Monoamine uptake inhibitors block α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation

Abstract

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.

Endogenous methyl palmitate modulates nicotinic receptor-mediated transmission in the superior cervical ganglion

“…SA, PA, and other saturated fatty acids with Ͻ20 hydrocarbon chains have been shown to potentiate ACh-induced, ␣7-nAChR-mediated inward currents, leading to facilitation of hippocampal neurotransmission (31). The postganglionic neurons/cell bodies of the rat SCG also are endowed with ␣7-nAChR (10,25,27). Whole-cell patch-clamp studies, however, demonstrated that PAME (Fig.…”

“…Detailed methods are found in SI Text. SCG cell culture.Detailed methods of culturing SCG neuronal cells (10,32) are found in SI Text. Electrophysiology.…”

“…Electrophysiology. Detailed methods of patch-clamp technique to record whole-cell currents (10,32) of SCG neuronal cells and 2-electrode voltage clamp for ␣7-nAChR-expressing oocytes (27) are found in SI Text.…”

Inhibition by ketamine and amphetamine analogs of the neurogenic nitrergic vasodilations in porcine basilar arteries

“…Whole-cell recording from neurons were obtained according to our previous reports (Si and Lee, 2002;Long et al, 2006; Chen et al, 2012) and those by others (Hamill et al, 1981). The recording electrodes pulled by a P-97 microelectrode puller (Sutter, Novato, CA) were filled with the intracellular solution composed of (in mM) K-gluconate 145, KCl 10, EGTA 1, and HEPES 10, at pH 7.4, and had resistance of 8-18 MΩ.…”

L‐type calcium channels in sympathetic α3β2‐nAChR‐mediated cerebral nitrergic neurogenic vasodilation

“…This is a new description of the autonomic control of the blood flow at least in the brainstem. Furthermore, nicotineinduced axo-axonal interaction-mediated dilation of isolated porcine basilar arteries is blocked by b-amyloid peptides (Si & Lee 2002, Si et al 2005, cholinesterase inhibitors (Mozayan et al 2006) and monoamine uptake inhibitors (Long et al 2006) and diminishes in hypertension (Chang et al 2012). All blockade by these different substances and inhibitors in normal animals is due to inhibition of nAChRs and is prevented by statins (Si et al 2005, Mozayan et al 2006, Mozayan & Lee 2007) and oestrogen (Si et al 2011) but not by testosterone (Lee et al 2011b).…”