Urinary Bladder: Pharmacology of Detrusor Receptors
Mechanisms of Smooth Muscle Detrusor Contraction
The interaction of actin and myosin is an ATP-dependent process. The myosin heads split ATP, this leads to a bending motion. The activation of myosin ATPase is controlled by the myosin light chain kinase, which is triggered by the intracellular increase of calcium. Membrane depolarization of smooth muscle cells causes an intracellular calcium increase. The membrane depolarization is triggered by the activation of muscarinic M3 acetylcholine receptors, which use as second messengers IP3, Ca2+ and DAG.
In comparison to skeletal muscle contraction, the contraction of smooth muscle cells is slow, leads to larger shortening of the muscle cell and is energy efficient and untiring. The poor electrical connection of the smooth muscle in the bladder wall prevents tetanic contractions and allows a good storage capacity of the bladder; in contrast to e.g. intestinal muscle cells. For a common contraction of all muscle cells of the detrusor muscle (micturition), the release of acetylcholine from parasympathetic nerves is necessary.
Molecular pharmacology of the bladder
Cholinergic Receptors of the Urinary Bladder
Five muscarinic receptor subtypes (M1 to M5) have been identified so far. The bladder has mainly M1, M2 (80%) and M3 (20%) cholinergic receptor types, but only M3 cholinergic receptors are responsible for the parasympathetic detrusor contraction. M3 receptors of the bladder are found mainly in smooth muscles and glands. Stimulation of M3 receptors with acetylcholine causes the release of IP3 and calcium, which leads to smooth muscle contraction (see above).
The extensive distribution of muscarinic receptors in the body explains a broad spectrum of adverse effects from anticholinergic medication (dry mouth, loss of accommodation, dizziness, headache, ileus,...). The development of specific M3 receptor antagonists does not help to improve the rate of adverse effects, as these receptors are also found in other organs. Actual goal is the development of tissue-specific (bladder specific) substances. At present, mainly tolterodine, oxybutynin, propiverine and trospium are used for the treatment of bladder instability.
Adrenergic Receptors of the Urinary Bladder
Adrenergic receptors of the sympathetic nervous system are classified into α1, α2, β1, β2 and β3-receptors.
The stimulation of β-receptors leads to the activation of adenylyl cyclase, to the release of cyclic AMP (cAMP) and to the inhibition of the detrusor muscle. Unspecific stimulation of β-receptors are not an option for inhibition of detrusor overactivitity due to cardiovascular side effects. However, β3-receptors are not responsible for cardiovascular effects and are also present in the bladder wall. Newly developed β3-agonists (Mirabegron, Solabegron) have shown efficiency in the treatment of overactive bladder and are well tolerated (Chapple, 2012). There are also efforts to identify a specific phosphodiesterase inhibitor for the bladder.
α-Receptors are located in the trigonum and in the urethra. α1-Receptors are common in men, α2-receptors are common in women. α-Receptors are rare in the detrusor muscle.
&apha;1-Receptors are classified into three subtypes (A, B and D), in the urinary bladder and urethra α1A-receptors prevail. The adrenergic stimulation of α1A-receptors leads to an increase of bladder closure. The inhibition of α1A-receptors leads to a reduction of bladder closure; adrenergic substances increase the bladder neck closure and are used to treat urinary incontinence.
Purinergic Receptors of the Urinary Bladder
The involvement of the neurotransmitter ATP in the control of the bladder is largely unclear. However, ATP plays a role in the unstable bladder and in the bladder afferent innervation.
Nitric Oxide (NO)
NO is one of the main transmitter for urethral smooth muscle relaxation during micturition. Nitric oxide is released from parasympathetic nerves.
Vanilloid Receptors of the Urinary Bladder
Vanilloid receptors are pain receptor fibers. In the bladder, the inactivation of vanilloid receptors by repeated doses of capsaicin or resiniferatoxin is used for the treatment of unstable bladder.
Many neuropeptides have been detected in the urinary bladder: Substance P, neurokinin A and B, calcitonin gene-related peptide (CGRP),... These substances are mainly found in capsaicin-sensitive afferent nerve fibers. After stimulation, these neurotransmitters are also the cause of the neurogenic inflammation that accompanies painful stimuli (plasma extravasation, vasodilation and increased smooth muscle activity).
PGF2α, PGE and PGE2 lead to detrusor contraction.
Index: 1–9 A B C D E F G H I J K L M N O P Q R S T U V W X Y Z
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Benninghoff 1993 BENNINGHOFF, A.:
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München; Wien; Baltimore : Urban und Schwarzenberg, 1993.
- Chapple, C. R.
- β3-Agonist Therapy: A New Advance in
the Management of Overactive Bladder?
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