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Nausch, Bernhard

Pharmacology

2010

PhD

The urinary bladder serves two functions, storage and elimination of urine. Micturition, the elimination of urine, is initiated by parasympathetic input resulting in the release of the neurotransmitters adenosine triphosphate (ATP) and acetylcholine (ACh). M3 muscarinic ACh receptors (mAChRs) have been established as the main mediator of nerve-induced contractions in urinary bladder smooth muscle (UBSM), but the exact mechanisms engaged by these receptors remain unresolved. Traditionally, inositol-l,4,5-trisphosphate (IP₃)-mediated Ca² release from the sarcoplasmic reticulum (SR) is considered the most important contractile mechanism, but recent evidence suggests otherwise. Ca²⁺ influx through L-type voltage-dependent Ca²⁺ channels (L-VDCCs) has been shown to contribute significantly to UBSM contraction. The mechanisms by which M3 mAChRs increase UBSM excitability to promote Ca²⁺ influx are not known to date. In this dissertation, we describe the primary events, IP3-mediated Ca²⁺ waves, Ca²⁺ flashes and action potentials (APs) evoked by nerve-released ACh. Furthermore, we determined the contribution of each of these primary signals to nerve-evoked UBSM contraction. Our data indicate that mAChRs trigger Ca²⁺ influx through L-VDCCs by increasing excitabilityindependently of IP₃ to contract UBSM.
Storage of urine, 'on the other hand, depends on quiescence of the detrusor and a sustained contraction of urinary sphincters. Large-conductance Ca² - and voltagedependent K⁺ (BK) channels seem to play an important role during the storage phase, because inhibition of BK channels leads to increased spontaneous phasic activity of the detrusor. Moreover, deletion of the gene that encodes BK channel (KCNMAl) gives rise to bladder overactivity. Conversely, injection of cDNA for the BK channel ameliorates overactivity induced by bladder outlet obstruction in rats. Therefore, BK channel openers promise to be effective therapeutics to treat bladder overactivity. Unfortunately, most BK openers developed to date lack specificity. We investigated the effects of the novel and selective BK channel opener NSl1021 on UBSM excitability and spontaneous contractile activity and found that activation of BK channels reduces UBSM excitability, spontaneous electrical (APs) and contractile activity.
The data presented in this dissertation provide valuable information about contractile mechanisms evoked by nerve-released ACh, the main transmitter for micturition, and regulation of bladder activity by BK channels.