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Background and Purpose Two distinct α1-adrenoceptor phenotypes (α1A and α1L) have recently been demonstrated to originate from a single α1A-adrenoceptor gene. Here, we examined the agonist profiles of recombinant α1A and α1L phenotypes and of lower urinary tract (LUT) α1-adrenoceptors. Experimental Approach A 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 α1A- and α1L-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. Key Results All the drugs were potent agonists of the α1A-adrenoceptor compared with the α1L-adrenoceptor phenotype. Among them, Ro 115–1240 was shown to be an α1A-specific partial agonist that produced partial contractions through α1A-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 α1A- and α1L-adrenoceptors, but was less selective than noradrenaline for α1A-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. Conclusions and Implications The α1A- and α1L-adrenoceptor phenotypes and LUT α1-adrenoceptors were demonstrated to have distinct agonist profiles. As adrenergic contractions in LUT are predominantly mediated through α1L-adrenoceptors, the development of α1L-selective agonists may provide clinically useful drugs for SUI therapy. |
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