Expression of distinct α₁‐adrenoceptor phenotypes in the iris of pigmented and albino rabbits

Abstract

Background and purpose:The expression of multiple pharmacological phenotypes including a1L-adrenoceptor has recently been reported for a1-adrenoceptors. The purpose of the present study was to identify a1-adrenoceptor phenotypes in the irises of pigmented and albino rabbits. and 5-methylurapidil, while two components with high and low affinities for prazosin, RS-17053 and 5-methylurapidil were identified in irises from albino rabbits. In contrast, specific binding sites for [ 3 H]-prazosin were not clearly detected because a high proportion of non-specific binding and/or low affinity for prazosin occurred. Contractile responses of iris dilator muscle to noradrenaline were antagonized by the above ligands, and their antagonist affinities were consistent with the binding estimates at low-affinity sites identified in both strains of rabbits. Conclusions and implications:A typical a1L phenotype with extremely low affinity for prazosin is exclusively expressed in the iris of pigmented rabbits, while two distinct phenotypes (a1A and a1L) with high and moderate affinities for prazosin are co-expressed in the iris of albino rabbits. This suggests that a significant difference in the expression of phenotypes of the a1-adrenoceptor occurs in the irises between the two strains of rabbits.

Phenotype pharmacology of lower urinary tract α1‐adrenoceptors

“…At present, the mechanisms underlying the expression of a1L-adrenoceptor phenotype and its functional predominance in several tissues remain unknown. However, it is likely that the expression of divergent a1L-adrenoceptor phenotypes is strongly dependent on any modification of the tissues of various species, rather than a simple variation of the a1a-adrenoceptor protein or additional subtypes (Muramatsu et al, 2009;Nishimune et al, 2010a).…”

“…The a1L-adrenoceptor exemplifies this type of variable affinity, as after homogenization, the phenotype changed from a 1L into a1A. It is likely that tissue integrity is an important factor to determine receptor properties (Su et al, 2008;Muramatsu et al, 2009). Therefore, we may have to re-evaluate pharmacodynamic and pharmacokinetic effects of currently used drugs, and to reconstruct drug development strategies.…”

“…3 H]-prazosin at subnanomolar concentrations cannot bind sufficiently to a1L-adrenoceptors (Su et al, 2008;Muramatsu et al, 2009). Silodosin and its tritiated radioligand are known to be of equally high affinity for both the a1A-and a1L-adrenoceptors Su et al, 2008) (Table 2).…”

“…However, the functional a1-adrenoceptors identified in the lower urinary tract are known to be relatively resistant to prazosin (Muramatsu et al, 2009) (pKB =~8) (Table 1). Thus, this pharmacological anomaly, despite the predominance of a1a-adrenoceptor mRNA, caused confusion about the a1-adrenoceptor subtypes in the lower urinary tract.…”

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

“…Nonetheless, it proved possible to detect the α 1L -AR in 'tissue fragments' that had not been subject to rigorous homogenization (21). Thus, the process of tissue disruption was able to explain the failure of previous attempts to demonstrate α 1L -ARs in the radioligand binding studies using isolated membrane fractions (8,22).…”