Effect of KMD-3213, an α1a-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta

Yamagishi, Ryoichi; Akiyama, Katsuyoshi; Nakamura, Shuichi; Hora, Masachiyo; Masuda, Naoyuki; Matsuzawa, Akane; Murata, Satoshi; Ujiie, Arao; Kurashina, Yoshikazu; Iizuka, Kinji; Kitazawa, Masato

doi:10.1016/s0014-2999(96)00589-4

Cited by 57 publications

(30 citation statements)

References 23 publications

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“…2). The rank order of ID 50 for KMD-3213, tamsulosin and prazosin (Table 1) corresponds well to the rank order previously reported for the inhibition of the phenylephrine-induced contraction in the isolated rabbit prostate 9 and norepinephrine-induced contraction in the human prostate. 14 KMD-3213 also exhibited greater uroselectivity than tamsulosin in i.d.…”

Section: Discussionsupporting

confidence: 85%

“…8 Furthermore, KMD-3213 has a higher tissue selectivity for rabbit prostate than for the rabbit and rat aorta. 9 Thus, the present results provide further evidence that a compound such as KMD-3213, which has a higher selectivity for an a 1A -subtype, is useful in the treatment of urinary outlet obstruction in BPH.…”

Section: Discussionsupporting

confidence: 66%

“…8 Moreover, Yamagishi et al reported that KMD-3213 selectively antagonized the a 1 -adrenoceptor in the rabbit prostate with a pA 2 value of 10.0, whereas in rat aorta, the pA 2 value was 8.1. 9 Because contraction of the human prostate is mediated by an a 1A -adrenoceptor subtype which is similar to the rabbit prostate, 10 KMD-3213 may be effective in treatment of urinary outlet obstruction in patients with BPH. Authors have also reported that KMD-3213 potently and selectively inhibited the phenylephrine-induced increase in the urethral pressure response at both intravenous and intraduodenal routes in the in vivo rat model.…”

Section: Introductionmentioning

confidence: 99%

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Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Akiyama

Noto²,

Nishizawa

et al. 2001

Int J of Urology

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Background: KMD-3213 is an a 1A -adrenoceptor-selective antagonist currently being developed for the treatment of urinary outlet obstruction in patients with benign prostatic hyperplasia. In the present study, the uroselectivity of KMD-3213 was evaluated and compared with that of prazosin and tamsulosin in a decerebrate dog model. Methods: Intercollicular decerebration was carried out in male mongrel dogs under anesthesia. The inhibitory effects of intravenously and intraduodenally administered compounds on the increase in intraurethral pressure (IUP) induced by electrical stimulation of the hypogastric nerve were estimated. Systemic blood pressure was measured simultaneously. Results:The a 1 -antagonists tested produced a dose-dependent inhibition of the induced IUP response and decreased mean blood pressure (MBP). The ID 50 of KMD-3213, tamsulosin and prazosin for IUP (dose required to inhibit the increase in IUP by 50%) was 3.15, 1.73 and 11.8 mg/kg i.v., respectively, and the ED 20 for the hypotensive effect (dose required to reduce MBP by 20%) was 8.03, 0.59 and 2.46 mg/kg i.v., respectively. The data indicate that uroselectivity (ED 20 /ID 50 ) of KMD-3213 is 12-and 7.5-fold higher than that of prazosin and tamsulosin, respectively. When the drugs were administered intraduodenally, KMD-3213 was sufficiently absorbed from the digestive tract and continued to demonstrate at least 3.8-fold higher uroselectivity than tamsulosin. Conclusion: Based on these findings, KMD-3213 appears to be an effective orally active compound for decreasing urethral resistance during micturition that does not induce any negative cardiovascular effects in patients with benign prostatic hyperplasia.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

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Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Akiyama

Noto²,

Nishizawa

et al. 2001

Int J of Urology

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“…Prazosin is a classical antagonist which shows no subtype selectivity (Muramatsu et al, 1995;Hancock, 1996). BMY 7378 and KMD-3213 are well characterized as highly selective antagonists for alpha-1D and alpha-1A AR subtypes, respectively (Goetz et al, 1995;Shibata et al, 1995;Saussy et al, 1996;Yamagishi et al, 1996;Murata et al, 1999). Furthermore, several agonists including phenylephrine show relatively high affinity for the alpha-1D subtype (Lomasney et al, 1991;Buckner et al, 1996;Graham et al, 1996;Piascik & Perez, 2001).…”

Section: Introductionmentioning

confidence: 99%

Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery

Taki

Tanaka

Zhang

et al. 2004

British J Pharmacology

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1 We examined reserpine-induced chemical denervation supersensitivity with special reference to alpha-1 adrenoceptor (AR) subtypes. 2 Chronic treatment with reserpine for 2 weeks depleted noradrenaline in the tail artery and spleen of rats. Noradrenaline in the thoracic aorta was negligible before and after reserpine treatment. 3 The treatment with reserpine produced supersensitivity in the contractile responses of the rat tail artery to phenylephrine, 5-HT and KCl, resulting in leftward shift of concentration-response curves (11.6-, 2.5-and 1.1-fold at EC 50 value, respectively). These results suggest a predominant sensitization of the alpha-1 AR-mediated response by reserpine treatment. 4 BMY 7378 at a concentration (30 nM) specific for blocking the alpha-1D AR subtype, but not KMD-3213 at a concentration (10 nM) selective for blocking the alpha-1A AR subtype, inhibited the supersensitivity of the phenylephrine-induced response in the reserpine-treated artery. On the other hand, the response to phenylephrine in reserpine-untreated artery was selectively inhibited by the same concentration of KMD-3213, but not by BMY 7378. Prazosin, a subtype-nonselective antagonist, blocked the responses to phenylephrine with the same potency, regardless of reserpine treatment. 5 In the thoracic aorta and spleen, no supersensitivity was produced in the responses to phenylephrine by reserpine treatment. 6 In a tissue segment-binding study using [ 3 H]-prazosin, the total density and affinity of alpha-1 ARs in the rat tail artery were not changed by treatment with reserpine. However, alpha-1D AR with high affinity for BMY 7378 was significantly detected in reserpine-treated tail artery, in contrast to untreated artery. Decreases in alpha-1A AR with high affinity for KMD-3213 and alpha-1B AR with low affinities for KMD-3213 and BMY 7378 were also estimated in reserpine-treated tail artery. 7 Alpha-1D AR mRNA in rat tail artery increased to three-folds by reserpine treatment, whereas the levels of alpha-1A and 1B mRNAs were not significantly changed. 8 The present results suggest that chronic treatment with reserpine affects the expression of alpha-1 AR subtypes of rat tail artery and that the induction of alpha-1D ARs with high affinity for catecholamines is in part associated with reserpine-induced supersensitivity.

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“…6,7 Moreover, silodosin has been shown to be highly selective for prostatic versus vascular tissue. [8][9][10] Consistent with this observation, results from phase III clinical studies suggest that silodosin carries minimal risk for orthostatic hypotension and overall has excellent cardiovascular tolerability. 11,12 Combined efficacy results from the phase III clinical studies showed that silodosin can promote rapid and significant improvement in BPH-associated urinary symptoms and peak urinary flow rate and can substantially improve LUTS-related quality of life.…”

Section: Dovepressmentioning

confidence: 78%

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies

Gittelman¹,

Marks²,

Hill³

et al. 2010

RRU

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Purpose: Pooled results from 2 randomized, placebo-controlled, US phase III studies (NCT00224107, NCT00224120) showed that silodosin, a uroselective α-blocker, significantly improved International Prostate Symptom Scores (IPSS) in men with symptomatic benign prostatic hyperplasia (BPH). This analysis evaluated the effect of silodosin on each symptom assessed by IPSS questionnaire. Materials and methods: Study participants (N = 923) were men aged $50 years with IPSS $13 and Qmax 4-15 mL/s. They received silodosin 8 mg or placebo once daily for 12 weeks. Patient responses to 7 IPSS questions were collected at weeks 0 (baseline), 0.5, 1, 2, 4, and 12 and scored on a 6-point scale. Efficacy of silodosin versus placebo was assessed by analysis of covariance. Results: For each symptom, the 2 treatment groups had similar mean baseline scores. Decrease in score from baseline (mean ± standard deviation) to last observation was significantly greater with silodosin than with placebo for all symptoms (P , 0.005); symptom improvement with silodosin (versus placebo) was greatest for weak stream (silodosin, −1.1 ± 1.4 versus placebo, −0.5 ± 1.2; P , 0.0001) and smallest for nocturia (silodosin, −0.6 ± 1.1 versus placebo, −0.4 ± 1.2; P = 0.0037). Compared with placebo, silodosin significantly improved nocturia within 1 week (silodosin, −0.5 ± 1.07 versus placebo, −0.3 ± 1.05; P = 0.009) and all other symptoms within 3 to 4 days (P , 0.01). Conclusions: Silodosin significantly improved all BPH-associated symptoms assessed by IPSS questionnaire within the first week of treatment. All improvements were maintained over the 12-week study period.

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Effect of KMD-3213, an α1a-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta

Cited by 57 publications

References 23 publications

Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies

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Effect of KMD-3213, an α1a-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta

Cited by 57 publications

References 23 publications

Effect of KMD‐3213, an α1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Effect of KMD‐3213, an α1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery

Effect of silodosin on specific urinary symptoms associated with benign prostatic hyperplasia: analysis of international prostate symptom scores in 2 phase III clinical studies

Contact Info

Product

Resources

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Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs

Effect of KMD‐3213, an α_1A‐adrenoceptor antagonist, on the prostatic urethral pressure and blood pressure in male decerebrate dogs