We compared the potency of a selective ureteral relaxant
KUL-7211 (beta(2)/beta(3)-
adrenoceptor agonist; (-)-2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenyloxy]
acetic acid) with those of various
spasmolytics on contractions in isolated canine ureteral preparations.
Drug effects were evaluated on the tonic contraction induced by KCl (80 mM) and on spontaneous, 1x10(-5) M
phenylephrine-, and 1x10(-6) M PGF(2alpha)-induced rhythmic contractions in isolated canine ureteral preparations using a functional experimental technique. The potencies (pD(2) value) of the following drugs were compared:
KUL-7211,
tamsulosin (an alpha(1A/1D)-
adrenoceptor antagonist),
prazosin (an alpha(1)-
adrenoceptor antagonist),
verapamil (a Ca(2+)-channel blocker),
butylscopolamine (a nonselective
muscarinic antagonist), and
papaverine (a
phosphodiesterase inhibitor). The rank order of relaxing potencies against KCl-induced tonic contraction was
KUL-7211 (6.60)>
tamsulosin(5.90)>
verapamil(5.70)>
papaverine(4.88)>
prazosin (4.54). The rank order of potencies for reductions in spontaneous rhythmic contractions was
KUL-7211 (6.80)>
verapamil(6.12)>
papaverine(5.05). Conversely, high concentrations of the two alpha-
adrenoceptor antagonists (
tamsulosin and
prazosin) and of
butylscopolamine enhanced the spontaneous contractions, although at low concentrations (up to 1x10(-6) M) they had no significant effects. For suppression of spasmogen-induced rhythmic contractions, the rank order of potencies was, against
phenylephrine-induced contractions:
KUL-7211 (6.95)>
tamsulosin(6.26)>
prazosin(5.68)>
verapamil(5.64)>
papaverine (5.03), and against PGF(2alpha)-induced contractions:
KUL-7211 (7.05)>
verapamil(6.70)>
papaverine (5.27). Our results suggest that in dogs, the beta(2)/beta(3)-
adrenoceptor agonist
KUL-7211 is the most efficacious ureteral relaxant among the
spasmolytics tested against various contractions. Possibly,
KUL-7211 might be useful for promoting stone passage and relieving
ureteral colic in
urolithiasis patients.