The effect of allopurinol on vascular function

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Name of InstitutionCHAPTER 1: INTRODUCTION

The absence of widespread effective acute therapy for stroke makes its prevention vital. However, even with optimal use of such strategies, many continue to suffer stroke; approximately a quarter of strokes are recurrent events and a quarter of stroke patients will suffer recurrence within 5 years. We therefore need to identify new therapeutic targets and treatments to improve long-term outcomes for this high-risk population.

One potential adjunctive secondary prevention strategy may be to inhibit xanthine oxidase with allopurinol. A wealth of epidemiological data shows that elevated serum uric acid (UA) level is associated with an increased risk of vascular events , including in the post-stroke period. Further, use of xanthine oxidase (XO) inhibition may yield additional benefits in addition to potent UA reduction. Allopurinol, the most commonly used XO inhibitor, reduces oxidative stress in the vasculature, improves endothelial function in a variety of cardiovascular disease states and reduces expression of proinflammatory molecules such as soluble intercellular adhesion molecule-1 (sICAM) in vitro. Recent data suggest allopurinol use yields potentially beneficial effects on inflammatory indices and peripheral vascular function in those with recent ischaemic stroke and that it improves cerebrovascular endothelial function in those with Type 2 diabetes.

Impaired regulation of the subcortical microvasculature has been proposed as a pathogenic mechanism in first and recurrent lacunar cerebral infarction. This impaired regulation can be assessed using a standard non-invasive ultrasound protocol that measures cerebrovascular reactivity (CVR), the compensatory dilatory capacity of cerebral resistance vessels in response to increased arterial carbon dioxide concentration, which can be manipulated by an acetazolamide infusion. The magnitude of the change in cerebral blood flow is the measure of CVR and is a functional assessment of the cerebral vasculature. Impaired CVR occurs in a variety of cardiovascular risk states and in those with cerebrovascular disease and is thus a potential therapeutic target in stroke prevention. It can be improved with statin and angiotensin converting enzyme (ACE) inhibitor therapy, which are known to reduce the incidence of stroke in high-risk individuals.

We hypothesized that the XO inhibitor allopurinol would improve cerebrovascular reactivity in those with recent subcortical stroke. We report results of a randomized, double-blind, placebo-controlled study designed to test this hypothesis. Allopurinol has been shown to improve mechano-energetic uncoupling in the myocardium during heart failure, which means that it decreases myocardial oxygen demand per unit of cardiac output. The mechanism probably involves an effect on myocardial energetics. Whatever the precise mechanism, the process whereby allopurinol reduces myocardial oxygen consumption has so far only been shown in heart failure and almost exclusively in experimental heart failure. However, a large group of patients who might benefit from a drug that decreases oxygen consumption are those with angina pectoris, but there are no studies (clinical or experimental) in which this possibility has been investigated. We therefore set out to investigate whether allopurinol prolongs exercise in patients with chronic stable angina pectoris.

CHAPTER 2: LITERATURE REVIEW

We found no effect of allopurinol treatment on CVR, as measured by ...