We have proposed that activation of cerebral perivascular sympathetic α7-nicotinic acetylcholine receptors (α7-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 α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced α7-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 α-bungarotoxin, and 0.1–10 μM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional α7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In α7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by α-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the α7-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 α7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.
Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys