HuBio 543 September 28, 2007

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

2. X X X ADRENERGIC NEURON BLOCKERS Tyrosine TH Tyrosine DOPA DDC Dopamine Reserpine DA ++ Ca ++ Ca DßH NE Bretylium NE Guane- thidine NE Bretylium NE Guane- thidine

3. MAO X Reserpine blocks catecholamine transport into vesicles TH Tyrosine DOPA DDC Dopamine Reserpine 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

4. RESERPINE-TREATED CONTROL

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

6. 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

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

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

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

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

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

12. MAO Guane- X thidine X Guanethidine (and guanadrel) TH Tyrosine DOPA DDC Dopamine ++ Ca Ca ++ NE DA DßH NE NE NE Guane- thidine NE 1. Displaces NE from vesicle 2. Blocks evoked release 3. Also blocks NE transport into terminal

13. Effect of guanethidine on NE release & VSM contraction NE Release VSM Contraction NS NS NS NS NS NS + Guanethidine

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

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

16. 60 50 40 30 20 10 0 Guanethidine can lead to supersensitivity of target organs: Increased numbers of adrenergic receptors Cardiac ß-Adrenergic Receptor Number Control Guanethidine- Treated

17. Effect of clonidine on arterial pressure in rabbit +20 30 µg/kg IV 0 Change in mean arterial pressure (mm Hg) -20 1 µg/kg ICV 60 0 40 20 Minutes

18. Sympathetic activity before clonidine: Sympathetic activity after clonidine:

19. Clonidine does not decrease BP in patients with transected spinal cord Transected Controls SC SBP 126 ± 4 109 ± 5† + Clonidine, SBP 104 ±3* 105 ± 5 DBP 74 ±3 66 ± 5† +Clonidine, DBP 59 ± 3* 59 ± 4 † p<0.05, different from controls * p<0.05, different from treated Patients w/ complete cervical SC transection (C3- C7) with separation of central from spinal and peripheral sympatehtic pathways

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

21. 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 Change in Plasma CA pg/ml X X X X X X 1 wk -100

23. 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

24. aMe-NE aMe-NE aMe-NE a -methyldopa is converted to a-methylnorepinephrine DßH DDC Dopa Norepinephrine a-Me-Dopa a-Me- Norepinephrine + a-METHYLDOPA NORMAL NE aMe-NE NE NE NE aMe-NE NE aMe-NE NE NE NE NE E NE NE NE

25. 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

26. Do not confuse a-methyldopa with a -methyltyrosine a -methyltyrosine (metyrosine): - Inhibits tyrosine hydroxylase activity- decreases catecholamine synthesis - Used occasionally for treatment of pheochromocytoma

27. MAO Inhibitors(pargyline) • Cause increased levels of catecholamines in both CNS and periphery • Introduced for the treatment of depression • Can cause hypotension

28. In presence of MAO inhibitor, dietary tyramine is converted to octopamine DßH Tyramine Octopamine + MAO INHIBITOR: NORMAL: Octop NE NE Octop NE NE NE Octop NE NE Octop NE Octop Octop NE NE NE NE Less NE released

29. Cheese Pickled herring Canned figs Chocolate Yeasts Yogurt Game Red wine Chicken livers Fava beans Beer Meat extracts Foods With High Levels of Tyraminewhich can cause hypertensive crisis if ingested with MAO inhibitor

30. 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

31. 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

32. 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

33. 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

34. 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”

35. NGF Promotes neuronal outgrowth from cultured DRG CONTROL + NGF

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

38. TYRAMINE