hubio 543 september 28, 2007 neil m. nathanson k-536a, hsb 3-9457 nathanso@u.washington.edu...

HuBio 543September 28, 2007

Neil M. NathansonK-536A, HSB3-9457nathanso@u.washington.edu Adrenergic Neuron Blockers and Other Stuff

ADRENERGIC NEURON BLOCKERS

DOPA

Dopamine

Tyrosine

Ca++

TyrosineTH

DDC

DA

NEDßH

NE

NE

Ca++

Reserpine X

X

Bretylium XGuane-thidine

NE

Guane-thidine

Bretylium

Reserpine blocks catecholamine transport into vesicles

DOPA

Dopamine

Ca++

TyrosineTH

DDC

DA

NE

DßH

NE

NE

Ca++

Reserpine X

NE

Depletes catecholamines because: 1. Blocks DA transport into vesicle-blocks de novo synthesis of NE 2. Blocks reuptake into vesicle of previously released NE 3. Blocks reuptake of NE that leaks out of vesicle

MAO

RESERPINE-TREATED CONTROL

+ Tyramine + Norepinephrine

Pretreat with Reserpine:

Reserpine blocks vasopressor response to tyramine and but not to norepinephrine

+ Norepinephrine+ Tyramine

BP

BP

Reserpine

• Decreases blood pressure and heart rate• Increases GI tone and motility• Causes:

– Postural hypotension– Diarrhea– Sexual dysfunction– CNS effects: sedation, depression

• Can be used for treatment of hypertension

Sym.Term. CNS

AdrenalMedulla

Cocaine-Like Effect

Guanethidine

Bretylium

Reserpine

ADRENERGIC NEURON BLOCKERS

YES YESYES NO

Bretylium blocks evoked release of NE

DOPA

Dopamine

Ca++

TyrosineTH

DDC

DA

NEDßH

NE

NE

Ca++

X

Bretylium X NE

Bretylium

+ Hexa-methonium

+ Bretylium

Pregang-lionicStimulation

+ NE

Effects of pretreatments on smooth muscle contraction

Control

Postgang-lionicStimulation

+ Phenoxyben- zamine

+ Bretylium

+ Reserpine Nerve

Stimu-lation

+ NE

Control

Effects of pretreatments on smooth muscle contraction

Sym.Term. CNS

AdrenalMedulla

Cocaine-Like Effect

Guanethidine

Bretylium

Reserpine

ADRENERGIC NEURON BLOCKERS

YES YESYES NO

YES YESNONO

Guanethidine (and guanadrel)

DOPA

Dopamine

Ca++

TyrosineTH

DDC

DADßH

NE

NE

Ca++

X

X

Guane-thidine

NE

Guane-thidine

NE

NE

1. Displaces NE from vesicle2. Blocks evoked release3. Also blocks NE transport into terminal

MAO

NERelease

VSMContraction

+ Guanethidine

Effect of guanethidine on NE release & VSM contraction

NS NSNSNSNSNS

Effect of Guanethidine on Blood Pressure Responses

+ NE

+ Tyramine

+ Amphetamine

After Guanethidine:Control:

+ NE

+ Tyramine

+ Amphetamine

Sym.Term. CNS

AdrenalMedulla

Cocaine-Like Effect

Guanethidine

Bretylium

Reserpine

ADRENERGIC NEURON BLOCKERS

YES YESYES NO

YES

YES

YES

YES

NO NO

NONO

Guanethidine can lead to supersensitivity of target organs:Increased numbers of adrenergic receptors

0

10

20

30

40

50

60Cardiac ß-

Adrenergic

Receptor Number

Control Guanethidine-

Treated

6040200

-20

+20

0

Change in mean arterial pressure

(mm Hg)

Minutes

30 µg/kg IV

1 µg/kg ICV

Effect of clonidine on arterial pressure in rabbit

Sympathetic activitybefore clonidine:

Sympathetic activityafter clonidine:

Patients w/ complete cervical SC transection (C3- C7) with separation of central from spinal and peripheral sympatehtic pathways

SBP 126 ± 4 109 ± 5†

+ Clonidine, SBP 104 ±3* 105 ± 5

DBP 74 ±3 66 ± 5†

+Clonidine, DBP 59 ± 3* 59 ± 4

Transected Controls SC

Clonidine does not decrease BP in patients with transected spinal

cord

† p<0.05, different from controls

* p<0.05, different from treated

-30 -10

-10

-30

Change in Heart

Rate

Change in BP, mm Hg

Decreased Blood Pressure and Heart Rate in Patients Taking

Clonidine

-30 -10

10

-50

-100

1 wk

3 mo.

Change in Plasma

CA pg/ml

Change in BP mm Hg

Decreased Blood Pressure and Plasma Catecholamines in Patients Taking Clonidine

X

X

X

XX

X

X

X

XX

XX

XX

X

Clonidine

• Selective 2 agonist• Acts in the CNS to decrease sympathetic outflow:

Sympathetic activitybefore clonidine:

Sympathetic activityafter clonidine:

Other 2 agonists used therapeutically: apraclonidine, guanfacine, guanabenz

Dopa DDC DßH Norepinephrine

-Me-Dopa -Me- Norepinephrine

NENE

NE

NE

NE

E NE NE NE

NE

NEMe-NE

NE

NE

Me-NE

Me-NE

Me-NE

Me-NE Me-NE

-methyldopa is converted to -methylnorepinephrine

NORMAL+ -METHYLDOPA

-Methyldopa

-methyldopa converted in nerve terminal to -methylnorepinephrine

-methylnorepinephrine is an 2-adrenergic agonist:acts in CNS to decrease sympathetic outflow

-methylnorepinephrine is stored in vesicles and released with nerve stimulation

-methyldopa is used for the treatment of hypertension

Do not confuse -methyldopa with -methyltyrosine

-methyltyrosine (metyrosine):- Inhibits tyrosine hydroxylase activity- decreases catecholamine synthesis- Used occasionally for treatment of pheochromocytoma

MAO Inhibitors(pargyline)

• Cause increased levels of catecholamines in both CNS and periphery

• Introduced for the treatment of depression

• Can cause hypotension

In presence of MAO inhibitor, dietary tyramine is converted to octopamine

DßHTyramine

Octopamine

NENE

NE

NE

NE

NE NE NE

NE

NE

Octop

NE

NE

Octop

OctopOctop

Octop Octop

NORMAL: + MAO INHIBITOR:

Less NE released

Foods With High Levels of Tyramine

which can cause hypertensive crisis if ingested with MAO inhibitor

• Cheese• Pickled herring

• Canned figs• Chocolate• Yeasts• Yogurt

• Game• Red wine• Chicken livers

• Fava beans• Beer• Meat extracts

MAO Inhibitors(pargyline)

• Cause hypotension- dietary tyramine converted to octopamine in nerve terminal– Octopamine acts as false transmitter

• High levels of dietary tyramine (with MAO inhibitor) can cause hypertensive crisis– Tyramine causes NE release

11/500 patients w/ hypertension or suspected pheo had baroreflex failure- volatile BP and HR

4 patients - tumors in carotid body3 patients - neck irradiation for

throat carcinoma1 patient - surgical ressection of

glossopharyngeal nerve1 patient- loss of cells in brainstem2 patients - ?

MAP 85 141 128

Plasma NE 524 1840 570

Phenylephrine-induced HR -13 ± 4 -1 ± 1 -9 ± 4increase

Baroreflex EssentialNormal Failure Hypertension

Clonidine alleviates symptoms of baroreflex failure

# of attacks Increase in Increase inTreatment per day systolic press. HR

Placebo 4.7 ± 1.1 92 ± 23 58± 9

Clonidine 0.9 ± 0.3 32 ± 16 33 ± 6

POB 4.4 ± 1.2 37 ± 21 62 ± 14

6-Hydroxydopamine

• Taken up by adrenergic nerves• Oxidized to toxic compounds• Causes “chemical sympathectomy”:– Causes destruction of nerve terminals

– In newborns, also destroys cell bodies

NGF: Nerve Growth Factor

• NGF and its receptors are important for survival of sympathetic and sensory neurons

• Antibodies against NGF destroy newborn’s sympathetic nervous system: “immunosympathectomy”

NGF Promotes neuronal outgrowth from cultured DRG

+ NGF CONTROL

Immunosympathectomy by anti- NGF Antibody

Treated with anti- NGF Ab

Control

Treated with anti- NGF Ab

Control

Sympathetic chains

Ganglion

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TYRAMINE

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