HuBio 543 September 28, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Adrenergic Neuron Blockers and Other Stuff

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

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

RESERPINE-TREATED CONTROL

Reserpine blocks vasopressor response to tyramine and but not to norepinephrine BP + Tyramine + Norepinephrine Pretreat with Reserpine: BP + Tyramine + Norepinephrine

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

ADRENERGIC NEURON BLOCKERS Sym. Term. Adrenal Medulla Cocaine- Like Effect CNS YES YES Reserpine YES NO Bretylium Guanethidine

Bretylium blocks evoked release of NE TH Tyrosine DOPA DDC Dopamine DA Ca ++ Ca ++ DßH NE Bretylium X NE NE X Bretylium NE

Effects of pretreatments on smooth muscle contraction Control + Hexa- methonium + Bretylium Pregang- lionic Stimulation Postgang- lionic Stimulation + NE

Effects of pretreatments on smooth muscle contraction Control + Phenoxyben- zamine + Bretylium + Reserpine Nerve Stimu- lation + NE

ADRENERGIC NEURON BLOCKERS Sym. Term. Adrenal Medulla Cocaine- Like Effect CNS Reserpine YES YES YES NO YES Bretylium YES NO NO Guanethidine

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

Effect of guanethidine on NE release & VSM contraction NS NS NS NS NS NS + Guanethidine

Effect of Guanethidine on Blood Pressure Responses After Guanethidine: Control: + NE + NE + Tyramine + Tyramine + Amphetamine + Amphetamine

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

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

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

Sympathetic activity before clonidine: Sympathetic activity after clonidine:

Clonidine does not decrease BP in patients with transected spinal cord 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 † 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

Decreased Blood Pressure and Heart Rate in Patients Taking Clonidine -30 -10 Change in Heart Rate Change in BP, mm Hg

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

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

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

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

Do not confuse a-methyldopa with a -methyltyrosine a -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

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

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 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 85 141 128 Plasma NE 524 1840 570 Phenylephrine- induced HR -13 ± 4 -1 ± 1 -9 ± 4 increase

Clonidine alleviates symptoms of baroreflex failure # of attacks Increase in Increase in Treatment 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 CONTROL + NGF

Immunosympathectomy by anti- NGF Antibody Control Treated with anti- NGF Ab Control Ganglion Sympathetic chains Treated with anti- NGF Ab

TYRAMINE