A Study of α2-adrenoceptor-mediated Vasodilatation in Mesenteric Resistance Arteries From Transgenic Mice

McBride, M., Daly, C.J. , McGrath, J.C. and Malekzadeh-Shafaroudi, M. (2004) A Study of α2-adrenoceptor-mediated Vasodilatation in Mesenteric Resistance Arteries From Transgenic Mice. University of Glasgow 2004, 2004.

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Publisher's URL: https://www.physoc.org/abstracts/a-study-of-2-adrenoceptor-mediated-vasodilatation-in-mesenteric-resistance-arteries-from-transgenic-mice/


We have previously established that α1-adrenoceptors mediate contractile responses in first order mesenteric resistance arteries [McBride et al, 2003, Daly et al, 2002]. The current work aimed to determine the α2-adrenoceptor-mediated response, which is poorly defined in this artery. The α2-selective agonist, UK14304 (UK) produced vasodilator responses that were studied in order to determine the site, mechanism of action, and subtypes of α-adrenoceptors involved in the response. Male mice aged 4-months (WT controls, D79N and α2A/D knockout/KO, n = 6) weighing 29.6-33.2gs were euthanased with CO2. First order mesenteric arteries were isolated, cut into 2mm rings, and mounted in Krebs at 37°C on a wire myograph. Non-cumulative UK response curves (1 x 10-9 to 1 x 10-4M in log increments) were constructed in the presence of U46619-induced tone, alone, in the presence of LNAME (1 x 10-4M), rauwolscine (3 x 10-8M), and in denuded vessels. Statistical analysis employed unpaired Student’s t-test, with p< 0.05 considered statistically significant. UK produced a concentration-related reduction in tone. At the highest agonist concentration tested a 59.0 ± 5.6 % reduction in tone occurred. At UK concentrations of 1 x 10-6 (p = 0.008) and 1 x 10-5M (p = 0.049), L-NAME (nitric oxide synthase inhibitor) significantly attenuated responses, but effects are surmountable at 1 x 10-4M. Similarly, rauwolscine (an α2-selective antagonist) inhibits relaxant effects of UK at 1 x 10-6 (p = 0.04) and 1 x 10-5M (p = 0.0003), but antagonism is surmountable at 1 x 10-4M. Removal of the endothelium, by rubbing with a human hair, resulted in a complete abolition of vasodilator responses, indicating that endothelial αadrenoceptors promote the release of nitric oxide, which subsequently leads to a reduction in vascular tone. The surmountable effect of L-NAME and rauwolscine indicates several things. Firstly, at very high agonist concentrations UK can induce a relaxation that is independent of nitric oxide release. Preliminary experiments, where the K+ concentration was elevated, suggest the involvement of EDHF (endothelial derived hyperpolarising factor). Secondly, the lack of effect of rauwolscine at high UK concentrations suggests the involvement of a receptor other than the α2A/D,or may indicate a receptor-independent mechanism of action. In the α2A/D KO and the D79N (α2A/D mutant), the relaxant effect of UK is attenuated, but not abolished. However, in the carotid and aortae from D79N and αKO mice UK-mediated 2A/D relaxations are abolished (unpublished observation), indicating that this subtype is solely responsible for vasodilatation. In mesenteric arteries, data from transgenic mice suggests the involement of additional receptors, and the involvement of EDHF at high agonist concentrations.

Item Type:Conference or Workshop Item
Additional Information:Communication.
Glasgow Author(s) Enlighten ID:McGrath, Professor John and Daly, Professor Craig
Authors: McBride, M., Daly, C.J., McGrath, J.C., and Malekzadeh-Shafaroudi, M.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences

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