Sympathetic Nervous System Needed for studying SNS PHARMACOLOGY PREREQUISITE Sympathetic Nervous System PHYSIOLOGY Needed for studying SNS PHARMACOLOGY

Differ in: Site of ganglia Length of pre & postganglionic fiber Mediators of postganglionic fiber Ramifies adrenal medulla and its mediator circulate in blood

Heart - parasympathetic Arterioles/arteries - sympathetic PREDOMINANT TONES OF MAJOR ORGAN SYSTEMS Heart - parasympathetic Arterioles/arteries - sympathetic Veins - sympathetic Iris - parasympathetic Ciliary muscle - parasympathetic GI tract (ENS) - parasympathetic Smooth muscle - parasympathetic Bladder - parasympathetic Sweat glands - sympathetic Salivary glands – parasympathetic Lacrimal glands – parasympathetic

Mainly norepinephrine [NE] Rarely Ach  M2 or Dopamine  D1 Transmitter is Mainly norepinephrine [NE] Rarely Ach  M2 or Dopamine  D1 Transmitter is Mainly epinephrine [E ]  circulates and acts a1, a2, b1 , b2 , b3 Gland cells

POSTGANGLIONIC SYMPATHETIC NERVE ENDING Na Norepinephrine (NE) Tyrosine Dopa Tyrosine SYNTHESIS DA STORAGE NE RELEASE Ca ACTION REUPTAKE NET DEGRADE NE  E Dopamine (DA) E ADRENAL MEDULLA COMT

Autoregulatory Function ADRENOCEPTORS [ADRs] D1 Postsynaptic Presynaptic a1 ADRs. a2 ADRs. b1 ADRs. b2 ADRs. b3 ADRs. a2 a1 b2 b1 b3 Autoregulatory Function a2

ADRENOCEPTORS [ADRs]

a1 ADRs couple to Gq to stimulate PLC Ca++ intracellular. ADRENOCEPTORS [ADRs] a1 ADRs couple to Gq to stimulate PLC Ca++ intracellular. a2 ADRs couple to Gi to inhibit AC  cAMP . B1,2 &3 ADRs couple to Gs to stimulate AC  cAMP

Some smooth muscles [SMC]  ADRs a1 ADRs Coupled to Gq Activates PLC  IP3 Ca++ & PKC Some smooth muscles [SMC]  Vascular [VSMC] N-VSMC [ Lung / GIT & UB (sphincters) / eye (dilator) ….etc ] Adr a1 Adrenoceptor Gq PLC a1 ADRs [VSMC] ↑Ca ++ At VSMCs VASOCONSTRICTION

Couple to Gi  Inhibit AC  cAMP ADRs a2 ADRs Couple to Gi  Inhibit AC  cAMP At presynaptic nerve ending At some VSMCs & N-VSMC [GIT motility] In pancreas   insulin Adr Gi a2 ADRs AC a 2 NE cAMP At VSMCs a2 ADRs activation postsynaptic cAMP leaves Ca signaling unopposed  Vasoconstriction At Presynaptic Nerve Ending NE release ????

+ ADRs Couple to Gs  stimulate AC  cAMP Gs ↑cAMP b1 ADRs b2 ADRs CARDIAC STIMULATION Renal (renin release) VSMCs Vasodilatation (cardiac,skeletal) N-VSMCs  RELAXATION = Bronchodilatation + GIT, UB, pregnant uterus, (motility)  glucagon secretion (glycogenolysis, glycolysis) Adipose T. (Lipolysis)

SNS ACTIVATION on VSMCs 1 2 2 VASOCONSTRICTION VASOCONSTRICTION VASODILATATION NET SUMMATION will dictate the FINAL ACTION

SNS actions at b receptors in organs controlling metabolism b2 ADRs b3ADRs

Eye Mydriasis IOP Accomodation Kept by a balance between formation & drainage Paralysis of constrictor pupilli (M) Contraction of dilator pupilli (a1) Accomodation If balance disturbed by increasing formation or decreasing drainage  IOP glaucoma Parasymp mimetics  glucoma (trabecular) Parasymp lytics   glucoma Sympathomimetics  ??? effect b blockers  glucoma (uveoloscleral) For near vision (M) For far vision (b2)

SYMPATHETIC ACTIONS Fight & Flight a receptors b1 receptors EYE: Contract Dilator Pupilli EYE: Relax Ciliary m. SALIVARY GLANDS  Salivation BLOOD VESSELS Vasoconstriction VESSELS Vasodilatation HEART  Force Inotropic HR Chronotropic AV conduction Dromotropic BRONCHUS Bronchodilatation GIT Contraction of sphincters GIT & G. Bladder Motility PANCREAS  Insulin secretion LIVER  Glucose KIDNEY Renin from Juxta-glomerular cells URINARY BLADDER Contraction of sphincters BLADDER Detrusal m.:Relax UTERUS Relax :Tocolysis PENIS Ejaculation

Sum up of physiological actions of Epinephrine (adrenaline) Acts on all ADR; b =/> a Heart  inotropic, chronotropic, dromotropic & lusiotropic (excitability)(b1) BP  systolic (b1) / diastolic   low dose (b2) &  high dose (a1) Vascular SMC; constrict skin + peripheral (a1) / dilate coronary+skeletal (b2) Non vascular SMC; Lung  bronchiodilatation (b2) GIT  motility (b2) / contract sphincter (a1) Bladder   detrusor m. (b2) / contract trigone & sphincter (a1) Pregnant uterus  tocolytic (b2) Eye  mydriasis (a1)  accommodation for far vision & little effect on IOP Metabolism insulin (a2) , glucagon (b2),  liver glycogenolysis + sk. m. glycolysis (b2) /   adipose lipolysis (b3 /b2) CNS little, headache, tremors & restlessness

GOOD LUCK

Adrenergic receptor subtypes and actions Alpha GPCRs Two subtypes A1 – Gq protein coupled A2 – Gi protein coupled Beta Three subtypes B1-3 – Gs protein coupled

Autonomic regulation of organ systems

Autonomic regulation of CVS function Baroreceptor reflex Increase in MAP Increased baroreceptor firing Increase parasympathetic tone Decrease sympathatic tone Decrease in MAP Decreased baroreceptor firing Decrease parasympathetic tone Increase sympathetic tone

Regulation of the heart Dominant tone = parasympathetic Sympathetic Increases heart rate and contractility via beta-1 and 2 (primarily beta-1) Parasympathetic Decreases heart rate and atrial contractility via M2

Regulation of the blood vessels Veins Dominant tone = parasympathetic Arterioles/arteries Dominant tone = sympathetic Contraction via alpha1 Relaxation via beta-2

Regulation of bronchi In autonomic ganglia there is cholinergic N and M1 receptors At postganglionic parasympathetic fibres there is M2 receptors and is also controlled by B2 ADRs fibres On bronchiolar SMCs there is M3 and B2 ADRs

Postganglionic Cholinergic Regulation of bronchi Adrenal Medulla ADRENERGIC Vasodilatation Exudation Mucous secretion Medulla Cholinergic Ganglia Postganglionic Cholinergic Ach M2 M1 CHOLINERGIC N SNS Ganglia ß2-AR AD Vagus n. AD Adrenaline is coming to bronchi mainly humoral AD AD ß2-AR Bronchodilatation Bronchoconstriction M3 Epithelial Irritation Shedding

Enteric Nervous System Large and highly organized system of neurons located in the walls of the gastrointestinal system It is often considered a third division of the autonomic nervous system Includes the myenteric plexus (of Auerbach) and the submucous plexus (of Meissner)

Enteric nervous system Parasympathetic Longitudinal muscle Myenteric plexus Circular muscle layer Submucosal plexus Walls constricted and sphincters relaxed via M3 Secretions increased via M3

Autonomic regulation of eye structures Dominant tone = Parasympathetic Iris radial – contracted via alpha-1 Iris circular – contracted via M3 Ciliary muscle – contracted via M3

Regulation of the liver Sympathetic Increase gluconeogenesis and glycogenolysis Provide glucose to fuel “flight or fight” response Primarily beta-2, possibly alpha-1

Control of stomach acid Parasympathetic Increase histamine release from ECL cell via M3 Increase H+ production from parietal cell in fundus via M3 Decrease somatostatin release from D cell in antrum Increases gastrin release from G cell

Regulation of the bladder Parasympathetic Bladder wall Constriction via M3 Relaxation via beta- 2 Sphincter Relaxation via M3 Constriction via alpha-1

Lacrimal gland (tear production) – increased via M Glandular secretion Sweat Salivary Increased via M3 Appocrine – increased via alpha-1 Eccrine – increased via M Lacrimal gland (tear production) – increased via M

PHYSIOLOGICAL EFFECTS OF ANS INNERVATION AND RECEPTORS THAT GOVERN SUCH EFFECT PARASYMPATHETIC SYMPATHETIC Contracts the iris radial muscle via alpha-1 Relaxes the ciliary muscle via beta Accelerates the sinoatrial node via beta-1,2 Accelerates ectopic pacemakers via beta-1,2 Increases cardiac contractility via beta-1,2 Relaxes bronchiolar smooth muscle via beta-2 Relaxes GI walls via alpha-2, beta-2 Contracts GI sphincters via alpha-1 Relaxes bladder wall via beta-2 Contracts bladder sphincter via alpha-1 Contracts uterus via alpha, relaxes uterus via beta-2 Contracts pilomotor smooth muscle via alpha Activates sweat glands via alpha, M Increases gluconeogenesis and glycogenolysis in liver via beta-2 and alpha Induces lipolysis via beta-2 Increases renin release from kidney via beta-1 Semine ejaculation alpha-1 Contracts the ciliary muscle via M-3 Decelerates the sinoatrial node via M-2 Decreases heart contractility via M-2 Releases EDRF in the endothelium via M-3, M-5 Contracts bronchiolar smooth muscle via M-3 Contracts GI walls via M-3 Relaxes GI sphincters via M-3 Increases GI secretions via M-3 Contracts the uterus via M-3 Causes erection of the penis via M