BladderPharmacologyCampbell-WalshCh-.ppt

Bladder PharmacologyCampbell-WalshCh. 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: Inhibition of adenylate cyclase = suppressing sympathetic mediated depression of detrusor Inactivation of K+ channels 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 ?-adr