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

We examined the effect of JTH-601 (3-?N-2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminom ethyl?-4-methoxy-2,5,6-trimethylphenol hemifumarate), a new alpha(1L)-adrenoceptor antagonist, on prostatic function in isolated canine prostate and in anesthetized dogs. In the contraction study, phenylephrine and noradrenaline produced concentration-dependent contractions in canine prostate and carotid artery, respectively. In these tissues, JTH-601, prazosin (a non-selective alpha(1)-adrenoceptor antagonist), and tamsulosin (an alpha(1A)-adrenoceptor antagonist) competitively antagonized contraction in a concentration-dependent manner. The pA(2) (pK(B)) values with 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 blood pressure or heart rate. Tamsulosin (0.1 mg/kg, i.d.) decreased urethral 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 canine prostate both in vitro and in vivo. In prostate, an important role of the alpha(1L)-adrenoceptor is suggested in the smooth muscle contraction mediated by alpha(1)-adrenoceptors. JTH-601 is expected to be an effective alpha(1)-adrenoceptor antagonist for the treatment of urinary outlet obstruction by benign prostatic hypertrophy with a minimum effect on the cardiovascular system.