&amp;alpha;&lt;sub&gt;1&lt;/sub&gt;-Adrenoceptor Selectivity: The North American Experience

Wyllie, Michael G.

doi:10.1159/000052320

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…It is known that tamuslosin is not a fully surmountable ( α 1A‐adrenoceptor antagonist in the human vas deferens (Furukawa et al , 1995; Noble et al , 1997). Furthermore, previous studies showed that tamuslosin may have an effect on subtypes of 5‐hydroxytryptamine and dopamine receptors (Wyllie, 1999; van Dijk et al , 2006). Hence, the effects on ejaculation may be caused by alterations in the central nervous system rather than peripheral tissues (van Dijk et al , 2006).…”

Section: Discussionmentioning

confidence: 99%

α₁‐Adrenoceptors are required for normal male sexual function

Sanbe

Tanaka

Fujiwara

et al. 2007

British J Pharmacology

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Background and purpose: a 1 -Adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for a 1A -adrenoceptors compared with other drugs of this class. This suggests that a 1A -adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. Experimental approach: The physiological contribution of each a 1 -adrenoceptor subtype was characterized using a 1 -adrenoceptor subtype-selective knockout (KO) mice (a 1A -, a 1B -and a 1D -AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of a 1 -adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in a 1 -adrenoceptor subtype-selective KO mice and in mice with all their a 1 -adrenoceptor subtypes deleted (a 1 -AR triple-KO mice). Key results: The pregnancy rate was reduced by 50% in a 1A -adrenoceptor KO mice, and this reduction was dramatically enhanced in a 1 -adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in a 1A -adrenoceptor KO mice, and this contraction was completely abolished in a 1 -adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. Conclusions and implications:These results demonstrate that a 1 -adrenoceptors, particularly a 1A -adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility.

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Section: Discussionmentioning

confidence: 99%

α₁‐Adrenoceptors are required for normal male sexual function

Sanbe

Tanaka

Fujiwara

et al. 2007

British J Pharmacology

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“…These observations support the hypothesis that cardiovascular side effects are primarily associated with blockade of ␣ 1b -adrenoceptors, whereas improvement of BPH symptoms is primarily associated with blockade of ␣ 1a -, and perhaps ␣ 1d -adrenoceptors (Testa et al, 1994;Take et al, 1998). It is difficult to say whether the reduced cardiovascular side effects for tamsulosin can be attributed to factors other than subtype selectivity, such as reduced peak to trough plasma concentrations (through modified release formulation) or dosing at submaximal efficacy (Wyllie, 1999). Indeed, the relative contribution of specific subtypes to efficacy and safety remains unclear (Hieble and Ruffolo, 1997;de May, 1999;Lowe, 1999).…”

Section: Discussionmentioning

confidence: 99%

Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α₁-Adrenoceptor Antagonists

Witte¹,

Brune²,

Katwala³

et al. 2002

J Pharmacol Exp Ther

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Fiduxosin is a new ␣ 1 -adrenoceptor antagonist targeted for the treatment of symptomatic benign prostatic hyperplasia. The purpose of this study was to determine and compare the potencies of the ␣ 1 -adrenoceptor antagonists terazosin, doxazosin, tamsulosin, and fiduxosin, based on relationships between plasma drug concentrations and blockade of phenylephrine (PE)-induced intraurethral (IUP) and mean arterial pressure (MAP) responses after single oral dosing in conscious male beagle dogs. Magnitude of blockade and plasma concentrations were evaluated at selected time points over 24 h. All drugs produced dose-dependent antagonism of PE-induced IUP and MAP responses. When IUP and MAP blockade effects were plotted against drug plasma concentrations, direct relationships were observed that were well described by the sigmoidal maximal effect model. IUP IC 50 values for terazosin, doxazosin, tamsulosin, and fiduxosin were 48.6, 48.7, 0.42, and 261 ng/ml, respectively. MAP IC 50 values were 12.2, 13.8, 1.07, and 1904 ng/ml, respectively. Uroselectivity index values, defined as MAP IC 50 /IUP IC 50 , were 0.25, 0.28, 2.6, and 7.3, respectively. These results extend previous observations with terazosin in this model, showing that doxazosin exhibits a uroselectivity index comparable to terazosin, consistent with the lack of ␣ 1 -adrenoceptor subtype selectivity or uroselectivity of these drugs. Tamsulosin, an ␣ 1a -/␣ 1d -subtype selective agent, had an index value approximately 10-fold greater than the nonselective drugs. Based on its pharmacokinetic profile and a relative uroselectivity 29-fold greater than the nonselective drugs, fiduxosin is expected to exhibit greater selectivity for urethral compared with vascular ␣ 1 -adrenoceptors in human and should be a novel, long-acting, uroselective ␣ 1 -adrenoceptor antagonist.␣ 1 -Adrenoceptor antagonists represent first-line therapy for the pharmacological treatment of benign prostatic hyperplasia (BPH), in part by relaxing prostatic smooth muscle (Lowe, 1999). Fiduxosin (ABT-980) is a novel ␣ 1 -adrenoceptor antagonist. Compared with other clinical agents, such as terazosin, doxazosin, and tamsulosin, fiduxosin exhibits a somewhat different ␣ 1 -adrenoceptor subtype selectivity profile. Radioligand binding potencies at human ␣ 1a -, ␣ 1b -, and ␣ 1d -adrenoceptors are reported to be 1.81, 1.16, and 0.67 nM for terazosin; 0.79, 0.80, and 0.81 nM for doxazosin; 0.03, 0.60, and 0.06 nM for tamsulosin; and 0.16, 24.89, and 0.92 nM for fiduxosin, respectively (Hancock et al., 1998b(Hancock et al., , 2002, showing fiduxosin to be selective for ␣ 1a -and ␣ 1d -adrenoceptors compared with ␣ 1b -adrenoceptors to a greater extent than tamsulosin.Accumulating data suggest that extraprostatic ␣ 1 -adrenoceptors in bladder, spinal cord, ganglia, or nerve terminals may also contribute to ameliorating the irritative and voiding symptoms of BPH (Fitzpatrick, 2000;Schwinn and Michelotti, 2000). Three subtypes of ␣ 1 -adrenoceptors are known to exist, ␣ 1A -, ␣ 1B -, and ␣ 1D -adr...

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“…This neurotransmitter also acts at presynaptic α 2 ‐adrenoceptors on the ends of nerve terminals to reduce noradrenaline release. It is unlikely that the α‐blockers used for LUTS would affect presynaptic α 2 ‐adrenoceptors given their selectivity profile [18–20]. There are few reports detailing the effect of α‐adrenoceptor antagonist use and improvements in ED.…”

Section: α‐Adrenoceptor Antagonism and Erectile Functionmentioning

confidence: 99%

Beneficial effects of extended‐release doxazosin and doxazosin standard on sexual health

et al. 2006

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The prevalence of benign prostatic hypertrophy (BPH) and erectile dysfunction (ED) both increase with age, and increasing evidence suggests a common cause rather than independent age‐related changes. Arterial hypertension often accompanies these urological disorders, suggesting the possibility that increased α‐adrenoceptor activity may be causal in all three conditions. As evidence for this model, α‐adrenoceptor antagonists such as doxazosin produce therapeutically beneficial effects in lowering blood pressure, reducing prostate growth and BPH symptoms, and relieving ED. At postjunctional α1‐receptors in the corpus cavernosa, noradrenaline causes vascular smooth muscle cell contraction, restricting blood flow, resulting in penile detumescence. Just as α‐adrenoceptor antagonism results in systemic vasorelaxation to lower blood pressure, the same mechanism in the penis modulates the effects of noradrenaline to favour vasodilatation, resulting in improved erectile function. Increasing clinical evidence attests to the effectiveness of doxazosin in relieving ED, even in patients refractory to ED‐specific treatment, as well as in reducing BPH symptoms and elevated blood pressure.

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α<sub>1</sub>-Adrenoceptor Selectivity: The North American Experience

Cited by 7 publications

References 19 publications

α₁‐Adrenoceptors are required for normal male sexual function

α₁‐Adrenoceptors are required for normal male sexual function

Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α₁-Adrenoceptor Antagonists

Beneficial effects of extended‐release doxazosin and doxazosin standard on sexual health

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&alpha;<sub>1</sub>-Adrenoceptor Selectivity: The North American Experience

Cited by 7 publications

References 19 publications

α1‐Adrenoceptors are required for normal male sexual function

α1‐Adrenoceptors are required for normal male sexual function

Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α1-Adrenoceptor Antagonists

Beneficial effects of extended‐release doxazosin and doxazosin standard on sexual health

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About

α<sub>1</sub>-Adrenoceptor Selectivity: The North American Experience

α₁‐Adrenoceptors are required for normal male sexual function

α₁‐Adrenoceptors are required for normal male sexual function

Modeling of Relationships between Pharmacokinetics and Blockade of Agonist-Induced Elevation of Intraurethral Pressure and Mean Arterial Pressure in Conscious Dogs Treated with α₁-Adrenoceptor Antagonists