HuBio 543 September 21, 2007 Neil M. Nathanson K-536A, HSB The Parasympathetic Nervous System and Muscarinic Agonists

(Based on Loewi, 1921)

nAChR (NMJ) mAChR (ANS) Discrete terminalsVaricosities Nerve close Nerve far (20 nm- 50 nm) (20 nm- 2 µm) Receptors localizedReceptors distributed uniformly Recetor action fast Receptor action slow ( 100 msec)

Autonomic nerves form many varicosities in their target organs

Diffuse autonomic innvervation in heart by nerve varicosities

Distant innervation in heart by a cholinergic varicosity

Diffuse localization of mAChR in heart

Slow action of mAChR in heart

Choline Esters Acetylcholine (CH 3 ) 3 NCH 2 CH 2 OCCH 3 + O (CH 3 ) 3 NCH 2 CHOCCH 3 + O CH 3 Acetyl-beta-methylcholine (Methacholine) (CH 3 ) 3 NCH 2 CH 2 OCNH 2 + O Carbamylcholine (Carbachol) (CH 3 ) 3 NCH 2 CHOCNH 2 + O CH 3 Carbamyl-beta-methylcholine (Bethanechol)

Comparison of Properties of Choline Esters AGONIST Hydrylosis By ChEs Muscarinic EffectsnAChR Effects C-V GI Urinary Acetylcholine Methacholine Carbachol Bethanechol - ±

Effects of ACh ± Atropine on Blood Pressure in Dog ACh 10 µg/kg ACh 50 µg/kg ACh 10 µg/kg Atropine 3 mg/kg ACh 100 µg/kg

Actions of the Choline Esters Vasodilation- blood vessels have mAChR Heart: low doses cause reflex tachycardia; very high doses can cause bradycardia Increase tone, motility, secretions from GI tract Bronchoconstriction Cause miosis Increase secretions from exocrine glands

ACh Relaxation of Vasculature Requires Endothelial Cells ACh CONCENTRATION Endothelium Removed Endothelium Intact VSM Contraction VSM Relaxation (resting)

Cross-Section of Vascular Smooth Muscle Connective Tissue Smooth Muscle Cells Endothelial Cells mAChR EDRF: mAChR stimulate production of Endothelial-Derived Relaxing Factor

EDRF is Nitric Oxide Connective Tissue Smooth Muscle Cells Endothelial Cells mAChR EDRF: mAChR stimulate production of NO NO diffuses from endothelial cells into smooth muscle cells (NO activates guanylyl cyclase, resulting in activation cGMP-dependent protein kinase) Causes relaxation of vascular smooth muscle

Is NO the only relaxing factor released by endothelial cells in response to ACh? NO

Connective Tissue Smooth Muscle Cells Endothelial Cells mAChR mAChR stimulate releases of EDHF from endothelial cells Recent evidence indicates that EDHF is C-type naturietic peptide C-NP receptors on smooth muscle activate a K channel which causes hyperpolarization Causes relaxation of small diameter vessels Endothelial-Derived Hyperpolarizing Factor

Therapeutic uses of choline esters GI stimulant (bethanechol) Miosis- extraction of cataracts and treatment of glaucoma Diagnosis (MeCh): –Belladonna poisoning –Familial dysautonomia –Airways hyperreactivity

Production and flow of aqueous humor

Therapeutic uses of choline esters GI stimulant (bethanechol) Miosis- extraction of cataracts and treatment of glaucoma Diagnosis (MeCh): –Belladonna poisoning –Familial dysautonomia –Airways hyperreactivity

Airway Hyperreactivity in Asthma FEV 1 % of Baseline Methacholine (mg.) Control Subjects Asthma Patients PD 20

Psychogenic asthma is vagally mediated

Alkaloid Agonists

Effects of Agonists on Isolated Heart

Effects of Agonists on Blood Pressure

Effects of Atropine Pretreatment on Blood Pressure Responses to High Doses of Oxotremorine and Carbachol Carbachol Oxotremorine + Atropine Carbachol

Patients Reporting Improvement in Oral Dryness (Radiation-Induced Xerostomia) WEEKS % Patients Reporting Improvement Placebo 5 mg. Pilocarpine 10 mg. Pilocarpine

AMANITA MUSCARIA

AChE Inhibitors in the ANS Ophthalmology- produce miosis to increase drainage of aqueous humor in glaucoma GI & Urinary Tracts- increase tone and motility (e.g., in paralytic ileum and acute colonic pseudo-obstruction) Treat toxic effects of muscarinic antagonists