scholarly journals Endothelin-1-induced vasoconstriction does not require intracellular Ca2+ waves in arteries from rats exposed to intermittent hypoxia

2014 ◽  
Vol 306 (5) ◽  
pp. H667-H673 ◽  
Author(s):  
Jessica M. Osmond ◽  
Laura V. Gonzalez Bosc ◽  
Benjimen R. Walker ◽  
Nancy L. Kanagy
Keyword(s):  
Sleep Apnea ◽  
Phospholipase C ◽  
Intermittent Hypoxia ◽  
Receptor Activation ◽  
Wave Activity ◽  
Mesenteric Arteries ◽  
Wave Frequency ◽  
Sprague Dawley ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Sleep apnea is associated with cardiovascular disease, and patients with sleep apnea have elevated plasma endothelin (ET)-1 concentrations. Rats exposed to intermittent hypoxia (IH), a model of sleep apnea, also have increased plasma ET-1 concentrations and heightened constriction to ET-1 in mesenteric arteries without an increase in global vascular smooth muscle cell Ca2+ concentration ([Ca2+]). Because ET-1 has been shown to increase the occurrence of propagating Ca2+ waves, we hypothesized that ET-1 increases Ca2+ wave activity in mesenteric arteries, rather than global [Ca2+], to mediate enhanced vasoconstriction after IH exposure. Male Sprague-Dawley rats were exposed to sham or IH conditions for 7 h/day for 2 wk. Mesenteric arteries from sham- and IH-exposed rats were isolated, cannulated, and pressurized to 75 mmHg to measure ET-1-induced constriction as well as changes in global [Ca2+] and Ca2+ wave activity. A low concentration of ET-1 (1 nM) elicited similar vasoconstriction and global Ca2+ responses in the two groups. Conversely, ET-1 had no effect on Ca2+ wave activity in arteries from sham rats but significantly increased wave frequency in arteries from IH-exposed rats. The ET-1-induced increase in Ca2+ wave frequency in arteries from IH rats was dependent on phospholipase C and inositol 1,4,5-trisphosphate receptor activation, yet inhibition of phospholipase C and the inositol 1,4,5-trisphosphate receptor did not prevent ET-1-mediated vasoconstriction. These results suggest that although ET-1 elevates Ca2+ wave activity after IH exposure, increases in wave activity are not associated with increased vasoconstriction.

Inhibition of TASK-1 potassium channel by phospholipase C

2001 ◽  
Vol 281 (2) ◽  
pp. C700-C708 ◽  
Author(s):  
Gábor Czirják ◽  
Gábor L. Petheő ◽  
András Spät ◽  
Péter Enyedi
Keyword(s):  
Phospholipase C ◽  
Lysophosphatidic Acid ◽  
Protein S ◽  
Receptor Activation ◽  
Xenopus Laevis Oocytes ◽  
Ang Ii ◽  
Inositol 1,4,5 Trisphosphate ◽  
Glomerulosa Cells ◽  
Pore Domain ◽  
Stimulation Of

The two-pore-domain K+ channel, TASK-1, was recently shown to be a target of receptor-mediated regulation in neurons and in adrenal glomerulosa cells. Here, we demonstrate that TASK-1 expressed in Xenopus laevis oocytes is inhibited by different Ca2+-mobilizing agonists. Lysophosphatidic acid, via its endogenous receptor, and ANG II and carbachol, via their heterologously expressed ANG II type 1a and M1 muscarinic receptors, respectively, inhibit TASK-1. This effect can be mimicked by guanosine 5′- O-(3-thiotriphosphate), indicating the involvement of GTP-binding protein(s). The phospholipase C inhibitor U-73122 reduced the receptor-mediated inhibition of TASK-1. Downstream signals of phospholipase C action (inositol 1,4,5-trisphosphate, cytoplasmic Ca2+ concentration, and diacylglycerol) do not mediate the inhibition. Unlike the Gq-coupled receptors, stimulation of the Gi-activating M2 muscarinic receptor coexpressed with TASK-1 results in an only minimal decrease of the TASK-1 current. However, additional coexpression of phospholipase C-β2 (which is responsive also to Giβγ-subunits) renders M2 receptor activation effective. This indicates the significance of phospholipase C activity in the receptor-mediated inhibition of TASK-1.

ATP stimulates Ca2+oscillations and contraction in airway smooth muscle cells of mouse lung slices

2002 ◽  
Vol 283 (6) ◽  
pp. L1271-L1279 ◽  
Author(s):  
Albrecht Bergner ◽  
Michael J. Sanderson
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Phospholipase C ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Mouse Lung ◽  
Airway Smooth Muscle Cells ◽  
Airway Caliber ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

In airway smooth muscle cells (SMCs) from mouse lung slices, ≥10 μM ATP induced Ca2+oscillations that were accompanied by airway contraction. After ∼1 min, the Ca2+oscillations subsided and the airway relaxed. By contrast, ≥0.5 μM adenosine 5′- O-(3-thiotriphosphate) (nonhydrolyzable) induced Ca2+oscillations in the SMCs and an associated airway contraction that persisted for >2 min. Adenosine 5′- O-(3-thiotriphosphate)-induced Ca2+oscillations occurred in the absence of external Ca2+but were abolished by the phospholipase C inhibitor U-73122 and the inositol 1,4,5-trisphosphate receptor inhibitor xestospongin. Adenosine, AMP, and α,β-methylene ATP had no effect on airway caliber, and the magnitude of the contractile response induced by a variety of nucleotides could be ranked in the following order: ATP = UTP > ADP. These results suggest that the SMC response to ATP is impaired by ATP hydrolysis and mediated via P2Y2or P2Y4receptors, activating phospholipase C to release Ca2+via the inositol 1,4,5-trisphosphate receptor. We conclude that ATP can serve as a spasmogen of airway SMCs and that Ca2+oscillations in SMCs are required to sustain airway contraction.

Partial calcium release in response to submaximal inositol 1,4,5-trisphosphate receptor activation

1994 ◽  
Vol 98 (2) ◽  
pp. 147-156 ◽  
Author(s):  
Ludwig Missiaen ◽  
Jan B. Parys ◽  
Humbert De Smedt ◽  
Masahiro Oike ◽  
Rik Casteels
Keyword(s):  
Calcium Release ◽  
Receptor Activation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Trisphosphate Receptor

Chronic intermittent hypoxia alters NMDA and AMPA-evoked currents in NTS neurons receiving carotid body chemoreceptor inputs

2007 ◽  
Vol 292 (6) ◽  
pp. R2259-R2265 ◽  
Author(s):  
Patricia M. de Paula ◽  
Gleb Tolstykh ◽  
Steve Mifflin
Keyword(s):  
Sleep Apnea ◽  
Nmda Receptors ◽  
Dose Response ◽  
Carotid Body ◽  
Intermittent Hypoxia ◽  
Receptor Activation ◽  
Response Curves ◽  
Ampa And Nmda Receptors ◽  
Afferent Inputs ◽  
Dose Response Curves

Chronic exposure to intermittent hypoxia (CIH) has been used in animals to mimic the arterial hypoxemia that accompanies sleep apnea. Humans with sleep apnea and animals exposed to CIH have elevated blood pressures and augmented sympathetic nervous system responses to acute exposures to hypoxia. To test the hypothesis that exposure to CIH alters neurons within the nucleus of the solitary tract (NTS) that integrate arterial chemoreceptor afferent inputs, we measured whole cell currents induced by activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors in enzymatically dispersed NTS neurons from normoxic (NORM) and CIH-exposed rats (alternating cycles of 3 min at 10% O2 followed by 3 min at 21% O2 between 8 AM and 4 PM for 7 days). To identify NTS neurons receiving carotid body afferent inputs the anterograde tracer 4- (4-(dihexadecylamino)styryl- N-methylpyridinum iodide (DiA) was placed onto the carotid body 1 wk before exposure to CIH. AMPA dose-response curves had similar EC50 but maximal responses increased in neurons isolated from DiA-labeled CIH (20.1 ± 0.8 μM, n = 9) compared with NORM (6.0 ± 0.3 μM, n = 8) rats. NMDA dose-response curves also had similar EC50 but maximal responses decreased in CIH (8.4 ± 0.4 μM, n = 8) compared with NORM (19.4 ± 0.6 μM, n = 9) rats. These results suggest reciprocal changes in the number and/or conductance characteristics of AMPA and NMDA receptors. Enhanced responses to AMPA receptor activation could contribute to enhanced chemoreflex responses observed in animals exposed to CIH and humans with sleep apnea.

scholarly journals NFAT regulation of cystathionine γ-lyase expression in endothelial cells is impaired in rats exposed to intermittent hypoxia

2017 ◽  
Vol 312 (4) ◽  
pp. H791-H799 ◽  
Author(s):  
Laura V. Gonzalez Bosc ◽  
Jessica M. Osmond ◽  
Wieslawa K. Giermakowska ◽  
Carolyn E. Pace ◽  
Jennifer L. Riggs ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Sleep Apnea ◽  
Mesenteric Artery ◽  
Intermittent Hypoxia ◽  
Mesenteric Arteries ◽  
Male Rats ◽  
Nuclear Factor ◽  
Activated T Cells ◽  
Rat Mesenteric Artery

Sleep apnea is a risk factor for cardiovascular disease, and intermittent hypoxia (IH, 20 episodes/h of 5% O2-5% CO2 for 7 h/day) to mimic sleep apnea increases blood pressure and impairs hydrogen sulfide (H2S)-induced vasodilation in rats. The enzyme that produces H2S, cystathionine γ-lyase (CSE), is decreased in rat mesenteric artery endothelial cells (EC) following in vivo IH exposure. In silico analysis identified putative nuclear factor of activated T cell (NFAT) binding sites in the CSE promoter. Therefore, we hypothesized that IH exposure reduces Ca2+ concentration ([Ca2+]) activation of calcineurin/NFAT to lower CSE expression and impair vasodilation. In cultured rat aortic EC, inhibiting calcineurin with cyclosporine A reduced CSE mRNA, CSE protein, and luciferase activity driven by a full-length but not a truncated CSE promoter. In male rats exposed to sham or IH conditions for 2 wk, [Ca2+] in EC in small mesenteric arteries from IH rats was lower than in EC from sham rat arteries (Δfura 2 ratio of fluorescence at 340 to 380 nm from Ca2+ free: IH = 0.05 ± 0.02, sham = 0.17 ± 0.03, P < 0.05), and fewer EC were NFATc3 nuclear positive in IH rat arteries than in sham rat arteries (IH = 13 ± 3, sham = 59 ± 11%, P < 0.05). H2S production was also lower in mesenteric tissue from IH rats vs. sham rats. Endothelium-dependent vasodilation to acetylcholine (ACh) was lower in mesenteric arteries from IH rats than in arteries from sham rats, and inhibiting CSE with β-cyanoalanine diminished ACh-induced vasodilation in arteries from sham but not IH rats but did not affect dilation to the H2S donor NaHS. Thus, IH lowers EC [Ca2+], NFAT activity, CSE expression and activity, and H2S production while inhibiting NFAT activation lowers CSE expression. The observations that IH exposure decreases NFATc3 activation and CSE-dependent vasodilation support a role for NFAT in regulating endothelial H2S production. NEW & NOTEWORTHY This study identifies the calcium-regulated transcription factor nuclear factor of activated T cells as a novel regulator of cystathionine γ-lyase (CSE). This pathway is basally active in mesenteric artery endothelial cells, but, after exposure to intermittent hypoxia to mimic sleep apnea, nuclear factor of activated T cells c3 nuclear translocation and CSE expression are decreased, concomitant with decreased CSE-dependent vasodilation.

Modulation of phospholipase C pathway and level of Gq alpha/G11 alpha in rat myometrium during gestation

1996 ◽  
Vol 271 (3) ◽  
pp. C895-C904 ◽  
Author(s):  
S. Lajat ◽  
Z. Tanfin ◽  
G. Guillon ◽  
S. Harbon
Keyword(s):  
Phospholipase C ◽  
G Proteins ◽  
Pertussis Toxin ◽  
Inositol Phosphates ◽  
Receptor Activation ◽  
Similar Increase ◽  
Inositol 1,4,5 Trisphosphate ◽  
M3 Subtype ◽  
Subtype A ◽  
Stimulation Of

The regulation of the receptor-G protein-phospholipase C (PLC) cascade was investigated in rat myometrium at midgestation (day 12) and at term (day 21) comparatively to the estrogen-treated tissue (day 0). Carbachol-mediated generation of [3H]inositol phosphates was insensitive to pertussis toxin and was enhanced at days 12 and 21 two- and threefold, respectively, with no alteration of muscarinic sites (M3 subtype). A similar increase could be detected in the production of inositol 1,4,5-trisphosphate, indicating the stimulation of a PLC degrading phosphatidylinositol 4,5-bisphosphate. AlF4- also enhanced PLC activation during gestation, suggesting pregnancy-related regulations that bypass receptor activation. Immunoreactive G proteins, Gq alpha and G11 alpha, and PLC-beta 3 were detected in all myometrial preparations. The amount of PLC-beta 3 was similar in day 0 and day 21 myometrium, although decreasing by 75% at midgestation. Of significance was the increased amount of Gq alpha in day 12 and day 21 myometrium (3- and 2-fold, respectively) which coincided with the enhanced phosphoinositide breakdown. The upregulation of Gq alpha may contribute to the enhanced PLC activity during pregnancy and at term.

scholarly journals Clopidogrel, independent of the vascular P2Y12 receptor, improves arterial function in small mesenteric arteries from AngII-hypertensive rats

2010 ◽  
Vol 118 (7) ◽  
pp. 463-471 ◽  
Author(s):  
Fernanda R. C. Giachini ◽  
David A. Osmond ◽  
Shali Zhang ◽  
Fernando S. Carneiro ◽  
Victor V. Lima ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Reactivity ◽  
Receptor Activation ◽  
Mesenteric Arteries ◽  
P2y12 Receptor ◽  
Sprague Dawley ◽  
Pharmacological Characterization ◽  
Vascular Responses ◽  
Functional Changes ◽  
Nitric Oxide Bioavailability

The P2Y12 receptor antagonist clopidogrel blocks platelet aggregation, improves systemic endothelial nitric oxide bioavailability and has anti-inflammatory effects. Since P2Y12 receptors have been identified in the vasculature, we hypothesized that clopidogrel ameliorates AngII (angiotensin II)-induced vascular functional changes by blockade of P2Y12 receptors in the vasculature. Male Sprague–Dawley rats were infused with AngII (60 ng/min) or vehicle for 14 days. The animals were treated with clopidogrel (10 mg·kg−1 of body weight·day−1) or vehicle. Vascular reactivity was evaluated in second-order mesenteric arteries. Clopidogrel treatment did not change systolic blood pressure [(mmHg) control-vehicle, 117±7.1 versus control-clopidogrel, 125±4.2; AngII–vehicle, 197±10.7 versus AngII–clopidogrel, 198±5.2], but it normalized increased phenylephrine-induced vascular contractions [(%KCl) vehicle-treated, 182.2±18% versus clopidogrel, 133±14%), as well as impaired vasodilation to acetylcholine [(%) vehicle-treated, 71.7±2.2 versus clopidogrel, 85.3±2.8) in AngII-treated animals. Vascular expression of P2Y12 receptor was determined by Western blot. Pharmacological characterization of vascular P2Y12 was performed with the P2Y12 agonist 2-MeS-ADP [2-(methylthio) adenosine 5′-trihydrogen diphosphate trisodium]. Although 2-MeS-ADP induced endothelium-dependent relaxation [(Emax %)=71±12%) as well as contractile vascular responses (Emax %=83±12%), these actions are not mediated by P2Y12 receptor activation. 2-MeS-ADP produced similar vascular responses in control and AngII rats. These results indicate potential effects of clopidogrel, such as improvement of hypertension-related vascular functional changes that are not associated with direct actions of clopidogrel in the vasculature, supporting the concept that activated platelets contribute to endothelial dysfunction, possibly via impaired nitric oxide bioavailability.

scholarly journals Intermittent hypoxia in rats reduces activation of Ca2+ sparks in mesenteric arteries

2015 ◽  
Vol 309 (11) ◽  
pp. H1915-H1922 ◽  
Author(s):  
Olan Jackson-Weaver ◽  
Jessica M. Osmond ◽  
Jay S. Naik ◽  
Laura V. Gonzalez Bosc ◽  
Benjimen R. Walker ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Hydrogen Sulfide ◽  
Sleep Apnea ◽  
Smooth Muscle Cell ◽  
Intermittent Hypoxia ◽  
Ryanodine Receptors ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
Phosphodiesterase Inhibition ◽  
Spark Generation

Ca+ sparks are vascular smooth muscle cell (VSMC) Ca2+-release events that are mediated by ryanodine receptors (RyR) and promote vasodilation by activating large-conductance Ca2+-activated potassium channels and inhibiting myogenic tone. We have previously reported that exposing rats to intermittent hypoxia (IH) to simulate sleep apnea augments myogenic tone in mesenteric arteries through loss of hydrogen sulfide (H2S)-induced dilation. Because we also observed that H2S can increase Ca2+ spark activity, we hypothesized that loss of H2S after IH exposure reduces Ca2+ spark activity and that blocking Ca2+ spark generation reduces H2S-induced dilation. Ca2+ spark activity was lower in VSMC of arteries from IH compared with sham-exposed rats. Furthermore, depolarizing VSMC by increasing luminal pressure (from 20 to 100 mmHg) or by elevating extracellular [K+] increased spark activity in VSMC of arteries from sham rats but had no effect in arteries from IH rats. Inhibiting endogenous H2S production in sham arteries prevented these increases. NaHS or phosphodiesterase inhibition increased spark activity to the same extent in sham and IH arteries. Depolarization-induced increases in Ca2+ spark activity were due to increased sparks per site, whereas H2S increases in spark activity were due to increased spark sites per cell. Finally, inhibiting Ca2+ spark activity with ryanodine (10 μM) enhanced myogenic tone in arteries from sham but not IH rats and blocked dilation to exogenous H2S in arteries from both sham and IH rats. Our results suggest that H2S regulates RyR activation and that H2S-induced dilation requires Ca2+ spark activation. IH exposure decreases endogenous H2S-dependent Ca2+ spark activation to cause membrane depolarization and enhance myogenic tone in mesenteric arteries.

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