- Pharmacy and Pharmacology

Dr K.A. Dora

Dr K.A. Dora

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Telephone: (01225) 383672
Lab Office: (01225) 383349
Fax: (01225) 386114
E-mail: k.a.dora@bath.ac.uk

Department of Pharmacy and Pharmacology
University of Bath (5 West - 3.32)
Claverton Down
Bath
BA2 7AY
ENGLAND
Research Interests

Endothelium-dependent intercellular communication in resistance arteries The cells in the wall of blood vessels can communicate with their neighbours both indirectly by the extracellular diffusion of signaling molecules and ions, and directly via aqueous pores called gap junctions. The latter can occur via the passage of signaling molecules such as Ca2+ and IP3, and also by the spread of depolarizing or hyperpolarizing current. This cell-cell communication enables the wall of blood vessels to act as a functional syncytium.

When agonists stimulate rises in endothelial cell Ca2+, the cells hyperpolarize due to opening of calcium-activated potassium channels (KCa). This hyperpolarization spreads to adjacent smooth muscle cells and evokes arterial dilatation. Even if only a small group of endothelial cells is directly stimulated by the agonist (eg. acetylcholine) the entire length of the artery can dilate both in vivo (Duling & Berne, Circ Res, 23, 163-170, 1970) and in isolated arteries. The mechanism for this spreading dilatation is intrinsic to the vessel wall, and likely occurs due to the rapid spread of current through gap junctions. Indeed, we have recently shown that the rise in endothelial cell Ca2+ only occurs within the vicinity of acetylcholine, whereas the cells hyperpolarize along the arterial length (Dora et al., 2003; Takano et al., 2004). Current research focuses on further establishing the mechanisms responsible for intercellular communication.

Techniques currently used in the laboratory include:

1.    Changes in diameter in isolated pressurized arteries.

Arteries are mounted in a pressure myograph and viewed using an >Olympus microscope and attached video or digital imaging hardware and software.

Response to acetylcholine in a rat cremaster artery. The artery developed myogenic tone and 1µM acetylcholine was added to the bath at Time = 0s.

2.    Changes in endothelial cell Ca2+ in isolated pressurized arteries.

Arteries are luminally loaded with Ca2+ - sensitive fluorescent dyes and viewed using an Olympus FV500 confocal microscope.

Response to acetylcholine in a rat cremaster artery.
Acetylcholine was added to the bath at Time = 0s.

3.    Protein expression and localization in isolated, pressurized arteries.

Arteries are fixed and processed whilst mounted in a pressure myograph and viewed using an Olympus FV500 confocal microscope.

Connexin40 expression in rat mesenteric artery Connexin40 expression in rat mesenteric artery. The Cx40 Ab was labelled using Alexa Fluor 488 secondary Ab (green), and the cell nuclei were labelled using propidium iodide (red).

Endothelial cells run horizontally, smooth muscle cells vertically. In this image the z-planes have been merged, but to see each z-plane, click image (6.6MB).
Recent Publications:

Dora KA, Gallagher NT, McNeish A, Garland CJ. (2008) Modulation of endothelial cell KCa3.1 channels during endothelium-derived hyperpolarizing factor signaling in mesenteric resistance arteries. Circ Res. 102:1247-1255.

Kansui Y, Garland CJ, Dora KA. (2008) Enhanced spontaneous Ca2+ events in endothelial cells reflects signalling through myoendothelial gap junctions in pressurized mesenteric arteries. Cell Calcium. 44:135-146.

Garland CJ, Dora KA. (2008) Evidence against C-type natriuretic peptide as an arterial 'EDHF'. Br J Pharmacol. 153: 4-5.

Winter P, Dora KA. (2007). Spreading dilatation to luminal perfusion of ATP and UTP in rat isolated small mesenteric arteries. J Physiol. 582: 335-347.

McSherry IN, Sandow SL, Campbell WB, Falck JR, Hill MA, Dora KA (2006). A role for heterocellular coupling and EETs in dilation of rat cremaster arteries. Microcirculation.

McNeish AJ, Sandow SL, Neylon CB, Chen MX, Dora KA, Garland CJ. (2006). Evidence for involvement of both IKCa and SKCa channels in hyperpolarizing responses of the rat middle cerebral artery. Stroke.

Dora KA (2005). Does arterial myogenic tone determine blood flow distribution in vivo? Am J Physiol Heart Circ Physiol. 289: H1323-H1325.

McNeish AJ, Dora KA, Garland CJ. (2005). Possible role for K+ in endothelium-derived hyperpolarizing factor-linked dilatation in rat middle cerebral artery. Stroke. 36: 1526-1532.

McSherry IN, Spitaler MM, Takano H, Dora KA. (2005). Endothelial cell Ca2+ increases are independent of membrane potential in pressurized rat mesenteric arteries. Cell Calcium. 38: 23-33.

Mather S, Dora KA, Sandow SL, Winter P, Garland CJ. (2005). Rapid endothelial cell-selective loading of connexin 40 antibody blocks endothelium-derived hyperpolarizing factor dilation in rat small mesenteric arteries. Circ Res. 97: 399-407.

Takano H, Dora KA, Spitaler MM, Garland CJ (2004). Spreading dilatation in rat mesenteric arteries associated with calcium-independent endothelial cell hyperpolarization. J Physiol. 556: 887-903.

Yao X, Kwan HY, Dora KA, Garland CJ, Huang Y. (2003). A mechanosensitive cation channel in endothelial cells and its role in vasoregulation. Biorheology. 40: 23-30.

Crane GJ, Walker SD, Dora KA, Garland CJ. (2003). Evidence for a differential cellular distribution of inward rectifier K channels in the rat isolated mesenteric artery. J Vasc Res. 40: 159-168.

Dora KA, Xia J, Duling BR. (2003). Endothelial cell signaling during conducted vasomotor responses. Am J Physiol Heart Circ Physiol. 285: H119-H126.

Crane GJ, Gallagher NT, Dora KA, Garland CJ. (2003). Small and intermediate calcium-dependent K+ channels provide different facets of endothelium-dependent hyperpolarization in rat mesenteric artery. J Physiol. 553: 183-220.

Dora KA, Sandow SL, Gallagher NT, Takano H, Rummery NM, Hill CE, Garland CJ. (2003). Myoendothelial gap junctions may provide the pathway for EDHF in mouse mesenteric artery. J Vasc Res. 40: 480-490.

Dora KA, Ings NT, Garland CJ. (2002). KCa channel blockers reveal hyperpolarization and relaxation to K+ in the rat isolated mesenteric artery. Am J Physiol. 283: H606-H614.

Dora KA, Garland CJ. (2001). Properties of smooth muscle hyperpolarization and relaxation to K+ in the rat isolated mesenteric artery. Am J Physiol. 280: H2424-H2429.

Dora KA. (2001). Intercellular calcium signalling: The artery wall. Semin Cell Dev Biol. 12: 27-35.

Dora KA. (2001). Cell-cell communication in the vessel wall. Vasc Med. 6: 43-50.

Walker SD, Dora KA, Ings NT, Crane GJ, Garland CJ. (2001). Activation of endothelial cell IKCa and 1-ethyl-2-benzimidazolinone evokes smooth muscle hyperpolarization in rat isolated mesenteric artery. Br J Pharmacol. 134: 1548-1554.

Dora KA, Garland CJ, Kwan HY, Yao X. (2001). Endothelial cell protein kinase G modulates the release of EDHF through a PKG-sensitive cation channel. Am J Physiol Heart Circ Physiol. 280: H1272-H1277.

Dora KA, Damon DN, Duling BR. (2000). A coordinating role for conducted vasomotor responses in functional dilation. Am J Physiol Heart Circ Physiol. 279: H279-H284.

Dora KA, Hinton JM, Walker SD, Garland CJ. (2000). An indirect influence of phenylephrine on the release of endothelium-derived vasodilators in rat small mesenteric artery. Br J Pharmacol. 129: 381-387.

Dora KA, Martin PEM, Chaytor AT, Evans WH, Garland CJ, Griffith TM. (1999). Role of heterocellular gap junctional communication in endothelium-dependent smooth muscle hyperpolarization: inhibition by a connexin-mimetic peptide. Biochem Biophys Res Commun. 254: 27-31.

Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. (1998). K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 396: 269-272.

Dora KA, Duling BR. (1998). Use of fluorescent reporters in the quantitation of microvascular function. Microcirculation. 5: 95-100.

Dora KA, Doyle MP, Duling BR. (1997). Elevation of intracellular calcium in smooth muscle causes endothelial cell generation of NO in arterioles. Proc Natl Acad Sci USA. 94: 6529-6534.