Silodosin, an α(1A)-Adrenoceptor Antagonist, May Ameliorate Ischemia-Induced Bladder Denervation and Detrusor Dysfunction by Improving Bladder Blood Flow.

BACKGROUND/AIMS: This study was performed to investigate the detailed mechanism underlying the effects of the selective α(1A)-adrenoceptor antagonist, silodosin, on bladder function in a rat model of atherosclerosis-induced chronic bladder ischemia (CBI). METHODS: The CBI model was prepared by balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, the CBI rats received either silodosin or vehicle alone subcutaneously for 8 weeks. Rats received a 2% cholesterol diet throughout the experiment. Bladder blood flow (BBF) was measured. Immunohistochemical staining was performed to determine the nerve distribution and nerve growth factor expression in the bladder. Bladders were used for muscle strip contraction analysis. The expression levels of muscarinic M2 and M3 receptors were measured. RESULTS: Silodosin abrogated the decrease in BBF in CBI rats. Silodosin prevented the decrease in nerve distribution and increase in nerve growth factor expression in the CBI model. Bladder contractile response was reduced in the CBI group. Silodosin ameliorated the effect on the bladder contractile response. The level of muscarinic M3 receptor mRNA present in the bladder of CBI rats was increased by silodosin. CONCLUSION: The results of this study suggest that silodosin ameliorates the denervation of the bladder and effects on detrusor contractile function under ischemic conditions by restoring BBF.

Effect of silodosin, a selective α(1A)-adrenoceptor antagonist, on voiding behavior and bladder blood flow in a rat model of bladder outlet obstruction.

This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF.

Effects of silodosin, a selective α1A-adrenoceptor antagonist, on bladder blood flow and bladder function in a rat model of atherosclerosis induced chronic bladder ischemia without bladder outlet obstruction.

PURPOSE: We investigated the effects of the selective α1A-adrenoceptor antagonist silodosin on bladder blood flow and bladder function in a rat model of atherosclerosis induced chronic bladder ischemia without bladder outlet obstruction. MATERIALS AND METHODS: The chronic bladder ischemia model was prepared by creating balloon endothelial injury of the bilateral iliac arteries in male rats. Using an osmotic pump, chronic bladder ischemia rats received silodosin subcutaneously at a rate of 0.1 or 0.3 mg/kg per day, or vehicle for 8 weeks. All groups received a 2% cholesterol diet throughout the experiment. For each α1-adrenoceptor subtype mRNA expression in bladder microvessels was examined by in situ hybridization. Bladder blood flow was measured using a laser speckle blood flow imager. Malondialdehyde in bladder tissue and 8-hydroxy-2'-deoxyguanosine in urine were measured as markers of oxidative stress. A metabolic cage study and cystometry were performed in conscious rats. RESULTS: The expression of all α1-adrenoceptor subtype mRNA was observed in rat bladder microvessels. Silodosin abrogated the decreased bladder blood flow in the empty bladder and during bladder distention that were evident in rats with chronic bladder ischemia. Levels of oxidative stress markers in these rats were significantly decreased by silodosin administration. Silodosin ameliorated bladder dysfunction in rats with chronic bladder ischemia in the metabolic cage study and on cystometry. CONCLUSIONS: Results suggest that in ischemic conditions α1-adrenoceptor antagonists such as silodosin may improve bladder function by restoring bladder blood flow.

Ureteral selectivity of intravenous ß-adrenoceptor agonists in pig model of acute ureteral obstruction: comparison of KUL-7211, a selective ß2/ß3 agonist, with isoproterenol, terbutaline, and CL-316243.

OBJECTIVES: To compare the potency and ureteral selectivity of the selective ß(2)/ß(3)-adrenoceptor agonist KUL-7211 with those of the nonselective ß-adrenoceptor agonist isoproterenol, selective ß(2)-adrenoceptor agonist terbutaline, and selective ß(3)-adrenoceptor agonist CL-316243, we performed the study using an isolated porcine ureter and a porcine model of acute unilateral ureteral obstruction. METHODS: The effects of the drugs on the 80-mM KCl-induced contraction of the ureteral segments isolated from male pigs were evaluated using a functional experimental technique. Anesthetized male miniature pigs with complete obstruction of the left lower ureter were used to evaluate the effects of the cumulative intravenous drug administration on the elevated intraureteral pressure and mean blood pressure. RESULTS: The KCl-induced contractions in the isolated ureter were concentration-dependently attenuated by KUL-7211, isoproterenol, terbutaline, and CL-316243, with a rank order of potency of 6.26, 6.98, 5.41, and 5.41, respectively. In the anesthetized pigs, all 4 drugs reduced the unilateral ureteral obstruction-induced elevated intraureteral pressure in a dose-dependent manner, with KUL-7211 reducing it with a lower hypotensive effect than either isoproterenol or terbutaline. The ureteral selectivity (defined as the ratio of the effective dose to decrease the mean blood pressure by 25% to the effective dose to decrease the intraureteral pressure by 50%) of KUL-7211 (1.5) was significantly greater than that of isoproterenol (0.04) or terbutaline (0.43). CONCLUSIONS: The present results have demonstrated that in pigs, KUL-7211 is a potent ureteral relaxant with a relatively small hypotensive effect. A selective ß(2)/ß(3)-adrenoceptor agonist, such as KUL-7211, warrants additional investigation as a potentially useful drug for the promotion of stone passage in patients with urolithiasis.

Characterization of α1-adrenoceptor subtypes mediating contraction in human isolated ureters.

OBJECTIVES: To characterize the contractile functions of the α(1)-adrenoceptor (AR) subtypes present in the human ureter. METHODS: Specimens were taken from patients with renal cancer ("upper ureters;" n = 51) or bladder cancer ("lower ureters;" n = 23) who had not been treated by chemotherapy, radiation therapy, or immunotherapy before surgery. Patients systemically taking an α(1)-AR agonist or antagonist were excluded from this study. The effects of α(1)-AR antagonists against phenylephrine (α(1)-AR agonist)-induced contractions were evaluated in human isolated ureteral preparations. RESULTS: Pooled data from all ureters showed that phenylephrine (α(1)-AR agonist) induced a concentration-dependent tonic contraction (pD(2) value, 4.92 ± 011). The phenylephrine-induced maximum contraction was significantly greater in lower ureters than in upper ones. Prazosin (nonselective α(1)-AR antagonist), silodosin (selective α(1A)-AR antagonist), and BMY-7378 (selective α(1D)-AR antagonist) all shifted the concentration-contractile response curve for phenylephrine to the right, the rank order of potencies in all ureters (pK(B) values) being silodosin (9.72 ± 0.14) > prazosin (8.64 ± 0.08) > BMY-7378 (7.04 ± 0.14). The α(1A)-AR antagonist silodosin was thus much more potent than the other 2 antagonists. CONCLUSIONS: Our results suggest that among α(1)-ARs, the α(1A) subtype plays the major role in contraction in the human ureter.

Effects of silodosin and naftopidil on the distal ureter and cardiovascular system in anesthetized dogs: comparison of potential medications for distal ureteral stone passage.

PURPOSE: We compared the effects of the selective alpha(1A)-adrenoceptor antagonist silodosin and the selective alpha(1D)-adrenoceptor antagonist naftopidil on intraureteral pressure in anesthetized dogs and evaluated their uroselectivity. MATERIALS AND METHODS: Using anesthesia the effects of silodosin and naftopidil were evaluated by the phenylephrine induced increase in intravesical ureteral pressure and on blood pressure. Each drug was administered intravenously in progressively increasing doses. The dose of each alpha(1)-adrenoceptor antagonist at which mean blood pressure was decreased by 15% (ED(15)) and the dose at which the phenylephrine induced increase in intravesical ureteral pressure was suppressed by 50% (ID(50)) were measured and uroselectivity was calculated as ED(15)/ID(50). RESULTS: Silodosin dose dependently suppressed the phenylephrine induced increase in intravesical ureteral pressure (ID(50) 2.5 microg/kg) but decreased mean blood pressure only at higher doses (ED(15) 143.4 microg/kg). In contrast, naftopidil decreased mean blood pressure (ED(15) 280.7 microg/kg) at the same doses as those that decreased the phenylephrine induced increase in intravesical ureteral pressure (ID(50) 225.1 microg/kg). Silodosin uroselectivity was markedly higher than that of naftopidil (58.6 vs 1.3). CONCLUSIONS: Results suggest that a selective alpha(1A)-adrenoceptor antagonist such as silodosin may facilitate distal ureteral stone passage at nonhypotensive doses.

Effects of four different alpha(1)-adrenoceptor antagonists on alpha-adrenoceptor agonist-induced contractions in isolated mouse and hamster ureters.

PURPOSE: To compare the efficacy of the selective alpha(1A)-adrenoceptor antagonist silodosin with those of doxazosin, terazosin, and alfuzosin against alpha-adrenoceptor agonist-induced contractions in mouse and hamster ureters. METHODS: The four alpha(1)-adrenoceptor antagonists were evaluated against norepinephrine-induced phasic contractions in mouse isolated ureteral preparations and against phenylephrine-induced sustained contractions in hamster isolated ureteral preparations using a functional experimental technique. RESULTS: In mouse ureters, silodosin (a selective alpha(1A)-adrenoceptor antagonist), doxazosin (a nonselective alpha(1)-adrenoceptor antagonist), terazosin (a nonselective alpha(1)-adrenoceptor antagonist), and alfuzosin (a nonselective alpha(1)-adrenoceptor antagonist) all shifted the norepinephrine concentration-response curve to the right. The rank order of potencies (pK(B) value) was silodosin (9.47 +/- 0.16) > doxazosin (8.62 +/- 0.15) > terazosin (8.39 +/- 0.16) > alfuzosin (8.03 +/- 0.12). In hamster ureters, all four antagonists shifted the phenylephrine concentration-response curve to the right, the rank order of potencies being silodosin (10.09 +/- 0.13) > doxazosin (8.22 +/- 0.16) > terazosin (7.75 +/- 0.15) > alfuzosin (7.70 +/- 0.10). In each case, silodosin was much more potent than the other three drugs. CONCLUSION: In this study, silodosin suppressed both mouse and hamster ureteral contractions more potently than doxazosin, terazosin, or alfuzosin. Hence, this alpha(1A)-adrenoceptor antagonist warrants further study as a potentially very useful medication for stone passage in urolithiasis patients.

Mechanical function and gene expression of alpha(1)-adrenoceptor subtypes in dog intravesical ureter.

OBJECTIVES: To characterize the contractile functions and gene expression of the alpha(1)-adrenoceptor (AR) subtypes present in the dog intravesical ureter. METHODS: In a functional study, alpha(1)-AR antagonists were evaluated against phenylephrine (alpha(1)-AR agonist)-induced contractions in dog isolated intravesical ureteral preparations. The quantitative expression of alpha(1)-AR subtype mRNA in this tissue was determined using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: In the isolated intravesical ureter, prazosin (nonselective alpha(1)-AR antagonist), silodosin (selective alpha(1A)-AR antagonist), naftopidil (selective alpha(1D)-AR antagonist), and BMY-7378 (selective alpha(1D)-AR antagonist) all shifted the concentration-contractile response curve for phenylephrine to the right. The rank order of potencies (pK(B) value) was silodosin (9.45 +/- 0.14), prazosin (8.16 +/- 0.08), naftopidil (7.39 +/- 0.19), and BMY-7378 (6.78 +/- 0.20). The alpha(1A)-AR antagonist silodosin was much more potent than the 2 alpha(1D)-AR antagonists. The rank order of mRNA expression levels among the alpha(1)-AR subtypes was alpha(1d) (72.68%), alpha(1a) (24.14%), and alpha(1b) (3.18%). CONCLUSIONS: In the dog intravesical ureter, alpha(1A)-AR plays a major role in contraction, despite the prevalence of alpha(1D)-AR.

Effects of silodosin and tamsulosin on the urethra and cardiovascular system in young and old dogs with benign prostatic hyperplasia.

We examined whether the effects (efficacy on the urethra and hypotension) of silodosin (alpha(1A)-adrenoceptor antagonist) and tamsulosin (alpha(1A+1D)-adrenoceptor antagonist) in dogs with benign prostatic hyperplasia altered with age. We used young and old dogs, diagnosed as having benign prostatic hyperplasia by veterinarian's palpation. Under anesthesia, the increase in intraurethral pressure evoked by hypogastric nerve stimulation was measured, together with the level of systemic mean blood pressure. Each drug was administered intravenously in progressively increasing doses. At the end of the experiment, the prostate was isolated from each dog, then weighed and investigated pathologically to confirm benign prostatic hyperplasia. The wet weight of the prostate was greater in old dogs with benign prostatic hyperplasia than in young dogs with benign prostatic hyperplasia. By light microscopy, hyperplasia in the prostatic epithelium was confirmed in both groups. Silodosin (0.3-300 microg/kg) dose-dependently inhibited the hypogastric nerve stimulation-induced increase in intraurethral pressure (without significant hypotensive effects) in both young and old dogs with benign prostatic hyperplasia. Tamsulosin (0.3-300 microg/kg) also dose-dependently inhibited the intraurethral pressure increase in both groups, but it had a hypotensive effect that was significantly greater in old than in young dogs with benign prostatic hyperplasia. In conclusion, as regards the effect of silodosin on intraurethral pressure, potency was similar between young and old dogs with benign prostatic hyperplasia, and it was without significant hypotensive effects. We therefore suggest that silodosin might be a good medication for lower urinary tract symptoms in patients with benign prostatic hyperplasia in all age groups.

Gene expressions and mechanical functions of α1-adrenoceptor subtypes in mouse ureter.

PURPOSE: This study was performed to characterize the α1-adrenoceptor subtypes in mouse ureters as regards gene expressions and contractile functions. METHODS: The mRNAs for these subtypes were quantified by the real-time quantitative reverse transcription polymerase chain reaction. In a functional study, α1-adrenoceptor antagonists were evaluated against the noradrenaline-induced contraction in mouse isolated ureteral preparations. RESULTS: In mouse ureter, the relative mRNA expression levels for α1a-, α1b- and α1d-adrenoceptors were 74.5, 14.3 and 11.2%, respectively. Adrenaline and noradrenaline each produced a concentration-dependent phasic contraction (pD 2 values, 5.73±0.05 and 5.69±0.06, respectively). Prazosin (non-selective α1-adrenoceptor antagonist), silodosin (selective α1A-adrenoceptor antagonist), and BMY-7378 (selective α1D-adrenoceptor antagonist) all shifted the concentration­response curve for noradrenaline to the right, the rank order of potencies (apparent pA 2 values) being silodosin (9.32±0.11)>prazosin (8.55±0.10)>BMY-7378 (6.06±0.15). The α1A-adrenoceptor antagonist silodosin was thus much more effective than the α1D-adrenoceptor antagonist BYM-7378. CONCLUSIONS: Our results demonstrate that in mouse ureters: the mRNA for the α1A-adrenoceptor was more prevalent than those for the α1B- and α1D-adrenoceptors, and that among these subtypes, the α1A-adrenoceptor plays the major role in noradrenaline-induced contraction.

Expressions and mechanical functions of alpha1-adrenoceptor subtypes in hamster ureter.

We characterized the alpha(1)-adrenoceptor subtypes in hamster ureters according to gene and protein expressions and contractile function. Real-time quantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis were performed to determine mRNA levels and receptor protein expressions respectively, for alpha(1A)-, alpha(1B)- and alpha(1D)-adrenoceptors in hamster ureteral smooth muscle. alpha(1)-Adrenoceptor antagonists were tested against the phenylephrine (alpha(1)-adrenoceptor agonist)-induced contraction in isolated hamster ureteral preparations using a functional experimental approach. In the smooth muscle, relative mRNA expression levels for alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptors were 10.7%, 1.2% and 88.1%, respectively, and protein expressions were identified for alpha(1A)- and alpha(1D)-adrenoceptors immunohistochemically. Noradrenaline and phenylephrine (alpha(1)-adrenoceptor agonist) each produced a concentration-dependent tonic contraction, their pD(2) values being 6.87+/-0.08 and 6.10+/-0.05, respectively. Prazosin (nonselective alpha(1)-adrenoceptor antagonist), silodosin (selective alpha(1A)-adrenoceptor antagonist) and BMY-7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride) (selective alpha(1D)-adrenoceptor antagonist) competitively antagonized the phenylephrine-induced contraction (pA(2) values, 8.60+/-0.07, 9.44+/-0.06 and 5.75+/-0.07, respectively). Chloroethylclonidine (3x10(-6) mol/L or more) produced a rightward shift in the concentration-response curve for phenylephrine. Thus, in hamster ureters, alpha(1A)- and alpha(1D)-adrenoceptors were more prevalent than the alpha(1B)-adrenoceptor, with contraction being mediated mainly via alpha(1A)-adrenoceptors. If these findings hold true for humans, alpha(1A)-adrenoceptor antagonists could become useful medication for stone passage in urolithiasis patients.

Uroselectivity in male dogs of silodosin (KMD-3213), a novel drug for the obstructive component of benign prostatic hyperplasia.

AIMS: Our main aim was to compare the prostatic selectivity of silodosin with that of other alpha(1)-adrenoceptor (AR) antagonists. METHODS: We examined uroselectivities in two sets of experiments namely, in vitro and in vivo functional studies using male dogs. In the in vitro study, after evaluating the inhibitory effects of silodosin on noradrenaline (NA)-induced contractions in the isolated prostate and isolated carotid artery using the Magnus method, we calculated prostatic selectivity. In the in vivo study, we examined the effects of drugs on the hypogastric nerve stimulation (HNS)-induced increase in intraurethral pressure (IUP) and on blood pressure. The uroselectivity of silodosin was compared with those of tamsulosin and naftopidil. RESULTS: In vitro, all drugs antagonized NA-induced contraction in both prostate and carotid artery. The prostatic selectivity of silodosin (79.4) was much higher than those of tamsulosin (1.78), naftopidil (0.55), BMY 7378 (0.115), and prazosin (0.01). In vivo, intravenously (i.v.) administered silodosin dose-dependently inhibited the HNS-induced increase in IUP with much less hypotensive effect than either tamsulosin or naftopidil, the uroselectivity (ED(15)/ID(50)) of silodosin (237) being significantly higher than those of tamsulosin (1.21) and naftopidil (2.65). CONCLUSIONS: Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.

[Effect of silodosin on intraurethral pressure increase induced by hypogastric nerve stimulation in dogs with benign prostatic hyperplasia].

We compared the urethral and cardiovascular effects of silodosin (selective alpha(1A)-adrenoceptor antagonist), a novel medication for benign prostatic hyperplasia (BPH), with those of tamsulosin (selective alpha(1A)/alpha(1D)-adrenoceptor antagonist) and naftopidil (selective alpha(1D)-adrenoceptor antagonist). We evaluated the effects of these three drugs on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve in anesthetized dogs with spontaneous BPH. All three drugs dose-dependently reduced both the increase in IUP and the mean blood pressure (MBP). The rank order of potencies was tamsulosin>silodosin>naftopidil for the reductions in both IUP and MBP. However, the uroselectivity (ED(15) value for hypotensive effect/ID(50) value for reduction in IUP) of silodosin (uroselectivity, 19.8) was about 21 and 4 times higher than that of tamsulosin (0.939) and naftopidil (4.94), respectively. These data suggest that silodosin might be one of the most useful medications for dysuria in BPH patients.

Effects of mitiglinide and sulfonylureas in isolated canine coronary arteries and perfused rat hearts.

Our aim was to compare the cardiovascular effects of mitiglinide ((+)-monocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate] dehydrate), a novel hypoglycemic drug, with those of glibenclamide and glimepiride, two sulfonylurea drugs. In isolated canine coronary arteries (organ-bath method), mitiglinide, glibenclamide, and glimepiride competitively antagonized the cromakalim-induced relaxation (pA2 values, 5.29, 7.36, and 7.49, respectively). In isolated perfused rat hearts (Langendorff method) subjected to a 12-min global ischemia followed by a 30-min reperfusion, mitiglinide (3 x 10(-6) mol/l) altered neither the change in coronary perfusion flow nor the alterations in cardiac functions associated with reperfusion. In contrast, both glibenclamide (3 x 10(-8) mol/l) and glimepiride (1 x 10(-7) mol/l) significantly reduced coronary perfusion flow after reperfusion. Moreover, at 30 min of reperfusion: (1) glibenclamide induced a significant increase in left ventricular end-diastolic pressure and significant decreases in left ventricular systolic pressure, left ventricular developed pressure, and the maximum first derivative of left ventricular pressure, while (2) glimepiride induced significant decreases in left ventricular developed pressure and the maximum first derivative of left ventricular pressure. Thus, the cardiovascular effects of mitiglinide (at least, in these rat and dog preparations) may be weaker than those of glibenclamide and glimepiride.

The potency of KUL-7211, a selective ureteral relaxant, in isolated canine ureter: comparison with various spasmolytics.

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.

Effects of cholinergic drugs on ureteral function in anesthetized dogs.

PURPOSE: We evaluated the effects of the nonselective muscarinic receptor agonist carbachol (CCh) and its antagonist atropine on ureteral function in anesthetized dogs. MATERIALS AND METHODS: Drug effects were evaluated on elevated pressure in a completely obstructed ureter and peristalsis in its partially obstructed fellow ureters as well as on intravesical isovolumetric pressure. RESULTS: CCh (0.1 to 1.0 microg/kg intravenously) dose dependently decreased elevated pressure and peristalsis in completely and partially obstructed ureters, respectively, and increased intravesical isovolumetric pressure. On the other hand, atropine (0.1 to 1.0 mg/kg intravenously) had no significant effects on these 3 variables. Prior administration of atropine (1.0 mg/kg intravenously) completely inhibited the described CCh induced effects. CONCLUSIONS: Our results demonstrate that in anesthetized dogs cholinergic receptor stimulation has a suppressive effect on ureteral pressure and peristalsis in obstructed ureters, in contrast to its activation of bladder smooth muscle.

Pharmacological characterization of beta-adrenoceptor subtypes mediating relaxation in porcine isolated ureteral smooth muscle.

PURPOSE: We pharmacologically characterized the functional beta-adrenoceptor subtypes mediating porcine ureteral smooth muscle relaxation. MATERIALS AND METHODS: The effects of various beta-adrenoceptor agonists and antagonists on KCl induced tonic contractions in isolated porcine ureteral preparations were evaluated using a functional experimental technique. RESULTS: The rank order of potency for the catecholamines tested was isoprenaline > adrenaline > noradrenaline. All beta2-adrenoceptor agonists tested (salbutamol, procaterol and terbutaline) attenuated the KCl induced contraction. The 2 beta3-adrenoceptor agonists CL-316243 ((R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethylamino]propyl]-1,3-benzodioxole-2,2-dicarboxylate], Kissei, Nagano, Japan) and CGP-12177A ((+/-)[4-[3[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2 H-benzimidazol-2-one hydrochloride], Funakoshi, Tokyo, Japan) also relaxed the ureter. The beta1-adrenoceptor agonist dobutamine had a relaxing effect on the ureter only at high concentrations (over 1 x 10 M). Isoprenaline induced relaxation was antagonized by the beta2-adrenoceptor antagonist ICI-118,551 ((+/-)-1-[(2,3-dihydro-7-methyl-1 H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride, Sigma, St. Louis, Missouri) but not by the beta1-adrenoceptor antagonist CGP 20712A ((+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1 H-imidazol-2-yl]phenoxy]propyl]amino]ethoxy]-benzamide methanesulphonate, Funakoshi). In the presence of 1x 10 M CGP 20712A plus 1 x 10 M ICI-118,551 the beta3-adrenoceptor antagonist SR 58894A (3-(2-allylphenoxy)-1-[(1 S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2 S)-2-propanol hydrochloride, Kissei) antagonized isoprenaline induced relaxation. CONCLUSIONS: Our results suggest that porcine ureteral smooth muscle is relaxed by beta2 and beta3-adrenergic stimulation, as in humans.

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.

Comparison between CL-316243- and CGP-12177A-induced relaxations in isolated canine ureter.

We compared the effects of CL-316243, a selective beta(3)-adrenoceptor agonist, and CGP-12177A, a nonconventional partial beta-adrenoceptor agonist, on the KCl-induced contraction in the isolated canine ureter. CL-316243 concentration dependently relaxed the ureteral contraction, the pD(2) value being 7.75 +/- 0.11. This relaxation was competitively antagonized by the selective beta(3)-adrenoceptor antagonist SR58894A and by the nonselective beta-adrenoceptor antagonist bupranolol, their pA(2) values being 7.08 +/- 0.08 and 6.43 +/- 0.09, respectively. CGP-12177A concentration dependently reduced the KCl-induced contraction, the pD(2) value being 6.30 +/- 0.25. Even at 1 x 10(-5) mol/l, CGP-20712A (a selective beta(1)- adrenoceptor antagonist) did not shift the concentration-response curves for CL-316243 or CGP-12177A. SR58894A did not induce a parallel rightward shift in the concentration-response curve for CGP-12177A, but bupranolol did produce such a shift, pA(2) and slope values in the Schild plot being 7.15 +/- 0.77 and 0.60 +/- 0.15, respectively. Hence, the competition characteristics for SR58894A and bupranolol differed between the CL- 316243-induced and CGP-12177A-induced relaxations. Our results suggest that CGP-12177A produces ureteral relaxation in the dog via an atypical beta-adrenoceptor (possibly, an atypical site/state of the beta(3)-adrenoceptor) as well as via the typical beta(3)-adrenoceptor.

Functional muscarinic cholinoceptors in the isolated canine ureter.

The purpose of present study was to characterize the functional muscarinic cholinoceptor (mAChR) subtypes in the isolated canine ureter. Carbachol (CCh), a non-selective mAChR agonist, concentration-dependently increased the frequency of the rhythmic contractions in isolated spiral ureteral preparations, the pD(2) value being 5.78+/-0.12. We then evaluated the effects of subtype-selective mAChR antagonists on the CCh-induced rhythmic contractions. The rank order of antagonistic potencies (apparent pA(2)) was 4-diphenylacetoxy- N-methylpiperidinemethiodide (4-DAMP; M3-subtype selective; 9.31+/-0.06) >atropine (non-selective; 9.16+/-0.10) >himbacine (M4-subtype selective; 7.32+/-0.18) >pirenzepine (M1-subtype selective; 6.78+/-0.16) >methoctramine (M2-subtype selective; 5.51+/-0.43). In sharp contrast, CCh concentration-dependently reduced the 80 mM KCl-induced contraction in longitudinal ureteral preparations, the pD(2) value being 4.83+/-0.10. On this CCh-induced ureteral relaxation, the rank order of antagonistic potencies (apparent pA(2)) was atropine (8.56+/-0.09) >4-DAMP (7.63+/-0.21) >himbacine (7.46+/-0.09) >methoctramine (6.54+/-0.18) >pirenzepine (6.33+/-0.22). The nitric-oxide-synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG; 1 x 10(-4) M) had no effect on the CCh-induced ureteral relaxation. These data suggest that the CCh-induced rhythmic contraction in the spiral preparation was mediated via the M3-receptor, while the CCh-induced relaxation in the longitudinal preparation was probably mediated mainly via the M4-receptor.