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Title
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Vasodilator efficacy of nitric oxide depends on mechanisms of intracellular calcium mobilization in mouse aortic smooth muscle cells
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Author
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Abstract
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| Background and purpose: Reduction of intracellular calcium ([Ca2+]i) in smooth muscle cells (SMCs) is an important mechanism by which nitric oxide (NO) dilates blood vessels. We investigated whether modes of Ca2+ mobilization during SMC contraction influenced NO efficacy. Experimental approach: Isometric contractions by depolarization (high potassium, K+) or α-adrenoceptor stimulation (phenylephrine), and relaxations by acetylcholine chloride (ACh), diethylamine NONOate (DEANO) and glyceryl trinitrate (GTN) and SMC [Ca2+]i (Fura-2) were measured in aortic segments from C57Bl6 mice. Key results: Phenylephrine-constricted segments were more sensitive to endothelium-derived (ACh) or exogenous (DEANO, GTN) NO than segments contracted by high K+ solutions. The greater sensitivity of phenylephrine-stimulated segments was independent of the amount of pre-contraction, the source of NO or the resting potential of SMCs. It coincided with a significant decrease of [Ca2+]i, which was suppressed by sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) inhibition, but not by soluble guanylyl cylase (sGC) inhibition. Relaxation of K+-stimulated segments did not parallel a decline of [Ca2+]i. However, stimulation (BAY K8644) of L-type Ca2+ influx diminished, while inhibition (nifedipine, 1100 nM) augmented the relaxing capacity of NO. Conclusions and implications: In mouse aorta, NO induced relaxation via two pathways. One mechanism involved a non-cGMP-dependent stimulation of SERCA, causing Ca2+ re-uptake into the SR and was prominent when intracellular Ca2+ was mobilized. The other involved sGC-stimulated cGMP formation, causing relaxation without changing [Ca2+]i, presumably by desensitizing the contractile apparatus. This pathway seems related to L-type Ca2+ influx, and L-type Ca2+ channel blockers increase the vasodilator efficacy of NO. |
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Language
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English
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Source (journal)
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British journal of pharmacology. - London
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Publication
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London
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2009
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ISSN
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0007-1188
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DOI
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10.1111/J.1476-5381.2009.00396.X
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Volume/pages
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158
:3
(2009)
, p. 920-930
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ISI
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000270826600026
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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