Central nicotinic acetylcholine receptor involved in Ca 2+- calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects

Pei Wen Cheng, Pei Jung Lu, Siang Ru Chen, Wen Yu Ho, Wen Han Cheng, Ling Zong Hong, Tung Chen Yeh, Gwo Ching Sun, Ling Lin Wang, Michael Hsiao, Ching Jiunn Tseng

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Abstract

BACKGROUND AND PURPOSE Recent evidence has suggested that nicotine decreases blood pressure (BP) and heart rate (HR) in the nucleus tractus solitarii (NTS), indicating that nicotinic acetylcholine receptors (nAChRs) play an important role in BP control in the NTS. However, the signalling mechanisms involved in nAChR-mediated depressor effects in the NTS are unclear. Hence, the aim of this study was to investigate these signalling mechanisms. EXPERIMENTAL APPROACH Depressor responses to nicotine microinjected into the NTS of Wistar-Kyoto rats were elicited in the absence and presence of an antagonist of α7 nAChR, the calcium chelator ethylene glycol tetraacetic acid, a calmodulin-specific inhibitor, nitric oxide (NO) synthase (NOS) inhibitor, endothelial NOS (eNOS)-selective inhibitor or neuronal NOS (nNOS)-specific inhibitor. KEY RESULTS Microinjection of nicotine into the NTS produced a dose-dependent decrease in BP and HR, and increased nitrate levels. This depressor effect of nicotine was attenuated after pretreatment with a nAChR antagonist or blockers of the calmodulin-eNOS pathway. In contrast, N5-(1-Imino-3-butenyl)-L-ornithine (vinyl-L-NIO), nNOS-specific inhibitor, did not diminish these nicotine-mediated effects. Calmodulin was found to bind eNOS after nicotine injection into NTS. However, nicotine did not affect the eNOS phosphorylation level or eNOS upstream extracellular signal-regulated kinases (ERK)1/2 and Akt phosphorylation levels. Furthermore, pretreatment with an ERK1/2 or Akt inhibitor did not attenuate nicotine-induced depressor effects in the NTS. CONCLUSIONS AND IMPLICATIONS These results suggest that the nAChR-Ca 2+-calmodulin-eNOS-NO signalling pathway, but not nNOS, plays a significant role in central BP regulation, and neither the ERK1/2 nor Akt signalling pathway are significantly involved in the activation of eNOS by nAChRs in the NTS.

Original languageEnglish
Pages (from-to)1203-1213
Number of pages11
JournalBritish Journal of Pharmacology
Volume163
Issue number6
DOIs
Publication statusPublished - 2011 Jul 1

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All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Cheng, P. W., Lu, P. J., Chen, S. R., Ho, W. Y., Cheng, W. H., Hong, L. Z., Yeh, T. C., Sun, G. C., Wang, L. L., Hsiao, M., & Tseng, C. J. (2011). Central nicotinic acetylcholine receptor involved in Ca 2+- calmodulin-endothelial nitric oxide synthase pathway modulated hypotensive effects. British Journal of Pharmacology, 163(6), 1203-1213. https://doi.org/10.1111/j.1476-5381.2010.01124.x