Agonist pharmacology at recombinant α1A - and α1L -adrenoceptors and in lower urinary tract α1 -adrenoceptors.

Abstract

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.

• Authors: Hatsumi Yoshiki, Junsuke Uwada, Hidenori Umada, Tadashi Kobayashi, Toshihiro Takahashi, Tomio Yamakawa, Akio Yamaguchi, Osamu Yokoyama, Ikunobu Muramatsu
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 170 Issue 6 Pg. 1242-52 (Nov 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 24024968 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The British Pharmacological Society.

Chemical References

• Adrenergic alpha-1 Receptor Agonists
• Receptors, Adrenergic, alpha-1
• Recombinant Proteins
• Calcium

Topics

• Adrenergic alpha-1 Receptor Agonists (pharmacology)
• Aged
• Animals
• Arteries (drug effects, physiology)
• CHO Cells
• Calcium (physiology)
• Cricetulus
• Female
• Humans
• Male
• Middle Aged
• Rats
• Rats, Wistar
• Receptors, Adrenergic, alpha-1 (physiology)
• Recombinant Proteins
• Urethra (drug effects, physiology)
• Urinary Bladder (drug effects, physiology)