The study of responses mediated by alpha2 and alpha1-adrenoceptors in the tail and mesenteric resistance arteries from transgenic mice

The work presented in this thesis describes the development of a method to investigate alpha2-mediated responses in the tail and first order mesenteric resistance arteries of the mouse. Furthermore, responses mediated by alpha1-adrenoceptors have been studied and, in part, subtyped in these vessels. These aims were achieved by using a combination of subtype selective ligands and transgenic technology. alpha2-adrenoceptors, expressed in the tail artery, mediate contractile responses that at 31°C are susceptible to profound, persistent desensitisation. In the absence of a fully functional alpha2A/D receptor pool, contractions are affected by the way in which an agonist is administered. At 22°C, the alpha2-mediated response is significantly potentiated, a response that does not rely on the alpha2A/D subtype, but is critically dependent on previous exposure to an alpha1-selective agonist. In mesenteric resistance arteries, alpha2-adrenoceptors, proposed to exist on the endothelium, mediate vasodilatations. Responses depend on more than one alpha2-subtype, and are mediated by nitric oxide, and possibly EDHF. In the tail artery, alpha1A-adrenoceptors mediate contraction with little, if any, contribution from the alpha1B-subtype, and increasing age has little effect on the responses gained. Like the tail artery, the alpha1A-receptor subtype is the major receptor mediating contraction of mesenteric arteries. However, in the absence of the alpha1B-adrenoceptor, a small, but significant contraction, mediated by the alpha1D-adrenoceptor is uncovered. The use of subtype selective ligands and transgenic mice, has clarified the function of and alpha2 and alpha1-adrenoceptors in two mouse blood vessels, and allowed partial subtyping of the response. Alone, neither technique would have provided such clarity