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Vasodilator efficacy of nitric oxide depends on mechanisms of intracellular calcium mobilization in mouse aortic smooth muscle cells
Author(s) -
Van Hove CE,
Van der Donckt C,
Herman AG,
Bult H,
Fransen P
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00396.x
Subject(s) - bay k8644 , phenylephrine , chemistry , serca , nitric oxide , medicine , contraction (grammar) , calcium , endocrinology , stimulation , vascular smooth muscle , vasodilation , acetylcholine , intracellular , calcium in biology , biophysics , voltage dependent calcium channel , biochemistry , biology , atpase , enzyme , smooth muscle , blood pressure
Background and purpose: Reduction of intracellular calcium ([Ca 2+ ] i ) in smooth muscle cells (SMCs) is an important mechanism by which nitric oxide (NO) dilates blood vessels. We investigated whether modes of Ca 2+ 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 [Ca 2+ ] 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 [Ca 2+ ] i , which was suppressed by sarcoplasmic reticulum (SR) Ca 2+ ATPase (SERCA) inhibition, but not by soluble guanylyl cylase (sGC) inhibition. Relaxation of K + ‐stimulated segments did not parallel a decline of [Ca 2+ ] i . However, stimulation (BAY K8644) of L‐type Ca 2+ influx diminished, while inhibition (nifedipine, 1–100 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 Ca 2+ re‐uptake into the SR and was prominent when intracellular Ca 2+ was mobilized. The other involved sGC‐stimulated cGMP formation, causing relaxation without changing [Ca 2+ ] i , presumably by desensitizing the contractile apparatus. This pathway seems related to L‐type Ca 2+ influx, and L‐type Ca 2+ channel blockers increase the vasodilator efficacy of NO.