Abstract
Acetylcholine causes endothelium-dependent relaxations in the rat aorta. Both muscarinic acetylcholine receptors (mAChRs) and nicotinic acetylcholine receptors (nAChRs) are expressed in endothelial cells. It is generally accepted that mAChRs are responsible for the endothelium-dependent relaxations evoked by acetylcholine. The present study was designed to investigate whether nAChRs can also be involved in such responses evoked by the cholinergic transmitter. Rings with or without endothelium of aortae of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) normotensive rats were suspended in organ chambers for the measurement of isometric tension. In WKY aortae the muscarinic antagonist atropine abolished the relaxations to increasing concentrations of acetylcholine, confirming that mAChRs are responsible mainly for the response under control conditions. In SHR aortae, atropine caused only partial inhibition of the endothelium-dependent relaxations to acetylcholine; the remaining decreases in tension were inhibited by the nicotinic antagonist mecamylamine, which did not significantly affect the response in the absence of atropine in either SHR or WKY preparations. Thus, when mAChRs are inhibited, nAChRs mediate relaxation to the cholinergic transmitter in the SHR but not the WKY aorta. Nicotine, a direct agonist of the nicotinic receptor, induced endothelium-dependent relaxations in both SHR and WKY rats via the activation of α7-nAChRs, but not by mecamylamine-sensitive nicotinic receptors (α3 subtype). The acetylcholine-induced, atropine-insensitive relaxations and those to nicotine both involve the phosphatidylinositol 3-kinase/AKT pathway. The present study demonstrates that the activation of nAChRs can contribute to acetylcholine-induced, endothelium-dependent relaxations in the aortae of hypertensive animals and suggests that these receptors may contribute to the endothelium-dependent regulation of vascular tone.
Footnotes
This work was supported in part by the Hong Kong Research Grant Council [Grant 780410M]; the Research Centre of Heart, Brain, Hormone and Healthy Aging of the University of Hong Kong; and the World Class University program funded by the Ministry of Education, Science, and Technology, South Korea [Grant R31-20029].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- EDRF
- endothelium-derived relaxing factor
- 4-DAMP
- 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide
- bp
- base pairs
- DHβE
- dihydro-β-erthroidine hydrobromide
- EC
- endothelial cell
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- IKCa
- intermediate-conductance calcium-activated potassium channel
- l-NAME
- Nω-nitro-l-arginine methyl ester
- mAChR
- muscarinic acetylcholine receptor
- MAP
- mitogen-activated protein
- MEK
- MAP kinase kinase
- nAChR
- nicotinic acetylcholine receptor
- NO
- nitric oxide
- PCR
- polymerase chain reaction
- PI3K
- phosphatidylinositol 3-kinase
- SHR
- spontaneously hypertensive rat
- SKCa
- small-conductance calcium-activated potassium channel
- WKY
- Wistar Kyoto
- LY294002
- 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
- PD98059
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
- SB203580
- 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole
- TRAM-34
- 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole
- U0126
- 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene
- UCL 1684
- 6,12,19,20,25,26-hexahydro-5,27:13,18:21,24-trietheno-11,7-metheno-7H-dibenzo[b,n][1,5,12,16]tetraazacyclotricosine-5,13-diium dibromide.
- Received January 18, 2012.
- Accepted March 12, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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