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HuBio 543 September 28, 2007 Neil M. Nathanson K-536A, HSB 3-9457
Adrenergic Neuron Blockers and Other Stuff
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X X X ADRENERGIC NEURON BLOCKERS Tyrosine Tyrosine DOPA Dopamine
TH Tyrosine DOPA DDC Dopamine Reserpine X DA Ca ++ Ca ++ DßH NE Bretylium X Guane- NE thidine NE X Bretylium Guane- NE thidine
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X Reserpine blocks catecholamine transport into vesicles Tyrosine DOPA
TH Tyrosine DOPA DDC MAO Dopamine Reserpine X DA Ca ++ Ca ++ DßH NE NE NE 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
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RESERPINE-TREATED CONTROL
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Reserpine blocks vasopressor response to tyramine and but not to norepinephrine
BP + Tyramine + Norepinephrine Pretreat with Reserpine: BP + Tyramine + Norepinephrine
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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
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ADRENERGIC NEURON BLOCKERS
Sym. Term. Adrenal Medulla Cocaine- Like Effect CNS YES YES Reserpine YES NO Bretylium Guanethidine
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Bretylium blocks evoked release of NE
TH Tyrosine DOPA DDC Dopamine DA Ca ++ Ca ++ DßH NE Bretylium X NE NE X Bretylium NE
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Effects of pretreatments on smooth muscle contraction
Control + Hexa- methonium + Bretylium Pregang- lionic Stimulation Postgang- lionic Stimulation + NE
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Effects of pretreatments on smooth muscle contraction
Control + Phenoxyben zamine + Bretylium + Reserpine Nerve Stimu- lation + NE
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ADRENERGIC NEURON BLOCKERS
Sym. Term. Adrenal Medulla Cocaine- Like Effect CNS Reserpine YES YES YES NO YES Bretylium YES NO NO Guanethidine
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Guanethidine (and guanadrel)
Tyrosine DOPA DDC MAO Dopamine Ca ++ Ca ++ NE DA Guane- thidine DßH NE X NE NE X Guane- thidine NE 1. Displaces NE from vesicle 2. Blocks evoked release 3. Also blocks NE transport into terminal
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Effect of guanethidine on NE release & VSM contraction
NS NS NS NS NS NS + Guanethidine
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Effect of Guanethidine on Blood Pressure Responses
After Guanethidine: Control: + NE + NE + Tyramine + Tyramine + Amphetamine + Amphetamine
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ADRENERGIC NEURON BLOCKERS
Sym. Term. Adrenal Medulla Cocaine- Like Effect CNS Reserpine YES YES YES NO YES Bretylium YES NO NO Guanethidine YES NO NO YES
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Guanethidine can lead to supersensitivity of target organs:
Increased numbers of adrenergic receptors 10 20 30 40 50 60 Cardiac ß-Adrenergic Receptor Number Control Guanethidine- Treated
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Change in mean arterial pressure
Effect of clonidine on arterial pressure in rabbit +20 30 µg/kg IV Change in mean arterial pressure (mm Hg) -20 1 µg/kg ICV 20 40 60 Minutes
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Sympathetic activity before clonidine: Sympathetic activity after clonidine:
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Clonidine does not decrease BP in patients with transected spinal cord
SBP ± ± 5† + Clonidine, SBP ±3* ± 5 DBP ± ± 5† +Clonidine, DBP ± 3* ± 4 Transected Controls SC † p<0.05, different from controls * p<0.05, different from treated 30 minutes after clonidine Kooner et al., Circulation, 84, 75 (1991) Patients w/ complete cervical SC transection (C3- C7) with separation of central from spinal and peripheral sympatehtic pathways
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Decreased Blood Pressure and Heart Rate in Patients Taking Clonidine
-30 -10 Change in Heart Rate Change in BP, mm Hg
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Change in Plasma CA pg/ml
Decreased Blood Pressure and Plasma Catecholamines in Patients Taking Clonidine Change in BP mm Hg -30 10 -10 X X X 3 mo. X X X X -50 X X X X Change in Plasma CA pg/ml X X X X 1 wk -100
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Clonidine Selective a2 agonist
Acts in the CNS to decrease sympathetic outflow: Sympathetic activity after clonidine: Sympathetic activity before clonidine: Other a2 agonists used therapeutically: apraclonidine, guanfacine, guanabenz
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a -methyldopa is converted to a-methylnorepinephrine
DDC DßH Dopa Norepinephrine a-Me-Dopa a-Me- Norepinephrine + a-METHYLDOPA NORMAL NE NE aMe-NE NE NE aMe-NE NE aMe-NE NE NE aMe-NE NE aMe-NE aMe-NE E NE NE NE NE
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a-Methyldopa a-methyldopa converted in nerve terminal to a-methylnorepinephrine a-methylnorepinephrine is stored in vesicles and released with nerve stimulation a-methylnorepinephrine is an a 2-adrenergic agonist: acts in CNS to decrease sympathetic outflow a-methyldopa is used for the treatment of hypertension
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Do not confuse a-methyldopa with a -methyltyrosine
a -methyltyrosine (metyrosine): - Inhibits tyrosine hydroxylase activity- decreases catecholamine synthesis - Used occasionally for treatment of pheochromocytoma
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MAO Inhibitors (pargyline)
Cause increased levels of catecholamines in both CNS and periphery Introduced for the treatment of depression Can cause hypotension
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Less NE released In presence of MAO inhibitor,
dietary tyramine is converted to octopamine DßH Tyramine Octopamine NE Octop NORMAL: + MAO INHIBITOR: Less NE released
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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
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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
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11/500 patients w/ hypertension or suspected pheo had baroreflex failure- volatile BP and HR
4 patients - tumors in carotid body 3 patients - neck irradiation for throat carcinoma 1 patient - surgical ressection of glossopharyngeal nerve 1 patient- loss of cells in brainstem 2 patients - ? Baroreflex Essential Normal Failure Hypertension MAP Plasma NE Phenylephrine- induced HR ± ± ± 4 increase
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Clonidine alleviates symptoms of baroreflex failure
# of attacks Increase in Increase in Treatment per day systolic press HR Placebo 4.7 ± ± ± 9 Clonidine ± ± ± 6 POB ± ± ± 14
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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
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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”
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NGF Promotes neuronal outgrowth from cultured DRG
CONTROL + NGF
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Immunosympathectomy by anti- NGF Antibody
Control Treated with anti- NGF Ab Control Ganglion Sympathetic chains Treated with anti- NGF Ab
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TYRAMINE
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