Endothelial function and nitric oxide: clinical relevance
- Centre for Clinical Pharmacology, University College London, London, UK
- Professor Patrick Vallance, Centre of Clinical Pharmacology, Gower Street Campus, 3rd Floor, Rayne Institute, 5 University Street, London WC1E 6JJ, UK
The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. Far from being inert, it is metabolically active and produces a variety of vasoactive mediators. Among these mediators, endothelial derived nitric oxide is essential in the maintenance of vascular homeostasis, and defects in the L-arginine: nitric oxide pathway have been implicated in a variety of cardiovascular diseases.
From EDRF to nitric oxide
In 1980, Furchgott and Zawadzki showed that the presence of vascular endothelial cells is essential for acetylcholine to induce relaxation of isolated rabbit aorta.1 If the vascular endothelium was removed, the blood vessel failed to relax in response to acetylcholine but still responded to glyceryl trinitrate. This endothelium dependent relaxation of vascular smooth muscle to acetylcholine is mediated by an endogenous mediator initially named endothelium derived relaxing factor (EDRF),1 which was subsequently identified as nitric oxide.2 3
L-arginine: nitric oxide pathway
Endothelium derived nitric oxide is synthesised from the amino acid L-arginine by the endothelial isoform of nitric oxide synthase, yielding L-citrulline as a byproduct.4 Nitric oxide is labile with a short half life (< 4 seconds in biological solutions). It is rapidly oxidised to nitrite and then nitrate by oxygenated haemoglobin before being excreted into the urine.4 Several co-factors are required for nitric oxide biosynthesis. These include nicotinamide adenine dinucleotide phosphate (NADPH), flavin mononucleotide, flavin adenine dinucleotide, tetrahydrobiopterin (BH4), and calmodulin. Once synthesised, the nitric oxide diffuses across the endothelial cell membrane and enters the vascular smooth muscle cells where it activates guanylate cyclase, leading to an increase in intracellular cyclic guanosine-3',5-monophosphate (cGMP) concentrations4 (fig 1). As a second messenger, cGMP mediates many of the biological effects of nitric oxide including the control of vascular tone and platelet function. In addition, nitric oxide has other molecular targets which include haem or other …