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Monoamine uptake inhibitors block 7-nAChR-mediated cerebral nitrergic neurogenic vasodilation

Departments of ¹Pharmacology and ⁴Neurology, School of Medicine, Southern Illinois University, Springfield, Illinois; ²Institute of Pharmacology and Toxicology, Tzu Chi University Center for Vascular Medicine, College of Life Sciences, and Neuro-Medical Scientific Center, Tzu Chi General Hospital, Hualien, Taiwan; and ³National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland

Submitted 11 November 2005 ; accepted in final form 7 February 2006

We have proposed that activation of cerebral perivascular sympathetic 7-nicotinic acetylcholine receptors (7-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 7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced 7-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 µM) but inhibited at higher concentrations (0.3–10 µM). 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 µM mecamylamine, 1–30 µM methyllycaconitine, 10–300 nM -bungarotoxin, and 0.1–10 µM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional 7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In 7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by -bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the 7-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 7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

imipramine; desipramine; in vitro tissue bath; porcine basilar artery

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