Dr Alister McNeish
Profile
My research focuses on how blood pressure and flow is controlled by the narrowing (constriction) or enlargement (dilatation/relaxation) of blood vessels. I am particularly interested in the endothelial cell layer that lines the inner surface of blood vessels and how it communicates with the underlying muscle layer to regulate constriction and dilatation. The endothelium can release a variety of factors relax vascular smooth muscle, including nitric oxide (NO) prostacyclin and endothelium-derived hyperpolarizing factor (EDHF). The majority of my studies investigate ion channels (on both endothelial cells and smooth muscle cells) that are involved in these endothelium-dependent dilatations and in particular those that underpin the EDHF response.
More specifically, I have several complementary research themes in the general area of cardiovascular pharmacology and in particular endothelium dependant modulation of vasomotor responses.
a) Regulation and differential modulation of calcium activated potassium channels (KCa) found in the endothelium. As these channels play a critical role in endothelium derived hyperpolarizing factor (EDHF) mediated responses this theme also encompasses how such modulation/regulation affects EDHF responses.
b) Characterisation and elucidation of the mechanisms that underlie the EDHF response, particularly in the cerebral vasculature with a particular focus on the role of arachidonic acid metabolites in these responses.
c) The role of the endothelium in regulating smooth muscle cell myogenic tone and vasomotion/vasospasm.p>
d) Study of crosstalk/interaction between two of the major endothelium dependant vasodilators nitric oxide and EDHF and how endothelial dysfunction may lead to changes in these interactions.
My most recent work indicates that NO can interact with thromboxaneA2 (a signal molecule which causes constriction) in blood vessels supplying the brain (cerebral arteries). I have discovered that a basal release of NO normally suppresses the synthesis/action of thromoboxaneA2 and this apparent increase thromboxaneA2 signalling can inhibit the ion channels that are involved in NO-independent vasodilatation attributed to EDHF. In other words it appears that in these arteries a constant basal release of NO may protect elements of the EDHF vasodilator pathway. These findings provide new insights into vascular function/disease where levels of NO are reduced; consequences of which include high blood pressure, strokes and heart attacks.
Publications
Roux, B.T., Aylett, S.-B., Cottrell, G.S., McNeish, A.J. and Van Den Brink, A.M., 2012. Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries. British Journal of Pharmacology, 167 (8), pp. 1679-1690.
McNeish, A.J., Jimenez-Altayo, F., Cottrell, G.S. and Garland, C.J., 2012. Statins and Selective Inhibition of Rho Kinase Protect Small Conductance Calcium-Activated Potassium Channel Function (K 2.3) in Cerebral Arteries. PLoS ONE, 7 (10), 46735.
McNeish, A. J., Altayo, F. J. and Garland, C. J., 2010. Evidence both L-type and non-L-type voltage-dependent calcium channels contribute to cerebral artery vasospasm following loss of NO in the rat. Vascular Pharmacology, 53 (3-4), pp. 151-159.
Yuill, K. H., McNeish, A. J., Kansui, Y., Garland, C. J. and Dora, K. A., 2010. Nitric oxide suppresses cerebral vasomotion by sGC-independent effects on ryanodine receptors and voltage-gated calcium channels. Journal of Vascular Research, 47 (2), pp. 93-107.
Dora, K. A., Gallagher, N. T., McNeish, A. and Garland, C. J., 2008. Modulation of endothelial cell K(Ca)3.1 channels during endothelium-derived hyperpolarizing factor signaling in mesenteric resistance arteries. Circulation Research, 102 (10), pp. 1247-1255.
