History of neurotransmission and introduction to ans


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History of neurotransmission and introduction to ans

  1. 1. History of neurotransmission and introduction to ANS Dr. Deepika G 1st year PG AIMS
  2. 2. • Introduction • History of neurons and neurotransmission • Scientists and their experiments • Introduction to Autonomic nervous system • ANS Receptor functions • Physiological Effects of ANS • References
  3. 3. Neurons And Synapses • Until 1838 – Globules in the tissue. • In Retrospect – 3 long steps.  1st Step : Discovery of neuron, dendrites and axons.  2nd Step : Neuron doctrine  3rd Step : Discovery of synapse and chemical transmission
  4. 4. 1st –Neurons, Dendrites and Axons 1. Anton Van Leeuwenhoek (1632- 1723) Built notable microscope, able to slice specimens of cow optical nerve(1674). 2. Robert Hooke (1635-1703) Used the word cell to describe smaller elements.
  5. 5. 3.Gabreiel Gustan Valentin (1810-1863) First to describe cell, nucleus, nucleolus of neurons(1836).
  6. 6. 4.Jan Evangelista Purkinje (1787-1869) • Studied nuerons in cerebellum, coined term protoplasm. • Described drop like cells have elongated fibre like processes in their vicinity -1837. • Proposed that there should be some connection between these processes and nucleated cell bodies.
  7. 7. 5. Robert Remak (1815-1865) • Described nervous tissue is entirely suffused with very fine and complex mesh of filamentous processes(1836). • Described existence of two types of nerve processes- myelinated and unmyelinated 6. Theodor schwann(1810- 1882) • Described myelin sheath covers nerve fibres • Organic tissues are composed of cells
  8. 8. 7.Alfonso Corti (1822-1876) • Obtained carmine red bright strain from insects(1850). • Become famous for his descriptions of inner ear organ of hearing which bears his name. 8. Joseph Von Gerlach (1820- 1886) • Obtained clearest images of neural cells and its filaments. • Improved fixatives for nervous tissue
  9. 9. 9. Otto Friedrich Karl Deiters (1834- 1883) • Developed micro dissection technique. • Isolated neurons under microscope • Found two different branching processes attached to soma  Tree like full fine branching - protoplasmic extensions.  Long fibre- axis cylinder.
  10. 10. 20 Years Later… Protoplasmic extensions  Dendrites – Wilhelm His(1889) Axis cylinder Axons – Rudolph A Von Kolliker(1896) Cell  Neuron – Wilhelm Von Waldeyer(1891)
  11. 11. Second Big Step: Neuron Doctrine SANTIAGO RAMON Y CAJAL (1852-1934) CAMILLO GOLGI (1843- 1926)
  12. 12. 10. Camillo Golgi(1843-1926) • Specific staining technique – The reazione nera (The black reaction). • Exceedingly clear and well contrasted picture of neuron against an yellow background. • Technique was unreliable as it didn’t stain all neurons. • Defended Reticularist hypothesis
  13. 13. 11. Santiago Ramon Y Cajal (1852-1934) • Improved Golgi technique - Used younger brains and brains of birds. • Saw individual neurons and stated that no continuity between axons and neurons. • Wilhelm His and Cajal gave embryological evidence about growth of neurons. • Action currents propagate in neuronal network in direction of dendrites to axons/soma – Dynamic Polarisation. • Increase in number of synapses could be mechanism of learning and memory.
  14. 14. THE NEURONAL DOCTRINE HAD FOUR TENETS The neuron is the structural and functional unit of nervous system.  Neurons are individual cells, which are not continues to other neurons.  The neuron has three parts : Dendrites, Soma, Axon.  Conduction takes place in direction from dendrites to soma, to the end arborization of the axon.
  15. 15. 3rd STEP:Discovery of SYNAPSE & Neurotransmission 12. George Palade - Morphological proof of synapse (1954). 13.Emil Dubois Raymond - Existence of synapse, could be electrical or chemical (1846).  Unidirectional flow of information.  Excitatory and inhibitory synapses.  Delay in transmission.
  16. 16. 14. John Newport Langley (1852-1925)  Coined the term autonomic nervous system.  Discovered function of sympathetic and parasympathetic components. Laid foundation for humoral neurotransmission and concept of receptor substance. Action of jaborandi (Pilocarpine) on heart - 1875
  17. 17.  Deduced that pilocarpine slowed heart rate by acting on inhibitory fibres in vagus nerve to the heart, stimulated salivation. With Dickinson Nicotine has ganglion blocking property – 1889. With sherrington established distribution of sympathetic fibres innervating skin and relation with sensory fibres of associated spinal nerve- 1890.  Leewandowsky(1889) and Langley(1901) noted independently the similarity between effects of injection of extract of adrenal gland and stimulation of sympathetic nerves.
  18. 18. 15. Sir Charles S Sherrington (1852-1952)  Coined the term SYNAPSE- To Clasp  Physiology of simple and complex motor reflexes – concept of integrative action of the nervous system.  Interplay of central excitation and inhibition are fundamental for the integration – Awarded Nobel prize 1921.
  19. 19. 16. Thomas Renton Elliot (1877-1961)  Concept of chemical neuro transmission.  Demonstrated effects of sympathetic innervation and exogenous epinephrine on bladder.  Adrenaline chemical stimulant liberated on each occasion when impulse arrived at the periphery – 1904.  Postulated epinephrine acted at myoneural junction not at the nerve endings or muscle fibres.
  20. 20. 17. Walter Ernest Dixon(1871- 1938) Interested in effect of drugs on nerves & nerve endings Opposed Erhlich statement and showed that strychnine was not bound , while it acted at the site Investigated action of vagus nerve on heart Argued against retention of heroin in clinical practice Practiced to induce labour, showed that ovarian secretion caused uterine contraction via an indirect effect by release of pituitrin
  21. 21. 18. Sir Henry Hallet Dale(1875-1968) • Distinguished muscarinic and nicotinic receptor • First to identify acetylcholine(1914) • Proposed term cholinergic and adrenergic synapses • Dale’s law: each neuron releases only one type of neurotransmitter. • Dale’s vasomotor reversal phenomenon: only fall in BP occurs when an alpha blocker is given before injecting adrenaline. He demonstrated in cats and used ergot alkaloids as alpha blockers.
  22. 22. Two kinds of effects produced by Ach. A. Ach causes a fall in BP due to vasodilation. B. A larger dose of Ach also produces bradycardia, further reducing BP. C. Atropine blocks the effect of Ach in lowering BP. D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and tachycardia. Sir Henry Hallett Dale (Nobel laureate, 1936) A, B: Muscarinic effects of Ach (M3, M2) C: Muscarinic antagonistic effect (M) D. Stimulation of sympathetic ganglia (NN) (Arterial pressure of an anesthetized cat was measured)
  23. 23. 19.Otto Loewi (1873-1961) • Proved the chemical transmission of the nerve impulses and received Nobel prize with Henry Dale • Idea of experiment in a dream and become a prototype for all investigations of chemical factors in the nervous system. • Coined term Neurohumoral transmission
  24. 24. • Findings of Experiment: 1. stimulation of vagus caused appearance of a substance in perfusated heart capable of producing in the second heart, an inhibitory effect resembling vagus stimulation. 2. stimulation of sympathetic nervous system caused appearance of a substance capable of accelerating the second heart, later concluded that substance was adrenaline.
  25. 25. 3.Atropine prevented the inhibitory action of vagus on the heart but did not prevent release of vagusstof. 4.physostigmine(eserine) potentiated the effect of vagus stimulation on the heart, prevented destruction of vagusstof by heart muscle, due to inhibition of cholinesterase which normally destroys acetylcholine.
  26. 26. 20.Wilhelm Feldberg & Otto Krayer first long experiment on role of Ach Stimulated vagus nerve of dog and cat, measured Ach in venous outflow of heart effect of parasympathetic out flow in contraction of tongue muscle
  27. 27. 21.Walter Bradford Cannon(1871-1945): Discovery of adrenaline & concept of autoreceptor • With Uridil: stimulation of sympathetic hepatic nerve in mammals release adrenaline like substance that increase blood pressure and heart rate.
  28. 28. • With Bacq: idea of Autoreceptor • With Rosenblueth: hepatic nerve stimulation caused rise in BP which persisted after administration of ergotoxin • Sympathin E- excitatory effects • Sympathin I- inhibitory effects of adrenaline • Studied effects of pituitrin on uterus and practiced to induce labour.
  29. 29. 22.Ulf Von Euler(1905-1983): • Discovered active biological agent from intestine: substance P • Prostaglandin & vesiglandin- 1935, piperidine-1942, noradrenaline-1946 • Studied about NA distribution in nerves & organs, excretion during various physiological and pathological conditions • Researched about uptake, storage and release from nerve granules as well as neurotransmission process.
  30. 30. 23.Raymond Ahlquist (1914-1983) • Effects of adrenaline, noradrenaline & isoproternol in variety of target tissues. • In 1948 divided adrenoceptors into α- and β-adrenoceptor subtypes • The pharmacology of the sympathetic nervous system. • In 1958, dichloroisoprenaline the first clinically useful beta-blocker. • Discovered that the peristalsis is enhanced by α- adrenoceptors and conversely inhibited by β- adrenoceptors.
  31. 31. • Nobel Laureate, 1970 • His discoveries concern the mechanisms which regulate the formation of norepinephrine in the nerve cells and the mechanisms which are involved in the inactivation of this important neurotransmitter. 24. Julius Axelrod (1912-2004)
  32. 32. 25. Sir Bernard Katz: • Study of neuromuscular junction with intracellular electrodes, role of Ach in synapse was demonstrated. • Discovered that small fluctuations in basement membrane potential due to release of synaptic vesicles
  33. 33. 26. Sir John Carew Eccles: • Believed that Synapses had electrical transmission • 1951-Inserted microelectrodes into nerve cells , recorded electrical responses produced by synapses
  35. 35. Neurohumoral Transmission • Nerves that transmit their message across synapses and neuroeffector junctions by release of humoral (chemical) messengers. • Criteria's for transmitter : a. Presynaptic neurone with synthesizing enzymes b. Released following nerve stimulation c. Produce response identical to nerve stimulated response d. Potentiated or antagonized by other substances
  36. 36. Steps Of Neurohumoral Transmission I. Impulse conduction: Resting transmembrane potential -70mv, high k+ & low Na+ concentration, Impulse ↑↑↑Na+  depolarize overshoot,+20 mv Normalize by activation of Na+ K+ pump. II. Transmitter Release Stored in vesicles prejunctionally, Fusion of vesical & axonal membrane through Ca+ influx.
  37. 37. III. Transmitter action on post junctional membrane EPSP: increase in cation permeability depolarisation followed k+ efflux IPSP: increase anion permeability hyperpolarisation IV. Post junctional activity V. Termination of transmitter action: parasympathetic Ach- hydrolyzed by AchE VIP- degrades by peptidases sympathetic NA- acts at junction, diffuses & recycles NPY- diffuses & degrades Gaba-ergic GABA- acts , diffuses & recycles
  38. 38. • Graded in magnitude • Have no threshold • Cause depolarization o Movement of Na+ and K+ • Summate • Have no refractory period Excitatory post synaptic potential
  39. 39. Inhibitory Post Synaptic Potential • Cause hyperpolarization o K+ or Cl- • Small in magnitude • Makes membrane less excitable
  40. 40. Synthesis & Storage Action potential Metabolism Recognition (action) Key Steps in Neurotransmission: Strategies for Pharmacological Intervention: Block synthesis and storage: Usually rate-limiting steps; produce long- term effects Block release: Rapid action and effective Block reuptake increases synaptic neurotransmitter concentrations Can be selective or non-selective Interfere with metabolism: Can be reversible or irreversible; blocking metabolism increases effective neurotransmitter concentrations Interfere with recognition: Receptor antagonists & agonists; high specificity Release Reuptake
  41. 41. Parsympathetic Nervous System • Cholinergic system • Craniosacral out flow- CN III, VII, IX, X & S2,3,4 • Preganglionic fibres myelinated, long • Post ganglionic fibres non myelinated, short • Parasympathetic ganglia: ciliary ganglia Sphenopalatine ganglia, submaxillary ganglia, otic ganglia. • EXCEPTION: ciliary post ganglionic fibres are myelinated
  42. 42. PARA SYMPATHETIC NEUROTRANSMITTERS: Acetylcholine(Ach)- Neurotransmitter a. Somatic motor neuron to skeletal muscle(NMJ) b. Preganglionic parasympathetic/ sympathetic fibres c. Post ganglionic parasympathetic fibres to NEJ EXCEPTION: postganglionic sympathetic fibres to sweat glands of palm and sole are cholinergic Hypothalamus is major controlling centre for PNS
  43. 43. Synthesis of acetylcholine: CH3 CH3 CH3 N+–CH2–CH2–OH CoA–S–C–CH3 O Choline Acetyl-CoA + Choline acetyltransferase CH3 CH3 CH3 N+–CH2–CH2–O–C–CH3 O CoA-SH + CoA Acetylcholine
  44. 44. Synthesis, storage and release of acetylcholine: Pre-synaptic cell Post-synaptic cell Ach Ca2+ Na+ Choline (10 mM) Choline Recognition by receptors Ca2+ Ach Ach Ach Nerve impulse NN NM Ach Ac-CoA ChAT Ach AchE AchE choline + acetic acid CAT = choline acetyltransferase AchE = acetylcholinesterase Synaptic cleft Antiporter
  45. 45. CH3COOH+ AchE (CH3)3 N+–CH2–CH2–OH(CH3)3 N+–CH2–CH2–O–C–CH3 O H2 O OH(-) AchE Glu202 Tyr337 Ser203 Glu334 His447 Degradation of acetylcholine: Steps involved in the action of acetylcholinesterase: 1. Binding of substrate (Ach) 2. Formation of a transient intermediate (involving -OH on Serine 203, etc.) 3. Loss of choline and formation of acetylated enzyme 4. Deacylation of AchE (regeneration of enzyme) 600,000 Ach molecules / AchE / min = turnover time of 150 microseconds Choline Acetic acid
  46. 46. Sympathetic Nervous System • Adrenergic system • Thoracolumber outflow • Preganglionic neurons leave spinal nerve and communicate with paravertebral chain of 22 sympathetic ganglia • 3 cervical and sacral ganglia run upward or downward making no synapse in between • T1- T4 preganglionic fibres synapse with post ganglionic fibres in paravertebral ganglia • T5-T11 preganglionic fibres -Coeliac ganglia
  47. 47. • T12-L1 preganglionic fibres - superior mesentric ganglia. • L2-L3 preganglionic fibres- inferior mesentric ganglia. • T10- T11 some preganglionic fibres terminate in chromaffin cells of adrenal gland i.e no post ganglionic fibres. • Pre ganglionic fibres: myelinated , shorter or equal with post ganglionic fibres • Post ganglionic fibres: non myelinated • Vasomotor centre in major controlling centre for SNS.
  48. 48. SYMPATHETIC NEUROTRANSMITTERS: • Neurotransmitter at sympathetic ganglia is acetylcholine • Sympathetic post ganglionic fibres release Norepinephrine(NE) at neuroeffector junction. • EXCEPTION: i. Postganglionic sympathetic fibres to sweat gland ii. Some post ganglionic sympathetic fibres to arterioles of skeletal muscle iii. Some post ganglionic sympathetic fibres at splanchnic and renal blood vessels are dopaminergic in nature. iv. Preganglionic sympathetic nerve fibres to adrenal medulla neurotransmitter is Ach but on stimulation cells secrete Epinephrine.
  49. 49. HO HO CH2 NHCH3 OH CH Epinephrine HO HO CH2 NH2 OH CH Norepinephrine HO HO CH2 NH2 CH2 Dopamine HO HO HC NH2 CH2 DOPA COOHHO HC NH2 CH2 Tyrosine COOH TH DD (L-AAD) DBH PNMT Adrenal medulla Synthesis of Catecholamines Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine b-hydroxylase N-methyl transferasePhenylethan olamine- 13 L-phenylalanine
  50. 50. Pre-synaptic Post-synaptic Ca2+ Na+ Tyrosine Cellular messengers and effects Diffusion, metabolism Tyrosine Dopa TH DD Dopamine (DA) NE DBH ATP Ca2+ NE DBH ATP NE NE aR bR a2R NE (-) Signal Regulation of Norepinephrine Synthesis and Metabolism: Uptake-1 Normetanephrine (NMN)
  51. 51. Rules & Exceptions of Autonomic innervations • Parasympathetic nervous system: energy storing and restorative system • Sympathetic nervous system: Prepares for E- situations i.e.. Emergency, exercise, embarrssment • Only sympathetic no parasympathetic innervations: radial muscle of iris, smooth muscle of eyelids, nictating membrane pilomotor muscle, ventricular myocardium  bladder neck(trigone), seminal vesical & vas deferens
  52. 52. • Only parasympathetic no sympathetic innervations: circular muscles of iris, ciliary muscle lacrimal glands, mucus membrane of GIT bronchial tree, pancreatic exocrine glands detrusor muscle of bladder, erectile tissue of penis • Only Adrenergic receptors no sympathetic innervations: Adipocytes – lipolysis Liver cells –gluconeogenesis, skeletal muscle cells –glycolysis
  53. 53. • Only cholinergic receptors no parasympathetic inervations: Blood vessels • Sympathetic in nature but cholinergic in character: Sweat galnds, arterioles of skeletal muscles • Sympathetic system is antagonist to parasympathetic system: On salivary glands its stimulatory
  55. 55. PNS Receptors - Pharmacological Classification: Cholinergic R Adrenergic R Dopamine R Muscarinic R Nicotinic R M1, M3, M5 (Gq coupled) M2, M4 (Gi coupled) NM (neuromuscular, or muscle type) NN (neuronal, or ganglion type) b1, a2a1, b2, b3 D1, D2, D3, D4, D5 Other receptors (receptors for NANC transmitters, e.g. nitric oxide, vasoactive intestinal peptide, neuropeptide Y) (mAChR) (nAChR)
  56. 56. “Nicotinic actions” -- similar to those induced by nicotine; action mediated by nicotinic cholinergic receptors: • stimulation of all autonomic ganglia (NN) • stimulation of voluntary muscle (NM) • secretion of epinephrine from the adrenal medulla (NN) Cholinergic receptors: Nicotinic Nicotiana tabacum (cultivated tobacco)
  57. 57. Nicotinic acetylcholine receptor: Function Ligand-gated ion (Na+) channel - an “Ionotropic Receptor” • Acetylcholine binds to the α- subunits of the receptor making the membrane more permeable to cations (Na+) and causing a local depolarization. The local depolarization spreads to an action potential, or leads to muscle contraction when summed with the action of other receptors. The ion channel is open during the active state. • Nicotine in small doses stimulates autonomic ganglia and adrenal medulla. When large doses are applied, the stimulatory effect is quickly followed by a blockade of transmission.
  58. 58. “Muscarinic actions” -- reproduced by injection of muscarine, from Amanita muscaria (fly agaric). Similar to those of parasympathetic stimulation Cholinergic Receptors: Muscarinic Multiple muscarinic cholinergic receptors distributed in different tissues. Therefore, the “muscarinic actions” are dependent on the receptors in different tissues and cells.
  59. 59. • Neural/enteric (M1): CNS, ENS, gastric parietal cells (excitatory; Gq) • Cardiac (M2): atria & conducting tissue; presynaptic (inhibitory; Gi) • Glandular/endothelial (M3): exocrine glands, vessels (excitatory; Gq) • Neural (M4): CNS (inhibitory; Gi) • Neural (M5): CNS (excitatory; Gq)
  60. 60. Agonist Muscarinic acetylcholine receptors – G Protein-Coupled Receptors (“Metabotropic” Receptors) Agonist M1 (enteric, neuronal) M2 (cardiac) M3 (glandular, vascular ) Gq Gi  IP3, DAG (Depolarizatio n) (Stimulation)  Intracellular Ca2+  cAMP  Ca2+ channel  K+ conductance  K+ conductance Mostly excitatory CNS excitation Gastric acid secretion Gastrointestinal motility Mostly inhibitory Cardiac inhibition Presynaptic inhibition Neuronal inhibition Glandular secretion Contraction of visceral smooth muscle Vasodilation (via NO) (Slow IPSP) (Inhibition) M5 (CNS) M4 (CNS)
  61. 61. Intracellular signaling triggered by acetylcholine in the Heart Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase
  62. 62. Clinical manifestation of excessive cholinergic effects D – Defecation U – Urination M – Miosis B – Bradycardia E – Emesis L – Lacrimation S – Salivation (DUMBELS)
  63. 63. Classification of adrenergic receptors by agonist potency a -- NE  Epi > Iso b -- Iso > Epi > NE NE = norepinephrine Epi = epinephrine Iso = isoproterenol HO HO CH2 NHCH3 OH CH Epi HO HO CH2 NH2 OH CH NE HO HO CH2 NH OH CH Iso CH(CH3)2
  64. 64. Agonist Signaling properties of adrenergic receptors AgonistAgonist a1 a2 b1,2,3 Gq Gi Gs  Inositol phosphates (IP3)  Diacyl glycerol (DAG)  cAMP cAMP  Calcium channels  K+ conductance Mostly excitatory Mostly inhibitory Mostly excitatory Norepinephrine Epinephrine Phenylephrine Norepinephrine Methyl NE Clonidine Isoproterenol Albuterol (b2) Dobutamine (b1)
  65. 65. Gs and Gi proteins have different functions Agonist bg as Agonist bg ai AC as bg ai bg Gs = stimulatory G protein Gi = inhibitory G protein AC = adenylyl cyclase (convert ATP to cAMP) Beta1 receptor Alpha2 receptor
  66. 66. a1: Postsynaptic effector cells, especially smooth muscle, salivary glands, liver cells Vasoconstriction, relaxation of intestine, salivary secretion, hepatic glycogenolysis a2 : Presynaptic adrenergic nerve terminals (autoreceptor), platelets, lipocytes, smooth muscle, β pancreatic cells Inhibition of transmitter release, platelet aggregation, contraction of vascular smooth muscle, inhibition of insulin release Distribution and Functions of Adrenergic Receptors:
  67. 67. b2 : postsynaptic effector cells: smooth muscle, cardiac muscle,coronary arteries Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis b1 postsynaptic effector cells: heart, lipocytes, brain, presynaptic adrenergic / cholinergic terminals, juxtaglomerular apparatus Increased heart rate & force of contraction, increased renin release b3 postsynaptic effector cells: lipocytes Lipolysis
  68. 68. HO HO CH2 NHCH3 OH CH Epinephrine HO HO CH2 NH2 OH CH Norepinephrine HO HO CH2 NH2 CH2 Dopamine HO HO HC NH2 CH2 DOPA COOH HO HC NH2 CH2 Tyrosine COOH TH DD (L-AAD) DBHPNMT Tyrosine hydroxylase Dopa decarboxylase (L-amino acid decarboxylase) Dopamine b-hydroxylase Phenylethanolamine- N-methyl transferase 13 Dopaminergic receptors
  69. 69. Dopaminergic receptors in the periphery Dopamine receptors play important roles in CNS. Notably, dopamine neurotransmission is involved in several diseases including Parkinson’s disease, schizophenia, and attention deficiency disorder. There are 5 types of dopamine receptors (D1 – D5). In periphery, D1 dopamine receptor mediates renal vasodilation, and increased myocardial contractility. Agonist Agonist D2,3,4D1,5 GiGs  cAMP  cAMP
  70. 70. Physiological Effects of ANS
  71. 71. Receptor distribution and effects in the autonomic nervous system: Organ Receptor Parasympathetic Receptor Heart Rate Force  Automaticity  Automaticity  Force  b1 b1 b1 b1 b1 Rate  Force  Conduction velocity  AV block M2 M2 M2 Arterioles SA node Atrial muscle AV node Ventricular muscle Blood vessels Coronary Skeletal muscle Viscera Skin Brain Erectile tissue Salivary gland Contraction Relaxation Contraction Contraction Contraction Contraction Contraction Contraction Relaxation a1 b2 a1 a1 a1 a1 a1 a1 b2 Relaxation Relaxation Vein M3 M3 Sympathetic (Continued, next page) M3
  72. 72. Organ Sympathetic Receptor Parasympathetic Receptor Relaxation Motility  Contraction Contraction Relaxation Viscera Bronchiolar SMC Glands GI track Smooth muscle Sphincters Glands Uterus a2, b2 a1 a1 b2 Secretion Motility  Relaxation Secretion Gastric acid secretion Variable M3 M3 M3 M3 M1 Skin Pilomotor SMC Contraction (piloerection) a1 Salivary glands Secretion a1, b1 Secretion M3 Lacrimal glands Secretion M3 Kidney Renin release b1 Liver Glycogenolysis Gluconeogenesis b2, a1 b2, a1 b2 Fat Lipolysis b3 M3Contraction
  73. 73. Cardiovascular Pharmacology (Blood Pressure)
  74. 74. Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenol in man. Norepinephrine (predominantly a-agonist) causes vasoconstriction and increased systolic and diastolic BP, with a reflex bradycardia. Isoproterenol (b-agonist) is a vasodilator, but strongly increases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.
  75. 75. Intracellular signaling triggered by acetylcholine in the endothelium eNOS ●NO L-Arg L-Citruline Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO eNOS Nitric oxide synthase
  76. 76. Nitric oxide (NO) signaling pathway for SMC relaxation Second messenger
  77. 77. Pulmonary Pharmacology (Asthma and COPD)
  78. 78. Ocular Pharmacology (Glaucoma)
  79. 79. Lens Pupillary dilator muscle (a1) Pupillary constrictor muscle (M3) Secretion of aqueous humor (b) (M3) Cholinergic effects: Adrenergic effects: • Contraction of pupillary constrictor muscle -- miosis • Contraction of ciliary muscle - bulge of lens -- near vision,  outflow of aqueous humor • Contraction of pupillary dilator muscle -- mydriasis • Stimulation of ciliary epithelium --  production of aqueous humor Trabecular meshwork (opened by pilocarpine)
  80. 80. Enteric nervous system • Collection of well organised neurons in wall of GIT with pupose of controlling its functions • Integrative capability to function independently of CNS • Major network of nerve fibres myentric (Auerbach’s) plexus: between longitudinal and circular muscle layers submucosal (meissner’s) plexus: between circular muscle layer and the mucosa • Nuerotransmitters: Ach, NE, neuropeptide, substance P, serotonin, dopamin, cholecystokinin.
  81. 81. References: • Goodman & Gilman’s The pharmacological basis of therapeutics: 10th 12th edition • Rang and Dale’s pharmacology: 6th edition • Sharma & Sharma’s principles of pharmacology: 1st edition • KD Tripathi’s essentials of medical pharmacology: 7th edition • Katzung’s basic &clinical pharmacology:12th edition • Golan’s principles of pharmacology: 3rd edition • Internet sources….