History of neurotransmission and introduction

to ANSDr. Deepika G1st year PG

AIMS

• Introduction• History of neurons and neurotransmission• Scientists and their experiments• Introduction to Autonomic nervous system• ANS Receptor functions • Physiological Effects of ANS• References

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

1st –Neurons, Dendrites and Axons1. 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.

3.Gabreiel Gustan Valentin (1810-1863) First to describe cell, nucleus, nucleolus of neurons(1836).

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.

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

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. 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.

20 Years Later…Protoplasmic extensions Dendrites – Wilhelm His(1889)Axis cylinder Axons – Rudolph A Von Kolliker(1896)Cell Neuron – Wilhelm Von Waldeyer(1891)

Second Big Step: Neuron Doctrine

SANTIAGO RAMON Y CAJAL (1852-1934)

CAMILLO GOLGI(1843- 1926)

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

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.

THE NEURONAL DOCTRINE HAD FOUR TENETSThe 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.

3rd STEP:Discovery of SYNAPSE &

Neurotransmission12. 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.

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

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.

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.

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.

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 heartArgued against retention of heroin in

clinical practicePracticed to induce labour, showed that ovarian secretion caused uterine contraction via an indirect effect by release of pituitrin

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.

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 ananesthetized cat wasmeasured)

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

• 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.

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.

20.Wilhelm Feldberg & Otto Krayerfirst long experiment on role of AchStimulated vagus nerve of dog and cat, measured Ach in venous outflow of hearteffect of parasympathetic out flow in contraction of tongue muscle

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.

• 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.

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.

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.

• 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)

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

26. Sir John Carew Eccles:• Believed that

Synapses had electrical transmission

• 1951-Inserted microelectrodes into nerve cells , recorded electrical responses produced by synapses

INTRODUCTION TO AUTONOMIC

NERVOUS SYSTEM

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

enzymesb. Released following nerve stimulationc. Produce response identical to nerve

stimulated responsed. Potentiated or antagonized by other

substances

Steps Of Neurohumoral Transmission

I. Impulse conduction: Resting transmembrane potential -70mv,high k+ & low Na+ concentration,Impulse ↑↑↑Na+ depolarize overshoot,+20 mvNormalize by activation of Na+ K+ pump.II. Transmitter ReleaseStored in vesicles prejunctionally,Fusion of vesical & axonal membrane through Ca+ influx.

III. Transmitter action on post junctional membraneEPSP: increase in cation permeability depolarisation followed k+ effluxIPSP: increase anion permeability hyperpolarisationIV. Post junctional activityV. 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

• Graded in magnitude

• Have no threshold

• Cause depolarizationo Movement of

Na+ and K+• Summate• Have no

refractory period

Excitatory post synaptic

potential

Inhibitory Post Synaptic Potential

• Cause hyperpolarizationoK+ or Cl-

• Small in magnitude

• Makes membrane less excitable

Synthesis & Storage

Actionpotential

Metabolism

Recognition(action)

Key Steps in Neurotransmission:

Strategies for Pharmacological Intervention:

Block synthesis and storage: Usually rate-limiting steps; produce long- term effectsBlock release: Rapid action and effectiveBlock reuptake increases synaptic neurotransmitter concentrations Can be selective or non-selectiveInterfere with metabolism: Can be reversible or irreversible; blocking metabolism

increases effective neurotransmitter concentrationsInterfere with recognition: Receptor antagonists & agonists; high specificity

Release

Reuptake

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

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

Synthesis of acetylcholine:

CH3

CH3

CH3

N+–CH2–CH2–OH

CoA–S–C–CH3

O

Choline

Acetyl-CoA

+

Cholineacetyltransferase

CH3

CH3

CH3

N+–CH2–CH2–O–C–CH3

O

CoA-SH

+

CoA

Acetylcholine

Synthesis, storage and release of acetylcholine:

Pre-synapticcell

Post-synapticcell

Ach

Ca2+

Na+

Choline(10 mM)

Choline

Recognitionby receptors

Ca2+

Ach

Ach

Ach

Nerveimpulse

NN

NM

AchAc-CoA

ChAT

Ach

AchE

AchE

choline+ acetic acid

CAT = choline acetyltransferaseAchE = acetylcholinesterase

Synapticcleft

Antiporter

CH3COOH+AchE

(CH3)3 N+–CH2–CH2–OH(CH3)3 N+–CH2–CH2–O–C–CH3

OH2

O

OH(-)AchE

Glu202Tyr337

Ser203Glu334His447

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

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

• 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.

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

glandii. 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.

HO

HO

CH2

NHCH3

OH

CH

Epinephrine

HO

HO

CH2

NH2

OH

CH

NorepinephrineHO

HO

CH2

NH2

CH2

Dopamine

HO

HO

HC

NH2

CH2

DOPA

COOHHOHC

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 transferasePhenylethanolamine-

13

L-phenylalanine

Pre-synapticPost-synaptic

Ca2+

Na+

Tyrosine

Cellular messengersand effects

Diffusion, metabolism

Tyrosine

Dopa

TH

DDDopamine(DA)

NE

DBHATP

Ca2+

NE

DBHATP NE

NE

COMT

aR

bR

a2R

NE

(-)

Signal

Regulation of Norepinephrine Synthesis and Metabolism:

Uptake-1

Normetanephrine (NMN)

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

• 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

• 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

PNS RECEPTOR FUNCTIONS

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)

“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)

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.

“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.

• 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)

Agonist

Muscarinic acetylcholine receptors –G Protein-Coupled Receptors (“Metabotropic” Receptors)

Agonist

M1(enteric, neuronal)

M2(cardiac)

M3(glandular, vascular )

Gq Gi

IP3, DAG

(Depolarization)

(Stimulation)

Intracellular Ca2+

cAMP

Ca2+ channel

­ K+ conductance K+ conductance

Mostly excitatoryCNS excitationGastric acid secretionGastrointestinal motility

Mostly inhibitoryCardiac inhibitionPresynaptic inhibitionNeuronal inhibition

Glandular secretionContraction of visceral smooth muscleVasodilation (via NO)

(Slow IPSP)

(Inhibition)

M5(CNS)

M4(CNS)

Intracellular signaling triggered by acetylcholine in the Heart

Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase

Clinical manifestation of excessive cholinergic effects

D – DefecationU – Urination M – MiosisB – BradycardiaE – EmesisL – Lacrimation S – Salivation

(DUMBELS)

Classification of adrenergic receptors by agonist potency

a -- NE Epi > Iso

b -- Iso > Epi > NE

NE = norepinephrineEpi = epinephrineIso = isoproterenol

HO

HO

CH2

NHCH3

OH

CH

Epi

HO

HO

CH2

NH2

OH

CH

NE

HO

HO

CH2

NH

OHCH

IsoCH(CH3)2

Agonist

Signaling properties of adrenergic receptors

AgonistAgonista1 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

NorepinephrineEpinephrinePhenylephrine

NorepinephrineMethyl NEClonidine

IsoproterenolAlbuterol (b2)Dobutamine (b1)

Gs and Gi proteins have different functions

Agonist

bg as

Agonist

bgai

AC

asbg

ai bg

Gs = stimulatory G protein

Gi = inhibitory G protein

AC = adenylyl cyclase (convert ATP to cAMP)

Beta1 receptor Alpha2 receptor

a1: Postsynaptic effector cells, especially smooth muscle, salivary glands, liver cells

Vasoconstriction, relaxation of intestine, salivary secretion, hepatic glycogenolysisa2 : 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:

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

3b postsynaptic effector cells: lipocytesLipolysis

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

COOHTH

DD (L-AAD)

DBHPNMT

Tyrosine hydroxylase

Dopa decarboxylase (L-amino acid decarboxylase)

Dopamine b-hydroxylase

Phenylethanolamine-N-methyl transferase

13

Dopaminergic receptors

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

Physiological Effects of ANS

Receptor distribution and effects in the autonomic nervous system:

Organ Receptor Parasympathetic Receptor

Heart

RateForce Automaticity

Automaticity Force

1­b1­

b1­

b1­

b1­

Rate Force Conduction velocity AV block

M2

M2

M2

Arterioles

SA nodeAtrial muscleAV node

Ventricular muscle

Blood vessels

CoronarySkeletal muscleVisceraSkinBrainErectile tissueSalivary gland

ContractionRelaxationContractionContractionContractionContractionContractionContractionRelaxation

a1

b2

a1

a1

a1

a1

a1

a1

b2

RelaxationRelaxation

Vein

M3

M3

Sympathetic

(Continued, next page)

M3

Organ Sympathetic Receptor Parasympathetic Receptor

Relaxation

Motility Contraction

ContractionRelaxation

Viscera

Bronchiolar SMC GlandsGI track Smooth muscle Sphincters Glands

Uterus

a2,­b2

a1

1ab2

Secretion

Motility RelaxationSecretionGastric acid secretion

Variable

M3

M3

M3

M3

M1

Skin Pilomotor SMC Contraction (piloerection) 1a

Salivary glands Secretion a1,­b1 Secretion M3

Lacrimal glands Secretion M3

Kidney Renin release b1

Liver GlycogenolysisGluconeogenesis

2,­ 1b a2,­ 1a

b2

Fat Lipolysis b3

M3Contraction

Cardiovascular Pharmacology(Blood Pressure)

Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenolin man. Norepinephrine (predominantly a-agonist) causes vasoconstriction and increased systolicand diastolic BP, with a reflex bradycardia. Isoproterenol (b-agonist) is a vasodilator, but stronglyincreases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.

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

Nitric oxide (NO) signaling pathway for SMC relaxation

Secondmessenger

Pulmonary Pharmacology(Asthma and COPD)

Ocular Pharmacology(Glaucoma)

Lens

Pupillary dilator muscle ( 1a )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)

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.

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….