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Bladder Pharmacology Campbell-Walsh Ch. 56: 1948-1972 Stephen Miller, DO Peripheral Pharmacology Muscarinic 4 different receptor subtypes based on Pharmacology (M1-M5) Human Bladder – M1 – M2 (Predominate) – M3: Mediate cholinergic contractions Key roles in: – Salivary secretion – Pupillary constriction – Digestive tract M3R Action Acetylcholine M3R IP3 hydrolysis (PLC) Intracellular Ca2+ Release = Smooth Muscle Contraction L- type Ca2+ channels have also been indicated in M3R mediated detrusor contractions M2R Coactivation could enhance response to M3: 1. Inhibition of adenylate cyclase = suppressing sympathetic mediated depression of detrusor 2. Inactivation of K+ channels 3. Activation of nonspecific cation channels Prejunctional Muscarinic Receptors M1R facilitate Acetylcholine release M2-M4R inhibit release Purinergic Mechanisms Parasympathetic stimulation ATP acts on 2 Receptors – P2X (ion channel) with 7 subtypes – P2Y (G-Protein coupled receptor) with eight subtypes May play a role in Pathological conditions – – – – Unstable bladders BOO Increased amount of P2X1R in obstructed bladders P2X3R in small diameter afferent neurons of the DRG are also found in the wall of bladder and ureter Mechanosensory and Nociceptive signaling Adrenergic Mechanisms Isoproterenol, Terbutiline β- Adrenergic – β 2 and β 3 Receptors results in direct relaxation of detrusor smooth muscle – 3 main receptor Mediated through stimulation of Adenylate cyclase and accumulation of cyclic AMP PDE inhibitors? – Selective inhibition of bladder PDE Increase cAMP Relax detrusor and/or enhance the sensitivity/efficacy of adrenergic agonists – Bladder Isoform of PDE? -Adrenergic Ephedrine, Phenylpropanolamine, Midodrine, Psuedoephedrine Bladder: (Not prominate in nml bladder) – -adrenergic density is increased in pathological conditions – NE induced responses convert from relaxation to contraction – 1dR subtype Urethra: Promote urine storage by increasing Urethral resistance – Hypogastic nerve stimulation and -adrenergic agonists produce a rise in intraurethral pressure – blocked by 1- adrenergic antagonists – 1a major subtype in Urethra/Prostate Nitric Oxide Major inhibitory transmitter mediating relaxation of the urethral smooth muscle during micturation Involved in controlling bladder afferent nerve activity Increase production of intracellular cGMP = Smooth muscle relaxation – Inactivated by PDE’s – Role for PDE-inhibitors? Afferent Neuropeptides Substance P Neurokinin A Calcitonin gene- related peptide (CGRP) Vasoactive Intestinal polypeptide (VIP) Pituitary adenylate cyclase-activating peptide (PACAP) Enkephalins Contained in capsaicin-sensitive, C-Fiber bladder afferents – Released in bladder by noxious stimulation – Inflammatory response plasma extrav., vasodilation, and alter bladder smooth muscle activity – transmitters at afferent terminals of the spinal cord Receptors of Tachykinins – NK1R blood vessels to induce plasma extrav. – NK2R bladder contractions – NK2R increase excitability during bladder filling or inflammation Prostanoids Prostaglandins, Thromboxane Manufactured throughout the lower urinary tract Bladder Mucosa Contains: – PGI2, PGE2, PGE2a, Thromboxane A – PGF2, PGE, PGE2 = Contraction Mediated by specific receptors on cell membranes – DP, EP, FP, IP, and TP Slow onset of action – Modulatory role – Affect neural release of transmitters or inhibit acetylcholinesterase activity Endothelins 21 amino acid peptides produced in endothelial cells ET-1 (ET-2, ET-3) – Control of bladder smooth muscle tone – Regulation of local blood flow – Bladder wall remodeling in pathological conditions involved in detrusor hyperplasia and overactivity seen in pts with BOO resulting from BPH Receptors: ETA , ETB Also have a role in nociceptive mech. in peripheral and Central Nervous System – Peripheral = induce detrusor activity – Spinal Cord = inhibit micturition through Opioid’s Parathyroid Hormone Related Peptide Manufactured by bladder smooth muscle Detrusor relaxation Sex Steroids Do not directly affect bladder contractility, but modulate receptors and influence growth of bladder tissues Estrogen: Effect on urinary continence in females probably reflects multiple actions on adrenergic receptors, vasculature, and urethral morphology – Increasing adrenergic receptors – NOS Progesterone: increases electrical and cholinergic contractions of bladder Transducer function of Urothelium Urothelial cells display properties of nociceptors and mechanoreceptors – Release NO, ATP, Acetylcholine, Substance P, Prostaglandins local chemical/mechanical stimuli chemical signals to bladder afferents CNS Serotonin (5-HT) Neuroendocrine cells along urethra and prostate Contraction in concentration dependent manner C-Fiber Pharmacotherapy Unmyelinated C-fibers are normally silent – Activated by noxious stimuli – Irritated state they become responsive to low pressure bladder distention Capsaicin and Resiniferatoxin (RTX) – Vanilloids that stimulate and desensitize C fibers to produce pain and release neuropeptides TRPV1 (transient receptor potential) Spinal cord, DRG, bladder, Urethra, Colon Activated calcium/Na influx afferent terminals CNS Capsaicin selectively excites and subsequently desensitizes C-fibers RTX causes desensitization without prior excitation Normal Conditions Pathologic Conditions Botulinum Toxin Inhibit acetylcholine release at the presynaptic cholinergic nerve terminal = Inhibiting striated and smooth muscle contractions Also shown to inhibit afferent nerve activity 4 steps required for Paralysis 1. 2. 3. 4. Toxin heavy chain Nerve terminal receptor(?) Internalization of toxin into nerve terminal Translocation of light chain into the cytosol Inhibition of neurotransmitter release Spinal cord injury suffering from detrusor-external sphincter dyssynergia and detrusor overactivity Pelvic floor spasticity BPH Urological uses (BTX-A) Actions of Drugs on Smooth Muscle Calcium Channel Blockers Potassium Channel Openers TCA Calcium Channel Blockers Diltiazem, Verapamil Less effective in suppressing nerve-mediated contractions Spontaneous and evoked contractile properties are mediated by membrane depol. And movement of calcium into the smooth muscle cell through L-type Ca channels – Dependent on both Extracellular Ca and Intracellular Calcium Develop a selective Ca channel blocking agent to eliminate spontaneous contractions without effecting micturition contractions? K channel Openers Cromakalim, Pinacidil Move K+ out of cell membrane hyperpolarization = reduction in spontaneous contractile activity 3 K channels identified – Katp, SKCa, BKCa Intravesicular instillation of bladder selective Katp = reduced detrusor activity in rats with BOO TCA Imipramine, Amitriptyline – Antimuscarinic activity – Inhibition of Ca translocation – Direct smooth muscle relaxant Spinal Ascending/Descending Paths Glutamatergic Inhibitory Amino Acids Adrenergic Serotonergic Opioid Purinergic Glutamatergic Glutamate – Bladder Contraction – Excitatory transmitter in afferent limb of micturation reflex Suppressed by NMDA receptor antagonists Inhibitory Amino Acids Intrathecal injection of GABAa or GABAb agonists increases bladder capacity and decreases voiding pressures (rats) Baclofen Glycine levels low in rats with chronic spinal cord injuries – Increasing dietary stores of glycine can restore bladder function Adrenergic adrenoceptors can mediate excitatory and inhibitory influences on the lower urinary tract Efferent and Afferent limbs of the Micturition reflex receive excitatory and inhibitory input, respectively from spinal noradrenergic systems Serotonergic Raphe nucleus of the caudal brainstem autonomic and sphincter motor nuclei in the lumbosacral spinal cord Inhibitory Duloxetine – Combined Norepinephrine/5 HT reuptake inhibitor – Increase neural activity to external urethral sphincter and decreases bladder activity through the CNS Opioids Inhibitory action of reflex pathways in the spinal cord Purinergic Adenosine A1 Inhibitory action PMC and Supraspinal Mech. Glutamate Excitatory in Micturition pathway Cholinergic Excitatory/Inhibitory M1R and Protein Kinase C GABA Inhibitory Acts on GABAa/GABAb Receptors Dopaminergic Inhibitory Reflex – D1 – D5 – Substantia nigra Facilitatory – D2 – D3 – D4 Opioids Inhibitory and δ Receptors Mechanisms of Detrusor Overactivity Spinal Cord Injury/Neurogenic Detrusor Overactivity Damage above the Sacral level = detrusor overactivity – reorganization of synaptic connections in spinal cord – Alteration of bladder afferents Nml Micturition by lightly myelinated Aδ afferents Post injury – Capsaicin-sensitive C- fiber mediated spinal reflex = Detrusor overactivity UMN: MS, PD – NGF (nerve growth factor) : Implicated as Chemical mediator of disease-induced changes – NGF Antibodies? Bladder Outlet Obstruction Changes: – – – – – – – Detrusor hypertrophy No change of myofilaments Axonal degeneration Decrease in percentage volume of Mitochondria Increase in sarcoplasmic reticulum Gap junctions are absent Enlarged density of afferent and efferent nerve fibers Unstable Contraction CNS alterations Obstruction-Induced detrusor overactivity with irritative voiding symptoms has been attributed to denervation supersensitivity. – New spinal circuits NGF – Increase precedes enlargement of bladder neurons and development of urinary frequency Aging Contractility – α – adrenergic stimulation increase and decrease in β – adrenergic inhibitory responses? – Innervation and development of Gap Junctions? – Low energy production? Future Pharmacogenetics Tissue Engineering Gene Therapy