Endothelial Dysfunction – The First Step Towards Coronary Disease

More than a quarter of a century ago Robert Furchgoldltt demonstrated that removing the endothelial layer from the isolated aorta of a rabbit prevents normal relaxation in response to acetylcholine.1 The ability of the endothelium to elicit relaxation was soon extended to more relevant physiological stimuli (adenosine triphosphate, bradykinin and serotonin).2,3 The endothelial cells cause arterial relaxation by releasing a powerful vasoactive substance(s) that diffuses to the underlying layers of vascular smooth muscle and thus was termed endothelium-derived relaxing factor (EDRF). EDRF stimulates the activity of soluble guanylyl cyclase with the subsequent production of cyclic guanosine monophosphate (cyclic GMP) in the vascular smooth-muscle cells; it is also avidly scavenged by superoxide anions.4,5 These findings led Robert Furchgott and Louis Ignarro to the proposal that EDRF is nitric oxide (NO),6,7 a hypothesis that was proved correct by Salvador Moncada.8 Further investigations have identified many components of the pathway producing NO, from the stimulation of muscarinic (and other) receptors on the endothelial cells to the eventual activation of an enzyme, endothelial NO synthase (eNOS or NOS3), that transforms L-arginine into NO. When inhibitors of the enzymes involved in the pathway became available, it soon appeared that NO is involved in many aspects of biology.8 However, in the years that followed it also became evident that endothelial cells can affect the tone of the underlying smooth muscle in more than one way.9–15 This article focuses on NO because its reduced production characterises endothelial dysfunction, which is the first step (at least in the author’s mind) in the long chain of events that leads to atherosclerosis and coronary disease.9,16–19