Clinical and experimental aspects of Adreno-muscarinic synergy in the bladder base and prostate.
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.
Roosen
Alexander
A
Institute of Urology, University College London, London, UK.
Blake-James
Ben T
BT
Wood
Daniel
D
Fry
Christopher H
CH
D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage*; D000818:Animals; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D011467:Prostate / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy*
D000317:Adrenergic alpha-Antagonists; D018727:Muscarinic Antagonists