Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs

Citation
Y. Suzuki et al., Effect of JTH-601, a novel alpha(1)-adrenoceptor antagonist, on prostate function in dogs, EUR J PHARM, 394(1), 2000, pp. 123-130
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN journal
0014-2999 → ACNP
Volume
394
Issue
1
Year of publication
2000
Pages
123 - 130
Database
ISI
SICI code
0014-2999(20000407)394:1<123:EOJANA>2.0.ZU;2-4
Abstract
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.