Evidence for Heterogeneity of Prejunctional Alpha-2-Adrenoceptors

Abstract

The interactions between SK&F 104078 and several selective alpha 2-adrenoceptor agonists at pre- and postjunctional alpha 2-adrenoceptors were investigated in order to assess the previously reported selectivity of SK&F 104078 for postjunctional alpha 2-adrenoceptors and to determine whether or not SK&F 104078 could uncover subtypes of alpha 2-adrenoceptors located prejunctionally as has also been suggested. The alpha 2-adrenoceptor agonists, UK 14,304, xylazine, B-HT 933, B-HT 920, clonidine and M-7, produced concentration-dependent prejunctional alpha 2-adrenoceptor-mediated inhibition of neurogenic responses in the guinea pig atrium and rat vas deferens and produced postjunctional alpha 2-adrenoceptor-mediated contraction of the canine saphenous vein. The alpha 2-adrenoceptor antagonist, rauwolscine, blocked all the agonists at both pre- and postjunctional alpha 2-adrenoceptors without demonstrating preference for any agonist or any synaptic location of alpha 2-adrenoceptors. In marked contrast, SK&F 104078 produced equivalent antagonism of all agonists in the canine saphenous vein but had no significant effect against the same agonists in the guinea pig atrium, suggesting a high degree of selectivity for postjunctional alpha 2-adrenoceptors in these test systems, consistent with our previous observations. In the rat vas deferens, however, SK&F 104078 significantly antagonized the prejunctional alpha 2-adrenoceptor-mediated effects of clonidine and M-7 but did not block the responses to UK 14,304, xylazine, B-HT 933 and B-HT 920. These results indicate that the prejunctional alpha 2-adrenoceptor antagonist effects of SK&F 104078 are tissue and agonist dependent, and that there may be at least two subtypes of prejunctional alpha 2-adrenoceptors that can be discriminated with SK&F 104078 but not with rauwolscine. Both subtypes of prejunctional alpha 2-adrenoceptors may be present in the rat vas deferens, while only the SK&F-104078-insensitive subtype is present in the guinea pig atrium.

Characterization of α2‐adrenoceptors mediating contraction of dog saphenous vein: identity with the human α2A subtype

“…Pharmacological characterization of this receptor has shown that it is similar to the human α 2A subtype (Smith et al , 1992), but that it has a low affinity for rauwolscine and yohimbine suggesting it is a species homologue, and classified as an α 2D ‐adrenoceptor (see Bylund et al , 1994). However, this assay is complex, since two other groups (Akers et al , 1991; Oriowo et al , 1991) have obtained affinity estimates for the antagonist SK & F 104078 that are agonist‐dependent, thus suggesting heterogeneity of receptors.…”

Normal distribution of alpha 2‐adrenoceptors in the rat spinal cord and its modification after noradrenergic denervation: A quantitative autoradiographic study

“…This spinal NA system exerts its physiological actions via adrenoceptors and, among them, the a2 subtypes (Howe et al, 1983;Rawlow and Gorka, 1986;Sullivan et al, 1987;Millan and Colpaert, 1991). Although there are many indications that multiple a,-adrenoceptors exist, no unified subclassification scheme is yet available that will resolve the discrepancies that exist between functional, radioligand binding, and structural studies (Oriowo et al, 1991).…”

L 1 ‐ Imidazoline Receptors: Historical Perspective

“…Hence a perhaps more likely explanation is the presence of multiple prejunctional a-adrenoceptors in this tissue, with one having novel characteristics. This hypothesis is made more plausible by recent observations suggesting prejunctional 1x2-adrenoceptor heterogeneity in the rat vas deferens (Oriowo et al. 1991).…”

“…Although subsequent evidence will show t h a t certain imidazolines can interact with non-adrenergic receptors, i t should be stressed t h a t these and other imidazolines function as classical agonists and antagonists at the al-and a 2 -adrenoceptor. The contractile or neuroinhibitory actions of imidazdine agonists such as clonidine, cirazoline, oxymetazoline and UK 14,304 are sensitive to blockade by a n imidazoline antagonists, such as prazosin or rauwolscine (Ruffolo et al 1982;Ruffolo and Zeid, 1985;Oriowo et al 1991). Imidazoline agonists can be relatively nonselective for a1 vs a2-adrenoceptors (e.g.…”