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摘要
Background and PurposeTwo distinct (1)-adrenoceptor phenotypes ((1A) and (1L)) have recently been demonstrated to originate from a single (1A)-adrenoceptor gene. Here, we examined the agonist profiles of recombinant (1A) and (1L) phenotypes and of lower urinary tract (LUT) (1)-adrenoceptors. %26lt;br%26gt;Experimental ApproachA series of drugs (A61603, Ro 115-1240, NS-49 , MK017 and ESR1150) originally developed for stress urinary incontinence (SUI) therapy were used to stimulate recombinant (1A)- and (1L)-adrenoceptor phenotypes, and their potencies and intrinsic activity estimated from Ca2+ responses. Agonist-induced contractions were also examined in LUT tissues of rats and humans and in human mesenteric artery and rat tail artery. %26lt;br%26gt;Key ResultsAll the drugs were potent agonists of the (1A)-adrenoceptor compared with the (1L)-adrenoceptor phenotype. Among them, Ro 115-1240 was shown to be an (1A)-specific partial agonist that produced partial contractions through (1A)-adrenoceptors in rat prostate and tail artery, but not in the other LUT tissues and human mesenteric artery. In contrast, P-come 102 showed full agonist activity at (1A)- and (1L)-adrenoceptors, but was less selective than noradrenaline for (1A)-adrenoceptors. Like noradrenaline, P-come 102 was highly potent at inducing contractions in all of the LUT tissues tested. However, the potency and intrinsic activity of P-come 102 were significantly lower than those of noradrenaline in human mesenteric artery. %26lt;br%26gt;Conclusions and ImplicationsThe (1A)- and (1L)-adrenoceptor phenotypes and LUT (1)-adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through (1L)-adrenoceptors, the development of (1L)-selective agonists may provide clinically useful drugs for SUI therapy.
- 出版日期2013-11
