ReviewAntimuscarinics and the Overactive Detrusor—Which Is the Main Mechanism of Action?
Introduction
The two main functions of the bladder, to store urine and to empty, involve a complex pattern of efferent and afferent signaling in autonomic (parasympathetic, sympathetic) and somatic nerves. These nerves are parts of reflex pathways which either maintain the bladder in a relaxed state, enabling urine storage at low intravesical pressure, or which initiate micturition by relaxing the outflow region and contracting the bladder smooth muscle. It is generally accepted that contraction of the detrusor smooth muscle and relaxation of the outflow region result from activation of parasympathetic neurons located in the sacral parasympathetic nucleus (SPN) in the spinal cord at the level of S2–S4 [1], [2]. The post-ganglionic neurons in the pelvic nerve mediate the excitatory input to the human detrusor smooth muscle by releasing acetylcholine (ACh) acting on muscarinic receptors. The pelvic nerve also conveys parasympathetic fibers to the outflow region and the urethra. These fibers mediate relaxation of the outflow region.
Disturbances of the normal control of the bladder reflexes may lead to an “overactive” bladder, clinically characterized by symptoms of urgency, with and without urge incontinence, usually with frequency and nocturia: the overactive bladder (OAB) syndrome [3]. In western Europe, OAB has been estimated to occur in nearly 17% of the population, and the syndrome increases with age [4].
Muscarinic receptors are involved in both normal and disturbed bladder contraction (see below), and the most common drug treatment of OAB is antimuscarinic drugs [5]. Antimuscarinics block, more or less selectively, muscarinic receptors. The common view is that in OAB, the drugs act by blocking the muscarinic receptors on the detrusor muscle, which are stimulated by ACh, released from activated cholinergic (parasympathetic) nerves. Thereby, they decrease the ability of the bladder to contract. However, antimuscarinic drugs act mainly during the storage phase, increasing bladder capacity and decreasing urge, and during this phase, there is normally no activity in parasympathetic nerves [1]. Furthermore, antimuscarinics are usually competitive antagonists. This implies that when there is a massive release of ACh, as during micturition, the effects of the drugs should be decreased, otherwise the reduced ability of the detrusor to contract would eventually lead to urinary retention. Undeniably, high doses of antimuscarinics can produce urinary retention, but in the dose range needed for beneficial effects in OAB, there is little evidence for a significant reduction of the voiding contraction. The question is whether there are other effects of antimuscarinics that can contribute to their beneficial effects in the treatment of OAB.
Muscarinic receptor functions may change in bladder disorders associated with OAB, implying that mechanisms, which normally have little clinical importance, may be upregulated and contribute to the pathophysiology of OAB.
Section snippets
Muscarinic receptors
Muscarinic receptors comprise five subtypes, encoded by five distinct genes [6]. The five gene products correspond to pharmacologically defined receptors, and M1–M5 is used to describe both the molecular and pharmacological subtypes. Muscarinic receptors are coupled to G-proteins, but the signal transduction systems vary [6]. M1, M3, and M5 receptors couple preferentially to Gq/11, activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium. M2 and M4
Conclusions
In OAB, there may be an increased release of ACh during urine storage, both from neuronal and non-neuronal (urothelium) sources. The release can be enhanced by stretch of the detrusor and increases with advancing age, and may contribute to the pathophysiology of OAB. This may explain why antimuscarinics are active during the storage phase.
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