A selective alpha1A-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia.

PURPOSE: Alpha(1)-adrenoceptor antagonists relax the obstructed prostatic urethra and suppress the irritative symptoms frequently observed in patients with benign prostatic hyperplasia. We investigated the effects of 3 alpha(1)-adrenoceptor antagonists on urodynamics in rats with hormone induced benign prostatic hyperplasia to determine which alpha(1)-adrenoceptor subtype selective antagonists would suppress irritative symptoms. MATERIALS AND METHODS: Rats were treated with testosterone and 17beta-estradiol by weekly intramuscular injections. After 4 weeks a pressure flow study was done and the effects of the alpha(1)-adrenoceptor antagonists KMD-3213 silodosin, tamsulosin and prazosin on urodynamics were compared. We especially investigated the involvement of the bladder and prostatic urethra to clarify the mechanism of detrusor overactivity expression. RESULTS: Hormone treatment induced benign prostatic hyperplasia and resulted in detrusor overactivity, as determined by cystometry. Baseline perfusion urethral pressure and the phenylephrine induced increase in it were significantly higher in rats with vs without benign prostatic hyperplasia. Cystometry in hormone treated female rats did not show detrusor overactivity. KMD-3213 decreased detrusor overactivity, similar to other alpha(1)-adrenoceptor antagonists. CONCLUSIONS: These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

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

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.

Effects of KMD-3213, a uroselective alpha 1A-adrenoceptor antagonist, on the tilt-induced blood pressure response in normotensive rats.

KMD-3213 ((-)-1-(3-hydroxypropyl)-5-((2R)-2-[[2-([2-[(2,2,2-trifluoroethyl)oxy]phenyl]oxy)ethyl]amino]propyl)-2,3-dihydro-1H-indole-7-carboxamide), an alpha(1A)-adrenoceptor antagonist with potency similar to that of tamsulosin, is under development for the treatment of bladder outlet obstruction in patients with benign prostatic hypertrophy. In the present study, we investigated the effects of KMD-3213 on the tilt-induced blood pressure response in anesthetized normotensive rats. Male normotensive Sprague-Dawley rats were placed in the supine position on a board under cocktail anesthetization (alpha-chloralose, urethane and sodium pentobarbital). The arterial blood pressure was measured from the carotid artery. The animals were given consistent 45 degrees head-up tilt from the horizontal position, following the transient decrease in the blood pressure, and then recovery of the blood pressure to the normal level. Significant orthostatic hypotension was seen with intravenous administration of both prazosin and tamsulosin at doses over 3 micro g/kg, and these drugs completely blocked the tilt-induced blood pressure responses at 30 micro g/kg. On the other hand, these responses were still retained when KMD-3213 was administered intravenously at a dose up to 75 micro g/kg of KMD-3213. Moreover, KMD-3213 showed the highest uroselectivity of the test drugs. These results indicate that KMD-3213 is not likely to induce orthostatic hypotension and would be a useful compound for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia.

Modification of ureteral motility and promotion of urine flow around an intraureteral obstruction by CL-316243, phenylephrine, and furosemide in dogs.

The aim of this study was to evaluate the effects of a beta3-adrenoceptor (AR) agonist (CL-316243), an alpha1-AR agonist (phenylephrine), and a loop diuretic (furosemide) on the spontaneous rhythmic contractions of the isolated canine ureter and on an acute ureteral obstruction produced by inflation of a balloon catheter in anesthetized dogs. In the isolated ureter, CL-316243 concentration dependently reduced both the amplitude and frequency of the rhythmic contractions (pD(2): 7.19 +/- 0.33), whereas phenylephrine significantly enhanced both variables (pD(2): 5.26 +/- 0.09) and furosemide reduced them only slightly. In the acute ureteral obstruction model, the intraureteral pressure (IUP) gradually rose to reach a plateau of 58.9 mm Hg after inflation of a balloon catheter within the lower ureter. Intravenous administration of CL-316243 (0.3 microg/kg) significantly reduced the elevated IUP and the resumed urine flow (UF), leading to a sustained reduction in the IUP. In contrast, the IUP continued to increase above the plateau level for 10 minutes after phenylephrine administration (10 microg/kg) and for 30 minutes after furosemide administration (1,000 microg/kg). In the phenylephrine group, the UF resumed when the IUP reached 75.8 mm Hg, and thereafter the IUP gradually decreased in parallel with the increase in the UF. From these results, we conclude that in dogs, CL-316243 reduces the IUP by allowing the UF to resume as a result of a relaxation of ureter at the obstruction site, whereas with phenylephrine, the reduction in the IUP is secondary to a resumption in the UF resulting from an induced contraction of ureter that causes an increase in hydrostatic pressure above the obstruction site.

Relationship between prostatic alpha(1)-adrenoceptor binding and reduction in intraurethral pressure following continuous infusion of KMD-3213 in rats.

The relationship between alpha(1)-adrenoceptor binding in rat tissues and pharmacodynamic effects of continuous infusion of KMD-3213 was examined. In vivo specific binding of [(3)H]KMD-3213 after continuous intravenous infusion of the ligand (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min for 60 or 90 min) differed largely among the tissues examined. Specific binding of [(3)H]KMD-3213 in aorta, heart, lung, and kidney was not different in terms of infusion time in the case of continuous infusion for 10, 70 and 100 min, whereas the binding in prostate, vas deferens, and submaxillary gland by 70- and/or 100-min infusion was significantly greater than that by the 10-min infusion. A similar extent of specific binding in the prostate was observed by the infusion (100 min) of a three-fold higher dose of [(3)H]KMD- 3213. Continuous intravenous infusion of KMD-3213 (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min) for 70 or 100 min significantly reduced the phenylephrine-induced increase in the mean blood pressure and that in the intraurethral pressure of anesthetized rats. Extent and time course of the KMD-3213 effect reduction in the phenylephrine-induced increase in intraurethral pressure were closely associated with those in prostatic [(3)H]KMD-3213 binding after continuous infusion of the corresponding dosage of the radioligand. The reduction in the phenylephrine-induced increase by the infusion of a three-fold higher dose of KMD-3213 was significantly greater in the case of the intraurethral pressure than in that of the mean blood pressure, thereby suggesting a greater selectivity for the alpha(1)-adrenoceptor in the lower urinary tract than for that in the vascular tissue. In conclusion, the present study has shown that specific binding of [(3)H]KMD-3213 in the rat prostate after the continuous intravenous infusion of the radioligand may be closely associated with the pharmacological effect of this drug on the lower urinary tract.