Functional evidence for atypical β-adrenoceptors in rat isolated arteries

Since the original classification by Lands et al. (1967a), it has become evident that not all β-adrenoceptor mediated responses can be classified as either pi or β1 or β2, with the existence of an additional β-adrenoceptor subtype, referred to as the atypical or β3-adrenoceptor. This β-adrenoceptor subtype has been identified in adipose and gastrointestinal tissue, as well as skeletal muscle and airway smooth muscle. The work presented in this thesis demonstrates the presence of atypical β-adrenoceptors in rat vasculature. The present in vitro results show that relaxations to isoprenaline in the rat thoracic aorta, mesenteric and pulmonary artery, are antagonized by propranolol in a non-competitive manner. In the thoracic aorta and mesenteric artery, relaxant responses to isoprenaline comprised a propranolol-sensitive (β2-adrenoceptor mediated) and -insensitive component. In the pulmonary artery, propranolol produced surmountable antagonism of isoprenaline-induced relaxations, but the antagonism did not satisfy the criteria for competitive antagonism. The β3-adrenoceptor agonists, ZD 7114 and BRL 37344, relaxed all three tissues and in addition, CGP 12177 and alprenolol were agonists, adding support to the hypothesis that atypical β-adrenoceptors are present in the vasculature. Although this β-adrenoceptor in rat vasculature has certain features in common with the β3-adrenoceptor in adipose and gut tissues, they do not appear to be identical. For example, the potency of BRL 37344 appears to be particularly low in rat vasculature compared with its relaxation of several gastrointestinal preparations, where it is one of the most potent β3-adrenoceptor agonists. Also, the β1-/β2- adrenoceptor antagonist, alprenolol which has been shown to be an antagonist at the β3-adrenoceptor in various preparations did not antagonize responses to isoprenaline (carried out in the presence of 10-6M propranolol) or ZD 7114. Furthermore, β3- adrenoceptor mRNA, which is consistently found in adipose and gut tissues, was not detected in rat vasculature, independently of adipose tissue. In summary, a third β-adrenoceptor population, referred to as the atypical β-adrenoceptor, exists in rat vasculature and this receptor has certain features which differ from the β3-adrenoceptor