Noradrenaline contractions of human prostate mediated by α<sub>1c</sub>‐(α<sub>1c</sub>‐) adrenoceptor subtype

Marshall, Ian; Burt, Richard P.; Chapple, Christopher R.

doi:10.1111/j.1476-5381.1995.tb15001.x

Cited by 151 publications

(121 citation statements)

References 30 publications

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“…5,6 Moreover, the contractile response to norepinephrine is mediated by the a 1A -adrenoceptor. 7 These findings suggest an a 1A -adrenoceptor antagonist specific for the prostate may be achievable. Such a compound may be useful in the treatment of BPH.…”

Section: Introductionmentioning

confidence: 90%

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: Introductionmentioning

confidence: 90%

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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“…Although all three a 1 -adrenoceptor subtypes have been detected in the prostate, the a 1a -adrenoceptor subtype predominates in prostatic stromal tissue (Hiraoka et al, 1999;Walden et al, 1999). This was evidenced at RNA level (Hirasawa et al, 1993;Nasu et al, 1996;Price et al, 1993) as well as at the protein level and in smooth muscle contraction assays (Faure et al, 1994;Lepor et al, 1994;Marshall et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate

Homma

Hamada

Nakayama³

et al. 2000

British J Pharmacology

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1 The prostate function is regulated by androgens and a-adrenergic activity. Clinically, antiandrogens and/or a 1 -adrenergic antagonists are commonly used to treat symptomatic prostatic hypertrophy. To elucidate the eects of androgen deprivation on prostate contractility via a 1 -adrenoceptor, the characteristics and expression of a 1 -adrenoceptors were examined in castrated rats. 2 Isolated prostate strips from intact and castrated rats were subjected to a phenylephrine stimulated contraction. Prazosin (10 nM), [ 3 H]-prazosin and phenoxybenzamine (3 ± 300 nM) were used for inhibition assay, receptor characterization and partial alkylation of a-adrenoceptor, respectively. The mRNA content of three subtypes of a-adrenoceptors was determined by reverse transcription combined with polymerase chain reaction (RT ± PCR). 3 Contractile response to phenylephrine increased in castrated rats, which could be explained by a relative increase of the stromal component. A lowered contraction potency was also noted in castrated rats. Receptor binding assay indicated minimal changes in the anity or density of a 1 -adrenoceptor. Escalating alkylation of the a 1 -adrenoceptor population resulted in a rightward shift in the contraction-response curves before depressing maximal contractile force, and the suppression was detected at lower doses in castrated rats. RT ± PCR study con®rmed the expression of three types of a 1 -adrenoceptor, a 1a , a 1b and a 1d -adrenoceptors, in intact rat prostate, and revealed that a 1a -adrenoceptor, but not a 1b or a 1d -adrenoceptors, was down-regulated in castrates. 4 The results show that androgen deprivation suppressed a 1 -adrenergic contractility of rat prostate strips, and the suppression was associated with down-regulation of receptor reserve for the a 1a -adreneroceptor population expressed in intact rat prostate.

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“…14 Each α-adrenergic subtype is present in the human prostate, bladder neck and proximal urethra but the α 1 subtype is responsible for contraction. 15 These findings have led to the assumption that α-blockers improve voiding symptoms by relaxing prostatic and urethral smooth muscle tone, which decreases outlet resistance, the dynamic component of BPH.…”

Section: Role Of α-Adrenergic Receptors In Voiding Dysfunctionmentioning

confidence: 99%

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

2005

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Purpose-We provide an overview of the medical literature supporting the combined use of muscarinic and α-adrenergic antagonist therapy for the treatment of voiding dysfunction. The MEDLINE database (1966 of the United States National Library of Medicine was searched for pertinent studies. Materials and Methods-Results-Although the mechanism of action of α-adrenergic antagonist therapy for voiding dysfunction has traditionally been assumed to be relaxation of the periurethral, prostatic and bladder neck smooth muscle, substantial evidence supports action at extraprostatic sites involved in micturition, including the bladder dome smooth muscle, peripheral ganglia, spinal cord and brain. Likewise the mechanism of action of anticholinergic therapy has been traditionally assumed to be inhibition of the M 3 muscarinic receptor subtypes that mediate normal bladder contractions. However, M 2 receptor mediates hypertrophied bladder contractions and there is evidence for an M 2 component to the suprasacral control of voiding.Conclusions-Based on the physiology of α-adrenergic and muscarinic receptors the inhibition of each one would be expected to be more beneficial than that of either alone because they would work on 2 components of detrusor function. Patients who would likely benefit from this combination therapy are men with lower urinary tract symptoms, women with urgency/frequency syndrome (overactive bladder), patients with uninhibited bladder contractions due to neurogenic bladder, and patients with pelvic pain and voiding symptoms, ie interstitial cystitis and chronic prostatitis/chronic pelvic pain syndrome. Keywordsbladder; prostate; adrenergic alpha-antagonists; muscarinic antagonists; urination disorders The wide range of patients who might benefit from this type of treatment combination is considered to be large, perhaps several times the estimated 17 million patients in the United States with overactive bladder. 1 A patent application has been filed for the treatment of lower urinary tract (LUT) symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) with this combination. 2

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Noradrenaline contractions of human prostate mediated by α_1c‐(α_1c‐) adrenoceptor subtype

Cited by 151 publications

References 30 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

Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

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Noradrenaline contractions of human prostate mediated by α1c‐(α1c‐) adrenoceptor subtype

Cited by 151 publications

References 30 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

Effects of castration on contraction and α1‐adrenoceptor expression in rat prostate

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

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Noradrenaline contractions of human prostate mediated by α_1c‐(α_1c‐) adrenoceptor subtype

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

Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate