Muscarinic receptors in the lower urinary tract

This thesis, comprising of clinical studies, basic research as well as review of data, has aimed to provide further insight into the role and function of muscarinic receptors in the lower urinary tract. In light of increasing evidence of beneficial effects of combinations of pharmacological therapies for lower urinary tract symptoms (LUTS), understanding mechanisms of action and interaction are crucial to maximize its therapeutic potency. The first part of this thesis focusses on the prostate, the second part on interaction of muscarinic and adrenergic signaling and the last part focusing on muscarinic antagonists in clinical practice. As muscarinic receptors are abundantly present in the prostate, and antimuscarinic therapy is increasingly used in male patients with LUTS, direct effects of antimuscarinics on the prostate need to be considered. Thereby we demonstrate that muscarinic receptors cause direct contraction and inhibition of relaxation in the bladder, but the two responses involve different subtypes and, at least for M3 receptors, different signaling pathways. The α1-adrenoceptor antagonist effects of muscarinic antagonist propiverine are explored and demonstrated, although these effects need to be confirmed in patients. In the third part we demonstrate that solifenacin, and perhaps other muscarinic receptor antagonists are similarly suitable for the treatment of OAB symptoms in both genders, irrespective of previous vaginal deliveries. Finally an overview is presented of antimuscarinics at risk for reduced tolerability in special patient populations, e.g. in those with impaired renal or liver function or those with comedications or genetic heterogeneity in drug metabolizing enzymes