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

Leloup, Arthur; Hove, Cor E. Van; Meyer, Guido R.Y. De; Schrijvers, Dorien M.; Fransen, Paul

doi:10.1016/j.ejphar.2015.04.011

Cited by 13 publications

(23 citation statements)

References 54 publications

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“…α 1 -Adrenoceptor stimulation of mouse aortic segments with 2 μM PE in the absence of external Ca 2+ caused phasic contractions (Fransen et al, 2015 ; Leloup et al, 2015a ), which decreased with higher preloads in static stretch segments, as described previously (De Moudt et al, 2017 ; Figures 3A–C ). Conditioning of the segments for 1 h with normal/high cyclic stretch amplitude caused smaller IP 3 -mediated contractions by PE.…”

Section: Resultssupporting

confidence: 81%

“…Both phasic (in the absence of extracellular Ca 2+ ) and tonic contractions (after addition of 3.5 mM Ca 2+ ) were measured. The PE-induced phasic contraction was measured 3 min after the removal of extracellular Ca 2+ by switching from normal KR to KR without Ca 2+ and containing 1 mM EGTA (0 Ca solution) (Leloup et al, 2015a ). Recordings of the phasic contractions were analyzed with a double exponential function…”

Section: Methodsmentioning

confidence: 99%

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Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments

et al. 2017

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Large, elastic arteries buffer the pressure wave originating in the left ventricle and are constantly exposed to higher amplitudes of cyclic stretch (10%) than muscular arteries (2%). As a crucial factor for endothelial and smooth muscle cell function, cyclic stretch has, however, never been studied in ex vivo aortic segments of mice. To investigate the effects of cyclic stretch on vaso-reactivity of mouse aortic segments, we used the Rodent Oscillatory Tension Set-up to study Arterial Compliance (ROTSAC). The aortic segments were clamped at frequencies of 6–600 bpm between two variable preloads, thereby mimicking dilation as upon left ventricular systole and recoiling as during diastole. The preloads corresponding to different transmural pressures were chosen to correspond to a low, normal or high amplitude of cyclic stretch. At different time intervals, cyclic stretch was interrupted, the segments were afterloaded and isometric contractions by α1-adrenergic stimulation with 2 μM phenylephrine in the absence and presence of 300 μM L-NAME (eNOS inhibitor) and/or 35 μM diltiazem (blocker of voltage-gated Ca2+ channels) were measured. As compared with static or cyclic stretch at low amplitude (<10 mN) or low frequency (0.1 Hz), cyclic stretch at physiological amplitude (>10 mN) and frequency (1–10 Hz) caused better ex vivo conservation of basal NO release with time after mounting. The relaxation of PE-precontracted segments by addition of ACh to stimulate NO release was unaffected by cyclic stretch. In the absence of basal NO release (hence, presence of L-NAME), physiological in comparison with aberrant cyclic stretch decreased the baseline tension, attenuated the phasic contraction by phenylephrine in the absence of extracellular Ca2+ and shifted the smaller tonic contraction more from a voltage-gated Ca2+ channel-mediated to a non-selective cation channel-mediated. Data highlight the need of sufficient mechanical activation of endothelial and vascular smooth muscle cells to maintain basal NO release and low intracellular Ca2+ in the smooth muscle cells in large arteries. Both phenomena may play a vital role in maintaining the high compliance of large arteries.

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Section: Resultssupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments

et al. 2017

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“…Results indicate that the contractile Ca 2+ stores of the SR of VSMC in the mouse aorta are extremely stretch-dependent. Previously, we have described that the IP 3 -mediated PE-induced contraction was dependent on baseline Ca 2+ influx via VGCC (Leloup et al, 2015a). If stretch depolarizes the VSMC, one should expect larger IP 3 -mediated contractions at high preload, which was, however not observed.…”

Section: Discussionmentioning

confidence: 93%

“…Removal of extracellular Ca 2+ caused a larger decrease of basal tonus at the higher than at lower preloads (Figure 3). In conditions of depolarized VSMC baseline Ca 2+ influx via VGCC is expected to be larger (Leloup et al, 2015a). Also in WKY rat aorta segments (1 mm) an increase of stretch tension from 8 to 50 mN caused increased spontaneous tone, especially after inhibiting basal release of NO (Sekiguchi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…In mouse aortic segments, implemented preloads are highly variable among different studies and range from about 1.2–8.0 mN/mm (Fransen et al, 2008, 2015; Van Hove et al, 2009; Ponnoth et al, 2012; van Langen et al, 2012; Lloyd et al, 2013; Taguchi et al, 2014; Gross et al, 2015; Leloup et al, 2015a; Zhou et al, 2015). According to Laplace's law, and assuming a thin, isotropic and homologous wall for large vessels such as the aorta, the transmural pressure (P, in mm Hg) is directly proportional to the preload (PL, in mN) and inversely proportional to its length (l, in mm) and radius (r, in mm): P = PL/(l × 2r) × 7.5) (Syyong et al, 2009; Van Herck et al, 2009; Butlin et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

et al. 2017

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Most vaso-reactive studies in mouse aortic segments are performed in isometric conditions and at an optimal preload, which is the preload corresponding to a maximal contraction by non-receptor or receptor-mediated stimulation. In general, this optimal preload ranges from about 1.2 to 8.0 mN/mm, which according to Laplace's law roughly correlates with transmural pressures of 10–65 mmHg. For physiologic transmural pressures around 100 mmHg, preloads of 15.0 mN/mm should be implemented. The present study aimed to compare vascular reactivity of 2 mm mouse (C57Bl6) aortic segments preloaded at optimal (8.0 mN/mm) vs. (patho) physiological (10.0–32.5 mN/mm) preload. Voltage-dependent contractions of aortic segments, induced by increasing extracellular K+, and contractions by α1-adrenergic stimulation with phenylephrine (PE) were studied at these preloads in the absence and presence of L-NAME to inhibit basal release of NO from endothelial cells (EC). In the absence of basal NO release and with higher than optimal preload, contractions evoked by depolarization or PE were attenuated, whereas in the presence of basal release of NO PE-, but not depolarization-induced contractions were preload-independent. Phasic contractions by PE, as measured in the absence of external Ca2+, were decreased at higher than optimal preload suggestive for a lower contractile SR Ca2+ content at physiological preload. Further, in the presence of external Ca2+, contractions by Ca2+ influx via voltage-dependent Ca2+ channels were preload-independent, whereas non-selective cation channel-mediated contractions were increased. The latter contractions were very sensitive to the basal release of NO, which itself seemed to be preload-independent. Relaxation by endogenous NO (acetylcholine) of aortic segments pre-contracted with PE was preload-independent, whereas relaxation by exogenous NO (diethylamine NONOate) displayed higher sensitivity at high preload. Results indicated that stretching aortic segments to higher than optimal preload depolarizes the SMC and causes Ca2+ unloading of the contractile SR, making them extremely sensitive to small changes in the basal release of NO from EC as can occur in hypertension or arterial stiffening.

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High‐dose phenylephrine increases meningeal blood flow through TRPV1 receptor activation and release of calcitonin gene‐related peptide

Dux

Babeș

Manchen

et al. 2019

European Journal of Pain

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Background The α1‐adrenoceptor agonist, phenylephrine, is used at high concentrations as a mydriatic agent and for the treatment of nasal congestion. Among its adverse side‐effects transient burning sensations are reported indicating activation of the trigeminal nociceptive system. Methods Neuropeptide release, calcium imaging and meningeal blood flow recordings were applied in rodent models of meningeal nociception to clarify possible receptor mechanisms underlying these pain phenomena. Results Phenylephrine above 10 mM dose‐dependently released calcitonin gene‐related peptide (CGRP) from the dura mater and isolated trigeminal ganglia, whereas hyperosmotic mannitol at 90 mM was ineffective. The phenylephrine‐evoked release was blocked by the transient receptor potential vanilloid 1 (TRPV1) antagonist BCTC and did not occur in trigeminal ganglia of TRPV1‐deficient mice. Phenylephrine at 30 mM caused calcium transients in cultured trigeminal ganglion neurons responding to the TRPV1 agonist capsaicin and in HEK293T cells expressing human TRPV1. Local application of phenylephrine at micromolar concentrations to the exposed rat dura mater reduced meningeal blood flow, whereas concentrations above 10 mM caused increased meningeal blood flow. The flow increase was abolished by pre‐application of the CGRP receptor antagonist CGRP8‐37 or the TRPV1 antagonist BCTC. Conclusions Phenylephrine at high millimolar concentrations activates TRPV1 receptor channels of perivascular afferents and, upon calcium inflow, releases CGRP, which increases meningeal blood flow. Activation of TRPV1 receptors may underlie trigeminal nociception leading to cranial pain such as local burning sensations or headaches caused by administration of high doses of phenylephrine. Significance Phenylephrine is used at high concentrations as a mydriaticum and for treating nasal congestion. As adverse side‐effects burning sensations and headaches have been described. Phenylephrine at high concentrations causes calcium transients in trigeminal afferents, CGRP release and increased meningeal blood flow upon activation of TRPV1 receptor channels, which is likely underlying the reported pain phenomena.

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

Cited by 13 publications

References 54 publications

Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments

Cyclic Stretch Alters Vascular Reactivity of Mouse Aortic Segments

Isometric Stretch Alters Vascular Reactivity of Mouse Aortic Segments

High‐dose phenylephrine increases meningeal blood flow through TRPV1 receptor activation and release of calcitonin gene‐related peptide

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