Pharmacological profile of KUL-7211, a selective beta-adrenoceptor agonist, in isolated ureteral smooth muscle.

Abstract

Since, in the human ureter, both beta(2)- and beta(3)-adrenoceptors mediate adrenergic-stimulation-induced relaxation, selective beta(2)-/beta(3)-adrenoceptor agonists might prove clinically useful for relieving ureteral colic and promoting stone passage. We evaluated the beta-adrenoceptor subtype selectivity and ureteral-relaxing efficacy of (-)-2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amin] ethyl)phenyloxy]acetic acid (KUL-7211), a new beta-adrenoceptor agonist, in vitro. In rat isolated organs, its selectivities, for inhibition of spontaneous uterine contraction (mediated via beta(2)-adrenergic stimulation) and inhibition of colonic contraction (via beta(3)-adrenergic stimulation) versus increase in atrial rate (via beta(1)-adrenergic stimulation), were 56.3 and 242.2, respectively. KUL-7211 relaxed 80-mM-KCl-induced tonic contractions in both rabbit (pD(2) value: 5.86 +/- 0.13, whose ureteral relaxation is mediated via beta(2)-adrenergic stimulation) and canine (pD(2) value: 6.52 +/- 0.16, via beta(3)-adrenergic stimulation) isolated ureters in a concentration-dependent manner. These KUL-7211-induced relaxing effects were antagonized by ICI-118,551 (selective beta(2)-adrenoceptor antagonist, pK(B) value: 8.91 +/- 0.24) in the rabbit ureter and by bupranolol (non-selective beta-adernoceptor antagonist, pK(B) value: 6.85 +/- 0.12) in the canine ureter. KUL-7211 also reduced the spontaneous rhythmic contraction in a canine ureteral spiral preparation in a concentration-dependent manner, the pD(2) value being 6.83 +/- 0.20. These data clearly demonstrate that KUL-7211 selectively stimulates both ureteral beta(2)- and beta(3)-adrenoceptors and potently relaxes ureteral smooth muscle. KUL-7211 may be a novel and useful medication for relieving ureteral colic and promoting stone passage in urolithiasis patients.

• Authors: Yoshitaka Tomiyama, Makoto Murakami, Kohichi Hayakawa, Katsuyoshi Akiyama, Yoshinobu Yamazaki, Masami Kojima, Nobuo Shibata, Masuo Akahane
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 92 Issue 4 Pg. 411-9 (Aug 2003) ISSN: 1347-8613 [Print] Japan
• PMID: 12939526 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Acetates
• Adrenergic beta-Agonists
• KUL7211
• Receptors, Adrenergic, beta

Topics

• Acetates (chemistry, pharmacology)
• Adrenergic beta-Agonists (chemistry, pharmacology)
• Animals
• Dogs
• Dose-Response Relationship, Drug
• Female
• In Vitro Techniques
• Male
• Muscle Contraction (drug effects, physiology)
• Muscle, Smooth (drug effects, physiology)
• Pregnancy
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Receptors, Adrenergic, beta (physiology)
• Ureter (drug effects, physiology)