Sympathetic α₃β₂-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine

Abstract

Lee RH, Liu YQ, Chen PY, Liu CH, Chen MF, Lin HW, Kuo JS, Premkumar LS, Lee TJ. Sympathetic ␣3␤2-nAChRs mediate cerebral neurogenic nitrergic vasodilation in the swine. Am J Physiol Heart Circ Physiol 301: H344 -H354, 2011. First published May 2, 2011; doi:10.1152/ajpheart.00172.2011.-The ␣7-nicotinic ACh receptor (␣7-nAChR) on sympathetic neurons innervating basilar arteries of pigs crossed bred between Landrace and Yorkshire (LY) is known to mediate nicotine-induced, ␤-amyloid (A␤)-sensitive nitrergic neurogenic vasodilation. Preliminary studies, however, demonstrated that nicotine-induced cerebral vasodilation in pigs crossbred among Landrace, Yorkshire, and Duroc (LYD) was insensitive to A␤ and ␣-bungarotoxin (␣-BGTX). We investigated nAChR subtype on sympathetic neurons innervating LYD basilar arteries. Nicotine-induced relaxation of porcine isolated basilar arteries was examined by tissue bath myography, inward currents on nAChR-expressing oocytes by two-electrode voltage recording, and mRNA and protein expression in the superior cervical ganglion (SCG) and middle cervical ganglion (MCG) by reverse transcription PCR and Western blotting. Nicotine-induced basilar arterial relaxation was not affected by A␤, ␣-BGTX, and ␣-conotoxin IMI (␣7-nAChR antagonists), or ␣-conotoxin AuIB (␣3␤4-nAChR antagonist) but was inhibited by tropinone and tropane (␣3-containing nAChR antagonists) and ␣-conotoxin MII (selective ␣ 3␤2-nAChR antagonist). Nicotine-induced inward currents in ␣ 3␤2-nAChR-expressing oocytes were inhibited by ␣-conotoxin MII but not by ␣-BGTX, A␤, or ␣-conotoxin AuIB. mRNAs of ␣ 3-, ␣7-, ␤2-, and ␤4-subunits were expressed in both SCGs and MCGs with significantly higher mRNAs of ␣ 3-, ␤2-, and ␤ 4-subunits than that of ␣7-subunit. The A␤-insensitive sympathetic ␣ 3␤2-nAChR mediates nicotine-induced cerebral nitrergic neurogenic vasodilation in LYD pigs. The different finding from A␤-sensitive ␣ 7-nAChR in basilar arteries of LY pigs may offer a partial explanation for different sensitivities of individuals to A␤ in causing diminished cerebral nitrergic vasodilation in diseases involving A␤.␣ 3␤2-nicotinic ACh receptor; axo-axonal interaction; ␤-amyloid; cerebral perivascular sympathetic nerves; superior cervical ganglion IT IS WELL ESTABLISHED THAT cerebral arteries receive dense sympathetic innervation originating in the superior cervical ganglion (SCG) (24, 50) and that nicotinic ACh receptors (nAChRs) on the nerve terminals regulate norepinephrine (NE) release (50). In the pigs crossbred between Landrace and Yorkshire in the United States, activation by nicotinic agonists of the nAChRs on perivascular sympathetic nerves innervating cerebral arteries results in release of NE, which then causes release of nitric oxide (NO) from the nearby parasympathetic nitrergic nerves and dilation of the arteries (22, 39). This nicotinic agonist-induced axo-axonal interaction leading to nitrergic vasodilation is mediated by the ␣ 7 -nAChR subtype (39). The vasodilation is blocked by ␤-amyloid peptide (A␤) via inhib...

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

“…It is possible that the concentration of increased released norepinephrine in the synapse is below that capable of significantly activating the β 2 -adrenoceptors and mediated neurogenic vasodilation, or the enhanced vasodilation is overcome by their possible direct α-adrenoceptor-mediated smooth muscle constriction effects (Easton et al, 2007). This latter suggestion in the basilar arteries is excluded, since porcine basilar arteries are endowed, from functional aspect, predominant β 1 -adrenoceptors (Lee et al, , 2011. Furthermore, the threshold concentration of these agonists (N 30 μM) for a direct constriction of smooth muscle was significantly higher than that for their inhibition of nicotine-induced vasorelaxations (our preliminary results).…”

“…The cerebral perivascular sympathetic nerves originate in the SCG (Lee et al, 2011). To elucidate whether ketamine and methamphetamine blocked native nAChRs, effects of these drugs on nicotine-induced inward currents in dissociated rat SCG neurons were examined.…”

“…Nitric oxide (NO) released from the parasympathetic nerve terminals is the major neurotransmitter which dilates the cerebral arteries (Kimura et al, 1997;Yu et al, 1998;Liu and Lee, 1999). In these arteries, the sympathetic-parasympathetic interaction plays a role in regulating neurogenic nitrergic vasodilation (Zhang et al, 1998;Si and Lee, 2002;Lee et al, 2011). According to this hypothesis, upon activation of nicotinic acetylcholine receptor (nAChR) on cerebral perivascular sympathetic nerves, norepinephrine (NE) released from the sympathetic nerves acts on β 2 -adrenoceptor located on parasympathetic nitrergic nerves, causing NO release.…”

Fatty acid methyl esters as a potential therapy against cerebral ischemia

“…With proper timing and dosage, administration of PAME and SAME can be a successful therapy against cerebral ischemia. Lin et al (2008) first reported that PAME released from SCG (the largest cervical ganglion in the sympathetic tract (Lee et al, 2011a(Lee et al, , 2011bLee et al, 2012;Wu et al, 2014)) is a novel vasodilator (Lin et al, 2008). Exogenous application of PAME directly onto the rabbit or rat thoracic aorta induced vasodilation in a concentration-dependent manner (Lin et al, 2008;Lee et al, 2010;Lee et al, 2011c).…”

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

“…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). The blockade by b-amyloid peptides, however, is dependent on the subtypes of nAChR in that a7-nAChR but not a3b2-nAChR is sensitive to b-amyloid peptides (Si & Lee 2002, Lee et al 2011a, although both types of receptors are sensitive to cholinesterase inhibitors and mediate sympatheticparasympathetic interaction mechanism in inducing cerebral nitrergic vasodilation (Lee et al 2011b).…”