The Effect Of Allopurinol On Vascular Function

Abstract Allopurinol has been shown to improve endothelial function in chronic heart failure. This study aimed to establish its mechanism of action and to construct a dose-response curve for the effect of allopurinol.

CHAPTER 1: INTRODUCTION

The prototypical xanthine oxidase (XO) inhibitor allopurinol, has been the cornerstone of the clinical management of gout and conditions associated with hyperuricemia for several decades. As they recount, the program grew up out of a very general notion that synthetic analogs of the purine and pyrimidine bases can interfere with nucleic acid biosynthesis. They soon found antibacterial activity for multiple compounds, some of which were tested at Sloan-Kettering Institute for their anticancer properties. 6-MP emerged as having very high activity against leukemia. These compounds rapidly progressed into clinical trials and culminated in regulatory approval in 1953, propelled by a desperate need for new treatments, especially for acute leukemia in children, which were limited at the time to methotrexate and steroids. This project ultimately led also to the discovery of allopurinol, when thiouric acid was identified as a major 6-MP metabolite generated by XO.

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 ...