Phenotype pharmacology of lower urinary tract α(1)-adrenoceptors

Abstract

α(1)-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α(1)-adrenoceptor subtypes remains controversial. Here, we review the literature regarding α(1)-adrenoceptors in the lower urinary tract from the standpoint of α(1L) phenotype pharmacology. Among three α(1)-adrenoceptor subtypes (α(1A), α(1B) and α(1D)), α(1a)-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, α(1A)-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional α(1)-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical α(1)-adrenoceptor phenotype (designated as α(1L)). The α(1L)-adrenoceptor occurs as a distinct binding entity from the α(1A)-adrenoceptor in intact segments of variety of tissues including prostate. Both the α(1L)- and α(1A)-adrenoceptors are specifically absent from Adra1A (α(1a)) gene-knockout mice. Transfection of α(1a)-adrenoceptor cDNA predominantly expresses α(1A)-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses α(1L)- and α(1A)-phenotypes. Under intact cell conditions, the α(1L)-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1α. In summary, recent pharmacological studies reveal that two distinct α(1)-adrenoceptor phenotypes (α(1A) and α(1L)) originate from a single Adra1A (α(1a)-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the α(1L)-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the α(1L)-adrenoceptor will become new targets for drug development and pharmacotherapy.

Figure 1

Autonomic innervation and main functional receptors involved in controlling smooth muscle tension in lower urinary tract tissues. NA, noradrenaline; α_1L, α_1L-adrenoceptor; β₃, β₃-adrenoceptor; M₃, M₃-muscarinic acetylcholine receptor.