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 Ca(2+) 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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http://dx.doi.org/10.1111/bph.12403 | DOI Listing |
Molecules
April 2023
Laboratory of Research and Development of Peptide Drugs and Vaccines, S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk 432017, Russia.
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May 2021
Instituto de Ciencias Físicas, Universidad Nacional Autónoma de México, Cuernavaca 62210, Morelos, México.
Inhibition of the expression of the human ether-à-go-go (hEAG1 or hK10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs.
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January 2021
S. P. Kapitsa Technological Research Institute, Ulyanovsk State University, Ulyanovsk, Russia.
Peptide toxins of arthropods are one of the potential sources of bioactive substances. Toxins are able to bind to calcium channels and block them. Ca ions play an important role in many cell processes, in particular, in apoptosis.
View Article and Find Full Text PDFBiochem Pharmacol
December 2018
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address:
Recently, we and other groups revealed that gain-of-function mutations in the human ether à go-go voltage-gated potassium channel hEAG1 (K10.1) lead to developmental disorders with associated infantile-onset epilepsy. However, the physiological role of hEAG1 in the central nervous system remains elusive.
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December 2017
Department of Audiology, Speech and Language Therapy, School of Biomedical and Allied Health Sciences, University of Ghana, PO Box 143, Korle Bu, Accra, Ghana.
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