HuBio 543September 28, 2007
Neil M. NathansonK-536A, [email protected] 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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