Clinical and experimental aspects of Adreno‐muscarinic synergy in the bladder base and prostate

Abstract

Recent clinical trials have shown that combination therapy using an alpha-receptor antagonist and an antimuscarinic is more effective than either agent alone in improving quality of life and objective urodynamic variables in men with bladder outflow obstruction. There appear to be no negative effects on bladder function. The mode of action of this combination is unknown but presumed to be an antimuscarinic reduction in detrusor overactivity and the alpha-receptor antagonist reduced outflow tract resistance. We have shown with in vitro experiments that in smooth muscles influencing outflow tract resistance (prostate, trigone) there is a profound contractile synergy between adrenergic and muscarinic pathways. We propose the hypothesis that both arms of the combination therapy reduce contractile tone of the outflow tract and that their simultaneous attenuation has a disproportionately large effect on outflow tract resistance. Our data from trigone muscle suggest that adrenergic and muscarinic receptor activation increase the intracellular [Ca(2+)] but the adrenergic pathway also operates through Ca(2+)-sensitisation of the contractile apparatus, primarily through a PKC-dependent pathway.

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M3 Muscarinic Receptors

“…However, another study has observed an adreno-muscarinic synergy in contraction of the human prostate (Roosen et al, 2009). Although the M 3 muscarinic receptor subtype has not been demonstrated in the human prostate, recent reviews of clinical trials using muscarinic receptor antagonists (which included the M 3 muscarinic receptor antagonists solifenacin and darifenacin) for the treatment of lower urinary tract symptoms, usually in combination with an adrenoceptor antagonist, show varying improvement in storage symptoms without worsening of voiding symptoms or significant development of acute urinary retention (Athanasopoulos, 2010;Chapple, 2010).…”

The Residual Nonadrenergic Contractile Response to Nerve Stimulation of the Mouse Prostate Is Mediated by Acetylcholine but Not ATP in a Comparison with the Mouse Vas Deferens

“…Acetylcholine is reported to potentiate the adrenergic component of nervemediated prostatic contraction in the guinea pig (Lau et al, , 2000, while inhibiting noradrenaline-mediated contraction in the prostates of dogs (Arver and Sjöstrand, 1982). Acetylcholine has also been shown to enhance noradrenalinemediated contraction in the human prostate (Roosen et al, 2009), indicating a possible synergism. It has been shown that there are functional muscarinic receptors mediating contraction in vasa deferentia taken from the mouse (Cuprian et al, 2005) and guinea pig (Solanki et al, 2007), and we also observed that atropine attenuated contraction in vasa deferentia taken from wild-type mice.…”

“…Nevertheless, a recent review of clinical trial data indicated that anticholinergics are a safe treatment option for the lower urinary tract symptoms associated with BPH and patients may benefit from a combination therapy of ␣ 1 -adrenoceptor and muscarinic receptor antagonists (Gallegos and Frazee, 2008). Although Gallegos and Frazee (2008) suggested that the mechanism of action was localized in the bladder, evidence of cholinergically mediated contraction of the prostatic smooth muscle suggests that the mechanism of action of solifenacin for relief of the lower urinary tract symptoms associated with BPH may be achieved by relaxing prostatic smooth muscle as suggested by Roosen et al (2009). This prostatic relaxation would alleviate the urethral blockade caused by the hyperplastic prostate allowing for an easier flow of urine.…”

Effect of Suo Quan Wan on the bladder function of aging rats based on the β-adrenoceptor

“…Therefore, bladder dysfunction is primarily associated with the change in β-AR (33). A number of clinical and experimental studies have demonstrated that β 3 -AR serves an important role in this process (34). This conclusion was also proven according to the result of qPCR, which revealed higher expression of β 3 -AR compared with β 1 -AR and β 2 -AR (β1:β2:β3≈1:1:70) found in the bladder detrusor (35,36).…”