Melinda Wüst, PhD

Investigation of different receptor-mediated pathways for the contraction of the detrusor muscle

Previous and current research
Many of the antimuscarinic drugs currently on the market for the therapy of overactive bladder (OAB) have side effects that limit their clinical usefulness. Development of new agents for treatment of OAB requires a sound understanding of physiological detrusor contractile function as well as reliable in vitro and in vivo models. We study detrusor contraction properties induced by different mechanisms: (i) direct stimulation muscarinic receptor-mediated detrusor contraction using the muscarinic receptor agonists acetylcholine or its analogue carbachol, (ii) electric field stimulation of intrinsic excitatory nerves leading to the release of different neurotransmitters and (iii) direct application of KCl leading to depolarization of the smooth muscle cells followed by a calcium-influx mostly via L-type calcium channels. Calcium currents are measured with the voltage clamp technique. Expression of mRNA for various receptor subtypes is determined semi-quantitatively and quantitatively by RT-PCR. Changes in cytosolic intracellular calcium concentration [Ca²⁺]_i can be detected by measuring the fluorescence with Fura-2. Comparison of detrusor function in mouse, pig and man allows insight into basic differences in contractile mechanisms. Drugs of interest are antimuscarinic compounds, potassium channel openers and various neurotransmitters.

Future projects and goals
For the development of new therapeutical targets for OAB it is important to understand the physiological detrusor function underlying contraction and relaxation processes. Based on the main muscarinic receptor mediated pathway we have also started to expand our investigations on the influence of other neurotransmitters like adenosine, ATP and noradrenaline on detrusor contraction and relaxation function using our different electrophysiological and molecular experimental approaches.