We examined the effect of JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylp
henoxy)ethyl]-N-methlaminoethyl}-4-methoxy- 2,5,6-trimethylphenol hemifumar
ate), a new alpha(IL)-adrenoceptor antagonist, on prostatic function in iso
lated canine prostate and in anesthetized dogs. In the contraction study, p
henylephrine and noradrenaline produced concentration-dependent contraction
s in canine prostate and carotid artery, respectively. In these tissues, JT
H-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tam
sulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized co
ntraction in a concentration-dependent manner. The pA(2) (pK(B)) values wit
h prostate were 8.49 +/- 0.07 for JTH-601, 7.94 +/- 0.04 for prazosin and 9
.42 +/- 0.22 for tamsulosin. The ratio of pA(2) (carotid artery/prostate),
i.e. prostatic selectivity, was 10.471 for JTH-601, 0.008 for prazosin and
0.371 for tamsulosin, respectively. In anesthetized dogs, JTH-601 (1 mg/kg,
i.d.) significantly decreased urethral pressure by 15% without affecting b
lood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethra
l pressure to the same extent as did JTH-601, but with a significant effect
on blood pressure and heart rate. JTH-601 showed higher selectivity for ca
nine prostate both in vitro and in vivo. In prostate, an important role of
the alpha(IL)-adrenoceptor is suggested in the smooth muscle contraction me
diated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective al
pha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruct
ion by benign prostatic hypertrophy with a minimum effect on the cardiovasc
ular system. (C) 2000 Elsevier Science B.V. All rights reserved.