Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: A placebo-controlled, double-blind crossover study

Radley, Stephen; Chapple, Christopher R.; Bryan, Nicolas P.; Clarke, David E.; Craig, D.A.

doi:10.1002/1520-6777(2001)20:1<43::aid-nau6>3.0.co;2-f

Cited by 53 publications

(24 citation statements)

References 20 publications

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“…Thus, as with other indices of autonomic activation such as increased heart rate, manipulations that increase NE tone generally elicit piloerection, whereas those that reduce NE transmission decrease piloerection. Several studies show that methoxamine produces piloerection in humans (Duke et al, 1963;Radley et al, 2001;Tomasi et al, 2005). Consistent with this pattern, it was found in the present studies that direct a1 agonists elicited piloerection.…”

Section: Discussionsupporting

confidence: 92%

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Alsene

Carasso²,

Connors

et al. 2006

Neuropsychopharmacol

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Prepulse inhibition (PPI) refers to the attenuation of startle when a weak prestimulus precedes the startling stimulus. PPI is deficient in several psychiatric illnesses involving poor sensorimotor gating. Previous studies indicate that a1 adrenergic receptors regulate PPI, yet the extent to which these effects are mediated by central vs peripheral receptors is unclear. The present studies compared the effects of intracerebroventricular (ICV) vs intraperitoneal (IP) delivery of several a1 receptor agonists on PPI. Male Sprague-Dawley rats received either cirazoline (0, 10, 25, 50 mg/5 ml), methoxamine (0, 30, 100 mg/5 ml), or phenylephrine (0, 3, 10, 30 mg/5 ml) ICV immediately before testing. Separate groups received either cirazoline (0, 0.25, 0.50, 0.75 mg/kg), methoxamine (0, 2, 5, 10 mg/kg), or phenylephrine (0, 0.1, 2.0 mg/kg) IP 5 min before testing. PPI, baseline startle responses, and piloerection, an index of autonomic arousal, were measured. Cirazoline disrupted PPI; effective ICV doses were approximately six times lower than effective IP doses. Methoxamine disrupted PPI after ICV infusion but failed to affect PPI with IP doses that were up to 30-fold higher than the effective ICV dose. Phenylephrine disrupted PPI with ICV administration, but did not alter PPI after IP injection of even a 20-fold higher dose. None of the ICV treatments altered baseline startle magnitude, but phenylephrine and methoxamine lowered startle after administration of high systemic doses. Piloerection was induced by cirazoline via either route of administration, and by IP methoxamine and phenylephrine, but not by ICV infusion of methoxamine or phenylephrine. These findings indicate that a1 receptor-mediated PPI disruption occurs exclusively through stimulation of central receptors and is dissociable from alterations in baseline startle or autonomic effects.

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Section: Discussionsupporting

confidence: 92%

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Alsene

Carasso²,

Connors

et al. 2006

Neuropsychopharmacol

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“…Thus, a selective a 1A/1L -AR full agonist appears somewhat 'uroselective' compared with a nonselective a 1 -AR full agonist when cardiovascular reflexes are intact. Even so, the magnitude of the haemodynamic effect seen with an a 1A/1L -AR full agonist would seriously limit its utility in treating a condition like SUI, in accordance with the observations of Radley et al [26].…”

Section: Fig 2 Effect Of Intravenous Amidephrine (Red Squares) and supporting

confidence: 69%

“…Marginally selective a 1 -AR agonists (methoxamine [26], midodrine [24,25] Clinically, midodrine has been evaluated for both symptomatic [24] and urodynamic [24,25,37] endpoints, with limited success. The lack of convincing efficacy with midodrine is not surprising given that its main indication is the treatment of symptomatic orthostatic hypotension.…”

Section: Fig 2 Effect Of Intravenous Amidephrine (Red Squares) and mentioning

confidence: 99%

“…Early attempts to treat women with SUI used indirect sympathomimetic agents, including ephedrine [22] and norephedrine (also called phenylpropanolamine [23]). There have also been investigations with the selective a 1 -AR agonists midodrine [24,25] and methoxamine [26]. However, none of these drugs selectively target the a 1A/1L subtype, and all cause side-effects that include dose-dependent elevation of blood pressure (BP), which preclude the use of effective doses [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

“…There have also been investigations with the selective a 1 -AR agonists midodrine [24,25] and methoxamine [26]. However, none of these drugs selectively target the a 1A/1L subtype, and all cause side-effects that include dose-dependent elevation of blood pressure (BP), which preclude the use of effective doses [26][27][28]. Accordingly, a pharmacological strategy was implemented to develop a selective a 1A/1L -AR agonist that could be effective in the treatment of SUI, but with minimal effects on haemodynamic variables.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological characteristics of Ro 115–1240, a selective α_1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

et al. 2003

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relative to noradrenaline were determined in native and cell-based assays using human recombinant a 1 -ARs; they acted as selective a 1A/1L -AR full and partial agonists, respectively. In anaesthetized micropigs and rabbits, amidephrine and Ro 115-1240 produced non-selective, dose-dependent increases in intraurethral and arterial blood pressures but the magnitude of the pressure increases evoked by Ro 115-1240 were about a third of those with amidephrine. In conscious micropigs both agents produced dose-dependent increases in urethral tension. Again, the magnitude of the urethral response to Ro 115-1240 was about a third of that with amidephrine. More importantly, only amidephrine produced dose-dependent increases in blood pressure and decreases in heart rate. Ro 115-1240 produced a maximum increase in urethral tension with no effect on blood pressure or heart rate. CONCLUSIONThese results show that by combining selectivity for the a 1A/1L -AR subtype with a reduction in intrinsic agonist efficacy, Ro 115-1240 has reduced haemodynamic effects while retaining to some degree the contractile effects on urethral smooth muscle. These studies indicate that Ro 115-1240 may be useful as a novel treatment for SUI. KEYWORDSstress urinary incontinence, a -adrenoceptor, urethral smooth muscle, blood pressure OBJECTIVETo describe the preclinical pharmacology of Ro 115-1240, a peripherally acting selective a 1A/1L -adrenoceptor (AR) partial agonist, compared with the a 1A/1L -AR full agonist amidephrine, as AR agonists have some utility in the treatment of stress urinary incontinence (SUI) but are limited by undesirable cardiovascular and central nervous system side-effects. RESULTSIn radioligand-binding studies Ro 115-1240 had greater affinity for a 1A than for a 1B and a 1D subtypes. The potency and intrinsic activity of amidephrine and Ro 115-1240

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Adrenergic drugs for urinary incontinence in adults

Alhasso¹,

Glazener²,

Pickard³

et al. 2003

The Cochrane Database of Systematic Reviews

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Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: A placebo-controlled, double-blind crossover study

Cited by 53 publications

References 20 publications

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Pharmacological characteristics of Ro 115–1240, a selective α_1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Adrenergic drugs for urinary incontinence in adults

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Effect of methoxamine on maximum urethral pressure in women with genuine stress incontinence: A placebo-controlled, double-blind crossover study

Cited by 53 publications

References 20 publications

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Pharmacological characteristics of Ro 115–1240, a selective α1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence

Adrenergic drugs for urinary incontinence in adults

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Product

Resources

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Pharmacological characteristics of Ro 115–1240, a selective α_1A/1L‐adrenoceptor partial agonist: a potential therapy for stress urinary incontinence