The α_1C‐adrenoceptor in human prostate: cloning, functional expression, and localization to specific prostatic cell types

Pharmacological characterization of A-131701, a novel ?1-adrenoceptor antagonist selective for ?1A- and ?1D-compared to ?1B-adrenoceptors

“…The functional antagonism of human prostatic contractile responses to NE is most likely mediated through blockade of α 1A -adrenoceptors, even though A-131701 (and most of its analogs) are also potent at α 1D -adrenoceptors, because in the human prostate α 1D -receptors do not appear to contribute to the contractile response induced by NE [Mason et al, 1997]. These results would be consistent with the hypothesis that α 1A -adrenoceptors control prostatic tone, as proposed by others [Lepor et al, 1993;Price et al, 1993;Testa et al, 1993;Kawabe, 1993;Chapple et al, 1994;Hatano et al, 1994;Teng et al, 1994;Forray et al, 1994;Tseng-Crank et al, 1995], that A-131701 should potently antagonize α 1A -adrenoceptors in human or canine prostatic tissue and that this compound might preferentially inhibit prostatic responses to adrenergic stimulation compared to cardiovascular or other responses mediated by α 1B -adrenoceptors [Kirby, 1997]. Therefore, A-131701 and several key analogs were compared to clinically used α 1 -adrenoceptor antagonists in vivo using models where prostatic tone and cardiovascular adrenoceptor function could be ascertained.…”

“…For example, the uroselectivity of REC 15/2739 has been linked to the α 1L -site Testa et al, 1997], a receptor first described on the basis of low potency for prazosin [Muramatsu et al, 1990]. Other investigators [Forray et al, 1994;Muramatsu et al, 1994;Tseng-Crank et al, 1995] have noted the weaker potency for many compounds in blocking functional responses in isolated prostate strips compared to their expected potency derived from radioligand binding assays of the α 1a -adrenoceptor. In the absence of molecular biological evidence to support the existence of additional subtypes of α 1 -adrenoceptor, it is difficult to reconcile the apparently conflicting sets of data that show weaker antagonism of human prostatic contractions by these compounds than in models of α 1A -adrenoceptors.…”

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

“…Moreover, we demonstrate for the first time that this AR subtype is much more expressed in cells derived from a primary PC lesion (RV1) than in cells derived from metastatic sites (LNCaP and DU145), suggesting that selective alpha1A-AR blockers might be more useful to counteract cell proliferation in tissue-confined than in metastatic PC. In general agreement with the literature [11,12,41], our results also demonstrate that alpha1B-and alpha1D-AR subtypes are expressed only in the androgen-independent PC cells, but with a different distribution: alpha1B-AR RNA appears almost exclusively in DU145, while alpha1D-AR is confined in PC3 cells. It should be underlined, however, that the presence of alpha1D-AR only in one of the PC cell lines tested does not ruled out its involvement in PC biology.…”

Current models of human prostate contractility

“…10 Consistent with this finding is evidence that ␣ 1A ( ␣ 1c -)-adrenoceptors predominate in this tissue. 11 ␣ -Adrenoceptor-mediated contractions are also inhibited by pertussis toxin and are sensitive to (L-type) Ca 2+ channel blockers. 12 In 1995, Eckert et al 13 used acutely dispersed prostatic myocytes to investigate second messenger coupling.…”