Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Fransen, Paul; Hove, Cor E. Van; Langen, Johanna van; Bult, Hidde

doi:10.5772/47771

Cited by 7 publications

(16 citation statements)

References 76 publications

(87 reference statements)

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“…Basal NO release was inhibited by incubation with 300 μM L-NAME. The first derivative of the individual concentration-response curves of (A,C) are displayed in (B,D) and correlate with window contraction curves because of L-type Ca 2+ influx (Fransen et al, 2012a , b ). The dashed lines correspond with the EC 50 of K + or the maximal change of relative tension per concentration of K + with eNOS active, whereas the arrows between (B) and (D) indicate the shifts of the concentration-contraction curves after inhibition of eNOS with L-NAME for aorta (ao), carotid artery (ca), and mesenteric artery (ma).…”

Section: Resultsmentioning

confidence: 94%

“…Basal NO activity can be determined with high accuracy and sensitivity by measuring the inhibitory action on contractions induced by α 1 -adrenoceptor stimulation with PE and by measuring shifts of the depolarization-mediated window contraction curves (Fransen et al, 2012a , b ; van Langen et al, 2012 , 2013 ). Therefore, contractions by PE and shifts of window contraction curves were measured before and after inhibition of basal NO formation by endothelial NO synthase (eNOS) with 300 μM N Ω -nitro-L-arginine methyl ester (L-NAME).…”

Section: Methodsmentioning

confidence: 99%

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Elastic and Muscular Arteries Differ in Structure, Basal NO Production and Voltage-Gated Ca2+-Channels

et al. 2015

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In the last decades, the search for mechanisms underlying progressive arterial stiffening and for interventions to avoid or reverse this process has gained much attention. In general, arterial stiffening displays regional variation and is, for example, during aging more prominent in elastic than in muscular arteries. We hypothesize that besides passive also active regulators of arterial compliance [i.e., endothelial and vascular smooth muscle cell (VSMC) function] differ between these arteries. Hence, it is conceivable that these vessel types will display different time frames of stiffening. To investigate this hypothesis segments of muscular arteries such as femoral and mesenteric arteries and elastic arteries such as the aorta and carotid artery were isolated from female C57Bl6 mice (5–6 months of age, n = 8). Both microscopy and passive stretching of the segments in a myograph confirmed that passive mechanical properties (elastin, collagen) of elastic and muscular arteries were significantly different. Endothelial function, more specifically basal nitric oxide (NO) efficacy, and VSMC function, more specifically L-type voltage-gated Ca2+ channel (VGCC)-mediated contractions, were determined by α1-adrenoceptor stimulation with phenylephrine (PE) and by gradual depolarization with elevated extracellular K+ in the absence and presence of eNOS inhibition with L-NAME. PE-mediated isometric contractions significantly increased after inhibition of NO release with L-NAME in elastic, but not in muscular vessel segments. This high basal eNOS activity in elastic vessels was also responsible for shifts of K+ concentration-contraction curves to higher external K+. VGCC-mediated contractions were similarly affected by depolarization with elevated K+ in muscular artery segments or in elastic artery segments in the absence of basal NO. However, K+-induced contractions were inhibited by the VGCC blocker diltiazem with significantly higher sensitivity in the muscular arteries, suggestive of different populations of VGCC isoforms in both vessel types. The results from the present study demonstrate that, besides passive arterial wall components, also active functional components contribute to the heterogeneity of arterial compliance along the vascular tree. This crucially facilitates the search for (patho) physiological mechanisms and potential therapeutic targets to treat or reverse large artery stiffening as occurring in aging-induced arterial stiffening.

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Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Elastic and Muscular Arteries Differ in Structure, Basal NO Production and Voltage-Gated Ca2+-Channels

et al. 2015

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“…As demonstrated for depolarization with extracellular K + elevation [ 9 , 10 ], PE-induced contractions displayed a bi-exponential time course with a fast and slow force component. Contrary to K + -depolarized segments, where the fast, transient component corresponded to a population of L-type Ca 2+ channels that quickly activated and completely inactivated [ 9 ], the fast and transient component of the PE-response was voltage-independent, independent of external Ca 2+ , could not be inhibited with L-type Ca 2+ channel blockers, but was sensitive to 2-APB.…”

Section: Discussionmentioning

confidence: 91%

“…In basal, non-stimulated conditions, there is a time-independent, baseline Ca 2+ influx via L-type Ca 2+ channels, which van be inhibited by removal of extracellular Ca 2+ , by hyperpolarization with levcromakalim or by L-type Ca 2+ channel blockers [ 9 , 10 ]. Hence, if PE induces depolarisation and opening of L-type Ca 2+ channels [ 15 – 19 ], the PE-elicited contraction of VSMC is expected to depend on shifts of V m in the hyper- or depolarizing direction.…”

Section: Resultsmentioning

confidence: 99%

Dissecting out the Complex Ca2+-Mediated Phenylephrine-Induced Contractions of Mouse Aortic Segments

et al. 2015

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L-type Ca2+ channel (VGCC) mediated Ca2+ influx in vascular smooth muscle cells (VSMC) contributes to the functional properties of large arteries in arterial stiffening and central blood pressure regulation. How this influx relates to steady-state contractions elicited by α1-adrenoreceptor stimulation and how it is modulated by small variations in resting membrane potential (Vm) of VSMC is not clear yet. Here, we show that α1-adrenoreceptor stimulation of aortic segments of C57Bl6 mice with phenylephrine (PE) causes phasic and tonic contractions. By studying the relationship between Ca2+ mobilisation and isometric tension, it was found that the phasic contraction was due to intracellular Ca2+ release and the tonic contraction determined by Ca2+ influx. The latter component involves both Ca2+ influx via VGCC and via non-selective cation channels (NSCC). Influx via VGCC occurs only within the window voltage range of the channel. Modulation of this window Ca2+ influx by small variations of the VSMC Vm causes substantial effects on the contractile performance of aortic segments. The relative contribution of VGCC and NSCC to the contraction by α1-adrenoceptor stimulation could be manipulated by increasing intracellular Ca2+ release from non-contractile sarcoplasmic reticulum Ca2+ stores. Results of this study point to a complex interactions between α1-adrenoceptor-mediated VSMC contractile performance and Ca2+ release form contractile or non-contractile Ca2+ stores with concomitant Ca2+ influx. Given the importance of VGCC and their blockers in arterial stiffening and hypertension, they further point toward an additional role of NSCC (and NSCC blockers) herein.

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“…Thereby, the capacitive Ca 2 þ influx has been shown to be the principal stimulus for sustained activation of eNOS on the plasma membrane (Boeldt et al, 2011;Lin et al, 2000). Unlike the direct inhibitory effect of NO on IP 3 -mediated contractions in 0Ca, NO has also been described to cause inhibition of basal Ca 2 þ influx through LCC (Blatter and Wier, 1994;Fransen et al, 2012b). Although it is expected that this inhibitory effect of NO on LCC Ca 2 þ influx would result in elevated phasic phenylephrine-induced contractions after inhibition of basal eNOS activity with L-NAME, it was observed that phasic contractions by phenylephrine were smaller in the presence of L-NAME and basal NO release inhibition.…”

Section: Phenylephrine-induced Phasic Contractions Are Inhibited and mentioning

confidence: 96%

Basal activity of voltage-gated Ca2+ channels controls the IP3-mediated contraction by α1-adrenoceptor stimulation of mouse aorta segments

Leloup

Hove

Meyer

et al. 2015

European Journal of Pharmacology

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Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

Cited by 7 publications

References 76 publications

Elastic and Muscular Arteries Differ in Structure, Basal NO Production and Voltage-Gated Ca2+-Channels

Elastic and Muscular Arteries Differ in Structure, Basal NO Production and Voltage-Gated Ca2+-Channels

Dissecting out the Complex Ca2+-Mediated Phenylephrine-Induced Contractions of Mouse Aortic Segments

Basal activity of voltage-gated Ca2+ channels controls the IP3-mediated contraction by α1-adrenoceptor stimulation of mouse aorta segments

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