Chadha, Preetpal Singh; (2007) Endothelial nicotinic acetylcholine receptors: A role in vascular function? Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The vascular endothelium plays an essential role in the regulation of cardiovascular homeostasis and is critically involved in the maintenance of vascular tone, through the release of several vasoactive substances, and inflammation by expressing and interacting with a variety of inflammatory mediators. Nicotinic acetylcholine receptors (nAChRs) are prototypic ionotropic receptors that have traditionally been considered to mediate fast synaptic transmission. However, in recent years these pentameric ligand-gated ion channels have been discovered on various types of non-neuronal cells, including endothelial cells. The role of these receptors here remains unclear; however, the expression of cholinergic components in non-neuronal cells indicates potential autocrine activity and, therefore, a widespread functional role for these receptors. Recently, it has been suggested that the α7 subtype of nAChR expressed by endothelial cells are involved in angiogenesis and the inflammatory process, activity of which may have implications in smoking related vascular and inflammatory disorders, as well as normal physiology. Here, the effects of nicotine, one of the components of cigarette smoke, upon endothelial function in relation to vascular tone and inflammation have been investigated in vitro and ex vivo. Experiments were performed to assess endothelium- dependent relaxation in rat mesenteric and pulmonary arteries using a small vessel wire myograph. Exposure to nicotine or its metabolite cotinine led to differential effects in arteries from the two vascular beds. In pulmonary arteries, nicotine and cotinine impaired acetylcholine (ACh)-induced relaxation whereas in mesenteric vessels, nicotine and cotinine led to an increase in maximum endothelium-dependent relaxation. an effect that was reversed by co-treatment with selective α7 antagonists. Interestingly, exposure to the α7 nAChR antagonist alone affected endothelial responses to ACh in both mesenteric and pulmonary arteries, suggesting that autocrine activity may be involved in the mechanics of vascular tone. The results of subsequent experiments suggested that in mesenteric vessels at least, this autocrine effect may be mediated via endogenous ACh. In vitro and ex vivo experiments confirm that pro-inflammatory cytokines impair endothelial function in isolated rat arteries. Furthermore, these studies showed that a single dose of nicotine administered along with an inflammatory cytokine prevents impairment of endothelium-dependent relaxation in rat mesenteric arteries, ex vivo. In summary, the results presented in this thesis suggest that endothelial nicotinic acetylcholine receptors and endogenous ACh modulate endothelium-dependent relaxation in rat mesenteric arteries. Nicotinic AChR expressed on endothelial cells could play a significant role in a variety of vascular functions including inflammation and the control of vascular tone.

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