HuBio 543 September 20, 2007 Neil M. Nathanson K-536A, HSB Introduction to the Autonomic Nervous System (ANS)

Skeletal NMJ Autonomic NS VoluntaryInvoluntary QuiescientSpontaneous Activity Presynaptic receptors CNS periphery No presynaptic receptors (at least, none that we will worry about) CNS  ganglia  periphery

The Sympathetic Nervous System

Stress can activate the sympathetic nervous system (Yosefy et al., NEJM, 350, 2315 [2004])

Sympathetic vs. Parasympathetic ganglia Sympathetic ganglia: –Close to spinal cord –One preganglionic fiber can innervate many ganglionic neurons –can innervate many target organs –Set up for widespread discharge –Preganglionic fibers originate in the intermediate portion of SC Parasympathetic ganglia: –Close to or in target organ –One preganglionic fiber usually innervates one ganglionic neurons –Usually innervate one target organ –Usually don’t have widespread discharge –Preganglionic fibers originate in the midbrain, medulla, and the sacral portion of SC

From CNS ACh N NE TargetTarget AdR Most Sympathetic Ganglia: To Target Parasympathetic Ganglia: From CNS ACh N To Target TargetTarget M ACh

From CNS ACh N Sympathetic Innervation of Chromaffin Cells in Adrenal Medulla: Into Circulation NE EPI From CNS ACh N To Target TargetTarget M Sympathetic Innervation of Sweat Glands: ACh

GangliaTarget Trans. Rec. Symp. (most) ACh nAChR NE Adren. R Symp. (sweat ACh nAChR ACh mAChR glands) Parasymp. ACh nAChR ACh mAChR AdrenalACh nAChR Epi. Adren. R Medulla(chromaffin cells)& NE

Parasympathetic Stimulation Slows the Rate of Diastolic Depolarization in the S-A Node Membrane Potential Time Control +AC h mAChR increases potassium permeability in S-A node

ACh Decreases the Duration of the Atrial Action Potential This decreases calcium entry and thus decreases the force of contraction Membrane Potential Time Control +ACh

Positive Chronotropic Effect of Sympathetic Stimulation Norepinephrine increases the rate of diastolic depolarization Membrane Potential Time Control +NE

Autonomic Effects on Vasculature Vasculature essentially only has sympathetic innervation Sympathetic stimulation causes constriction of most vasculature Sympathetic stimulation (and pharmacological administration of epinephrine) can cause dilation or constriction of skeletal muscle vasculature (due to multiple types of adrenergic receptors)

Dual Innervation of the Iris Constriction (Miosis) Dilation (Mydriasis)

Dual Innervation of the Ciliary Muscle Parasympathetic: Contraction of Ciliary Muscle Increased curvature of the lens Accommodation for near vision Sympathetic: Relaxation of Ciliary Muscle Decreased curvature of the lens Allows far vision

Predominant Tone Predominantly sympathetic tone: –Blood vessels –sweat glands Predominantly parasympathetic tone: –Heart –GI and urinary tracts –Salivary glands –Eye “Sets” the level of activity of a given target organ

Sympathetic and parasympathetic denervation in humans Controls Heart Transplant Transplant, partial sympathetic reinnervation Resting HR (bpm) 79 89*90* Exercise time (min) 10 6* # 8* Peak HR (bpm) * # 143 (* diff from cont; # diff from reinnerv)

Your brain is important… because of the autonomic reflexes Baroreceptors (stretch receptors) in the carotid sinus and aortic arch Send fibers to the CNS, to regulate activity of the ANS: –If blood pressure is “too high”: decreases sympathetic activity increases parasympathetic activity –If blood pressure is “too low”: increases sympathetic activity decreases parasympathetic activity

Indicators of abnormal autonomic function associated with increased mortality: Resting Heart Rate > 90 beats/min Inability to achieve 85% of predicted maximal HR on treadmill testing Abnormal HR recovery (failure to decrease HR≥ 12 bpm during first minute after peak exercise) Abnormal HR variability (failure to change HR by ≥10 bpm during 1 minute of slow deep breaths) (Curtis and O’Keefe, Mayo Clin Proc 77, 45 [2002])

Pay attention: the ANS is important! Mortality as a function of recovery of heart rate 1 min after exercise: Beat-to-beat variation in heart during 1 min. of deep breathing: (heart rate variability)

From CNS ACh N Synaptic Transmission Through a Sympathetic Ganglion: To Target M Main Pathway Modulatory Pathway

Synaptic Transmission in the Sympathetic Ganglia Main Pathway: ACh acting at (excitatory) nicotinic AChR Modulatory Pathway: ACh acting at (excitatory) muscarinic ACh R Synaptic Transmission in the Parasympathetic Ganglia Main Pathway: ACh acting at (excitatory) nicotinic AChR Transmission in the Adrenal Medulla Main Pathway: ACh acting at (excitatory) nicotinic AChR Modulatory Pathway: ACh acting at (excitatory) muscarinic ACh R

ACh AChE ACh Ch +Ac ACh Choline + AcetylCoA ACh + CoA Choline Acetyltransferase Choline Ca ++ Ca ++ AChR Na +

Nicotinic Ganglionic Antagonists

Effects of nicotinic antagonists at ganglia and NMJ C6C6 C 10

Effects of Ganglionic Blockade Site Predominant ToneEffect of Blockade Blood vesselsSympatheticVasodilation Sweat GlandsSympatheticAnhidrosis HeartParasympatheticTachycardia IrisParasympatheticMydriasis Ciliary MuscleParasympatheticCycloplegia G-I TractParasympathetic tone & motility Urinary TractParasympatheticUrinary Retention Salivary GlandsParasympatheticXerostomia

Therapeutic Uses of Ganglionic Blockers Decrease BP in emergency hypertensive crisis Produce controlled hypotension to decrease blood loss during surgery Decrease symptoms of autonomic hyperreflexia

Standing Heart Rate + Mecamylamine Recumbent Blood Pressure + Mecamylamine Effects of Administration of Mecamylamine to Humans

Nicotinic Ganglionic Agonists * = drug list * *

Effect of Ganglionic Stimulants and Blockers + Hexamethonium: + DMPP BP HR