The USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

Jp, Hieble; Rr, Ruffolo

doi:10.1006/phrs.1996.0022

Cited by 69 publications

(37 citation statements)

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“…In particular, ␣ 1 -ARs are crucial for the stimulation of smooth muscle contraction (Bylund et al, 1994). Agonists at the ␣ 1 -ARs may be associated with an alerting or antidepressant action, whereas antagonists are being used and refined for the treatment of benign prostatic hypertrophy (Hieble and Ruffolo, 1996). Peptides with improved selectivity and restricted to peripheral compartments have the potential to treat diseases such as benign prostatic hypertrophy.…”

Section: A -Conopeptide Inhibitors Of ␣1-adrenoceptorsmentioning

confidence: 99%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

393

424

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Section: A -Conopeptide Inhibitors Of ␣1-adrenoceptorsmentioning

confidence: 99%

Conus Venom Peptide Pharmacology

Lewis¹,

Dutertre²,

Vetter³

et al. 2012

Pharmacol Rev

393

424

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“…Clinical trials have demonstrated that long-term administration of doxazosin significantly increases both the maximum and mean rates of urinary flow in men with BPH [1,[13][14][15][16]. The agent is well-tolerated by both normotensive and hypertensive patients [15].…”

Section: Introductionmentioning

confidence: 99%

Influence of the ?1-adrenergic antagonist, doxazosin, on noradrenaline-induced modulation of cytoskeletal proteins in cultured hyperplastic prostatic stromal cells

Smith

Rhodes

et al. 1999

Prostate

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BACKGROUND. Doxazosin, an ␣ 1 -adrenergic antagonist, inhibits sympathetic contraction of prostatic stromal smooth muscle cells and is used in the relief of obstructive benign prostatic hyperplasia (BPH). In vitro application of noradrenaline stimulates expression of cytoskeletal filaments, particularly actin and myosin, by prostatic stromal cells, thus enhancing their differentiation towards smooth muscle cells. This study examined the possible role of doxazosin in reversing this phenotypic modulation as well as in inhibiting smooth muscle cell contraction. METHODS. Stromal cell tissue cultures derived from 10 human hyperplastic prostates were rendered quiescent by reduction of stripped fetal calf serum (FCS) to 1% (v/v) in the medium followed by treatment with 20 M noradrenaline and/or 1 M doxazosin for 10 days. Doxazosin, in 10-fold increments of concentration, was also added, separately, to two of these cell cultures, which were either quiescent or growing in 10% normal (unstripped) FCS. Harvested cells were labelled with fluorescein-labelled antisera to smooth muscle cytoskeletal filaments, and their individual fluorescence levels were analyzed flow-cytometrically. RESULTS. Noradrenaline increased expression of all cytoskeletal filaments studied. This effect was greatest for actin and myosin in proliferating cell cultures. Doxazosin largely reversed the increase in filament expression. This effect was most significant for actin and myosin and greatest in quiescent cultures. However, inhibition of the agonist effect of noradrenaline by doxazosin showed no clear dose-related response, in that expression of cytoskeletal filaments was differentially inhibited. CONCLUSIONS. The data suggest that doxazosin may inhibit not only stromal contraction of differentiated smooth muscle cells in BPH but also the phenotypic modulation of stromal smooth muscle cell differentiation induced by noradrenaline. These actions, together, may render prostatic stroma less contractile, and hence less able to respond to sympathetic stimulation, in patients with BPH. While effects on isolated stromal cells are of undoubted importance, failure to demonstrate a consistent dose-response relationship between expression of smooth muscle cell phenotype and inhibition by doxazosin suggests that additional influences, including humoral factors as well as the proximity of differentiated epithelium, are also Abbreviations: FITC, fluorescein isothiocyanate; BPH, benign prostatic hyperplasia; FCS, fetal calf serum.

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“…1 Clinical studies have demonstrated the efficacy of a 1 -adrenoceptor antagonists such as prazosin and terazosin in relieving bladder outlet obstruction in patients with BPH by reducing the prostatic urethral resistance during micturition. 2 However, these a 1 -adrenoceptor antagonists induce postural hypotension as a sideeffect, due primarily to the decrease in the peripheral resistance caused by blockade of vascular a 1 -adrenoceptors. Consequently, recent efforts have focused on the development of novel a 1 -adrenoceptor antagonists, which demonstrate urethral and prostatic a 1 -adrenoceptor selectively, in order to reduce the risk of cardiovascular side-effects in patients with BPH.…”

Section: Introductionmentioning

confidence: 99%

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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The USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

Cited by 69 publications

References 0 publications

Conus Venom Peptide Pharmacology

Conus Venom Peptide Pharmacology

Influence of the ?1-adrenergic antagonist, doxazosin, on noradrenaline-induced modulation of cytoskeletal proteins in cultured hyperplastic prostatic stromal cells

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

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The USE OFα-ADRENOCEPTOR ANTAGONISTS IN THE PHARMACOLOGICAL MANAGEMENT OF BENIGN PROSTATIC HYPERTROPHY: AN OVERVIEW

Cited by 69 publications

References 0 publications

Conus Venom Peptide Pharmacology

Conus Venom Peptide Pharmacology

Influence of the ?1-adrenergic antagonist, doxazosin, on noradrenaline-induced modulation of cytoskeletal proteins in cultured hyperplastic prostatic stromal cells

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

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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