Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.
We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.
Long
Cheng
C
Department of Pharmacology, School of Medicine, Southern Illinois University, Springfield, Illinois, USA.
Chen
Mei-Fang
MF
Sarwinski
Susan J
SJ
Chen
Po-Yi
PY
Si
Minliang
M
Hoffer
Barry J
BJ
Evans
M Steven
MS
Lee
Tony J F
TJ
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage*; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology*; D015306:Biogenic Monoamines / Q000378:metabolism*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D003891:Desipramine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D007099:Imipramine / Q000008:administration & dosage; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000187:drug effects / Q000502:physiology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009569:Nitric Oxide; D007099:Imipramine; D003891:Desipramine