused significant vasodilation in
previously unresponsive ring segments. The extent of the vasodilatation in response to
the transferred solution was dependent on the concentration of UA and ox-Hb sensitive.
The decay in vasodilator response if the exposure of the denuded ring was delayed had a
half-life of 29 minutes. These results implied that the stimulation of an endotheliumintact vessel by ACh in the presence of both UA and LDL results in the formation of an
endothelium-independent vasodilator that releases NO and may be a derivative of UA.
In summary, the results of these experiments suggest that acute exposure to UA in
physiological concentrations does not impair either endothelium-dependent or -
independent vascular responses. Conversely, UA reverses the impairment of AChinduced vasodilatation caused by LDL and does so more effectively than other high
concentration hydrophilic antioxidants. Furthermore, UA appears to enable the formation
of an NO-releasing compound when it is present with LDL and endothelial cells
stimulated by ACh. The presence and nature of a possible NO-donor compound formed
in these circumstances requires further investigation. Taken together, this work implies
that UA exposure is not directly injurious to vascular function and may protect against
the effects of LDL on the vascular endothelium. This might offer a physiological role for
a compound which is found in much higher concentration in the extracellular fluids of
humans than almost any other species.