Notoginsenoside R1 Attenuates Hypoxia and Hypercapnia-Induced Vasoconstriction in Isolated Rat Pulmonary Arterial Rings by Reducing the Expression of ERK

2014 ◽  
Vol 42 (04) ◽  
pp. 799-816 ◽  
Author(s):  
Yixiao Xu ◽  
Lina Lin ◽  
Lanlan Tang ◽  
Mengxiao Zheng ◽  
Yingchun Ma ◽  
...  
Keyword(s):  
Pulmonary Arteries ◽  
Panax Notoginseng ◽  
Underlying Mechanism ◽  
Sprague Dawley ◽  
Third Order ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Specific Objective ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries characterized by increased vascular resistance. Pulmonary vasoconstriction has been proven to play a pivotal role in PAH. We have previously hypothesized that Panax notoginseng saponins (PNS) might attenuate hypoxia–hypercapnia-induced pulmonary vasoconstriction. The specific objective of the present study was to investigate the role of notoginsenoside R1, a main ingredient of PNS, in this process and the possible underlying mechanism. The third order pulmonary rings from the Sprague-Dawley rats were treated with different concentrations of notoginsenoside R1 (8, 40, and 100 mg/L, respectively) both before and during the conditions of hypercapnia and hypoxia. Contractile force changes in the rings were detected and the optimal concentration (8 mg/L) was selected. Furthermore, an ERK inhibitor, U0126, was applied to the rings. In addition, pulmonary arterial smooth muscle cells (PASMCs) were cultured under hypoxic and hypercapnic conditions, and notoginsenoside R1 was administered to detect the changes induced by ERK1/2. The results revealed biphasic vasoconstriction in rings under hypoxic and hypercapnic conditions. It is hypothesized that the observed attenuation of vasoconstriction and the production of vasodilation could have been induced by notoginsenoside R1. This effect was found to be significantly reinforced by U0126 (p < 0.05 or p < 0.01). ERK expression in the PASMCs under hypoxic and hypercapnic conditions was significantly activated (p < 0.05 or p < 0.01) and the observed activation was attenuated by notoginsenoside R1 (p < 0.05 or p < 0.01). Our findings strongly support the significant role of notoginsenoside R1 in the inhibition of hypoxia–hypercapnia-induced vasoconstriction by the ERK pathway.

Pulmonary vascular pressure effects by endothelin-1 in normoxia and chronic hypoxia: a longitudinal study

1996 ◽  
Vol 271 (6) ◽  
pp. H2246-H2253 ◽  
Author(s):  
S. Tjen-A-Looi ◽  
R. Ekman ◽  
J. Osborn ◽  
I. Keith
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pressure Effects ◽  
Blood Levels ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Calcitonin Gene ◽  
Eta Receptor ◽  
Pulmonary Arterial

The role of endothelin (ET)-1 in pulmonary arterial pressure (Ppa) homeostasis and hypoxia-induced pulmonary hypertension was examined. ET-1 was chronically infused (2 and 4 pmol.kg-1.min-1) into the pulmonary circulation of male Sprague-Dawley rats for 3, 7, and 14 days while they were exposed to normoxia or hypobaric hypoxia (inspired O2 fraction 10%). The role of endogenous ET was examined by infusion of ET antiserum (ET-AS; 0.25 and 0.5 microliter.rat-1.h-1; cross-reacting with ET-1, -2, and -3) or the ETA-receptor blocker BQ-123 (10 pmol.kg-1.min-1). ET-1 (4 pmol) increased Ppa at 3 and 7 days in normoxia and hypoxia and was ineffective at 14 days, probably from ETA-receptor downregulation. BQ-123 blunted the hypoxic Ppa rise at all times, confirming a role for ETA receptors. ET-AS (0.5 microliter) was mostly ineffective but exacerbated hypoxic Ppa at 14 days, in contrast to BQ-123, suggesting that a different ET receptor could be involved. ET-1 infusion (2 pmol) caused right ventricular hypertrophy (RVH) in normoxia and exacerbated RVH in hypoxia, whereas BQ-123 and ET-AS (0.25 microliter) reduced hypoxic RVH. In conclusion, endogenous ET-1 plays a role in hypoxia-induced pulmonary hypertension and RVH by augmenting the level of hypoxic response. ET-1 also affects hematocrit and may reduce blood levels of the vasodilator calcitonin gene-related peptide.

Thromboxane A2 mediates increased pulmonary microvascular permeability after intestinal reperfusion

1997 ◽  
Vol 82 (2) ◽  
pp. 592-598 ◽  
Author(s):  
Richard H. Turnage ◽  
John L. Lanoue ◽  
Kevin M. Kadesky ◽  
Yan Meng ◽  
Stuart I. Myers
Keyword(s):  
Intestinal Ischemia ◽  
Thromboxane A2 ◽  
Microvascular Permeability ◽  
Sprague Dawley ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor ◽  
Krebs Buffer

Turnage, Richard H., John L. LaNoue, Kevin M. Kadesky, Yan Meng, and Stuart I. Myers. Thromboxane A2 mediates increased pulmonary microvascular permeability after intestinal reperfusion. J. Appl. Physiol. 82(2): 592–598, 1997.—This study examines the hypothesis that intestinal reperfusion (IR)-induced pulmonary thromboxane A2(TxA2) release increases local microvascular permeability and induces pulmonary vasoconstriction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of IR. Sham-operated animals (Sham) served as controls. After IR or Sham, the pulmonary vessels were cannulated, and the lungs were perfused in vitro with Krebs buffer. Microvascular permeability was quantitated by determining the filtration coefficient ( K f), and pulmonary arterial (Ppa), venous (Ppv), and capillary (Ppc) pressures were measured to calculate vascular resistance (Rt). After baseline measurements, imidazole (TxA2 synthase inhibitor) or SQ-29,548 (TxA2-receptor antagonist) was added to the perfusate; then K f, Ppa, Ppv, and Ppc were again measured. The K fof lungs from IR animals was four times greater than that of Sham ( P = 0.001), and Rt was 63% greater in the injured group ( P = 0.01). Pc of IR lungs was twice that of controls (5.4 ± 1.0 vs. 2.83 ± 0.3 mmHg, IR vs. Sham, respectively; P < 0.05). Imidazole or SQ-29,548 returned K fto baseline measurements ( P < 0.05) and reduced Rt by 23 and 17%, respectively ( P < 0.05). IR-induced increases in Pc were only slightly reduced by 500 μg/ml imidazole (14%; P = 0.05) but unaffected by lower doses of imidazole (5 or 50 μg/ml) or SQ-29,548. These data suggest that IR-induced pulmonary edema is caused by both increased microvascular permeability and increased hydrostatic pressure and that these changes are due, at least in part, to the ongoing release of TxA2.

scholarly journals Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Yahan Liu ◽  
Xiao Yu Tian ◽  
Yu Huang ◽  
Nanping Wang
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Progressive Increase ◽  
Differential Regulation ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Peroxisome Proliferator Activated Receptor ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptorγ(PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγagonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence ofL-NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increasedETBRbut decreasedETARlevel in pulmonary arteries from PAH rats.ETBRantagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγagonists in PAH.

Congenital Bilateral Vocal Cord Paralysis and the Role of Glycine

2005 ◽  
Vol 114 (6) ◽  
pp. 494-498 ◽  
Author(s):  
Robert G. Berkowitz ◽  
Qi-Jian Sun ◽  
Paul M. Pilowsky
Keyword(s):  
Vocal Cord ◽  
Vocal Cord Paralysis ◽  
Clinical Manifestations ◽  
Underlying Mechanism ◽  
Sprague Dawley ◽  
Bilateral Vocal Cord Paralysis ◽  
Sprague Dawley Rats ◽  
Motoneuron Activity ◽  
Made In

Objectives: We sought to modify normal laryngeal constrictor (LC) motoneuron activity to induce a pattern of aberrant LC muscle function that may serve as a model of congenital bilateral vocal cord paralysis. Methods: Single unit extracellular recordings of functionally identified LC motoneurons were made in anesthetized Sprague-Dawley rats, and the response to both intravenous and iontophoretic application of the glycine antagonist strychnine was studied. Results: The postinspiratory firing pattern of LC motoneurons became inspiratory after intravenous injection of strychnine (4 of 5 rats), but no change was recorded in response to strychnine iontophoresis (7 of 8 rats). Conclusions: Blockade of glycinergic inhibitory neurotransmission by strychnine, acting above the level of the LC motoneuron, causes LC motoneurons to fire during inspiration rather than after inspiration. This observation suggests that impaired glycine neurotransmission may be an underlying mechanism that explains the clinical manifestations of congenital bilateral vocal cord paralysis.

scholarly journals Inactivation of carboxyl terminus of Hsc70-interacting protein prevents hypoxia-induced pulmonary arterial smooth muscle cells proliferation by reducing intracellular Ca2+ concentration

2019 ◽  
Vol 9 (3) ◽  
pp. 204589401987534 ◽  
Author(s):  
Fang Dong ◽  
Jun Zhang
Keyword(s):  
Smooth Muscle ◽  
Striated Muscle ◽  
Pulmonary Arteries ◽  
Underlying Mechanism ◽  
Carboxyl Terminus ◽  
Cell Phenotype ◽  
Interacting Protein ◽  
Aortic Smooth Muscle ◽  
Pulmonary Arterial

Carboxyl terminus of Hsc70-interacting protein (CHIP) is a 35-kDa cytoplasmic protein expressed in human striated muscle, brain, aortic smooth muscle, endothelial cells, and other tissues. Studies have confirmed that CHIP regulates cell growth, apoptosis, cell phenotype, metabolism, neurodegeneration, etc. However, whether CHIP is involved in pulmonary artery smooth muscle cell (PASMC) proliferation, a vital contributor to chronic hypoxia-induced pulmonary hypertension (CHPH), remains unknown. In this study, we first evaluated CHIP expression in the pulmonary arteries (PAs) of CHPH model rats. Subsequently, by silencing CHIP, we investigated the effect of CHIP on hypoxia-induced PASMC proliferation and the underlying mechanism. Our results showed that CHIP expression was upregulated in the PAs of CHPH model rats. Silencing CHIP significantly suppressed the hypoxia-triggered promotion of proliferation, [Ca2+]i, store-operated Ca2+ entry (SOCE), and some regulators of SOCE such as TRPC1 and TRPC6 in cultured PASMCs. These results indicate that CHIP likely contributes to hypoxia-induced PASMC proliferation by targeting the SOCE-[Ca2+]i pathway through the regulation of TRPC1 and TRPC6 in the PASMCs. In conclusion, the findings of the current study clarify the role of CHIP in hypoxia-induced PASMC proliferation.

scholarly journals EXPRESS: Endothelial-derived eNAMPT drives EndMT and preclinical PH: Rescue by an eNAMPT-neutralizing mAb

2021 ◽  
pp. 204589402110597
Author(s):  
Mohamed Ahmed ◽  
Nahla Zaghloul ◽  
Prisca Zimmerman ◽  
Nancy G. Casanova ◽  
Xiaoguang Sun ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Unmet Need ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Molecular Pattern ◽  
Sprague Dawley Rats ◽  
Sequencing Studies ◽  
Pulmonary Arterial ◽  
Nicotinamide Phosphoribosyl Transferase

Rationale: Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyl-transferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothe-lial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Methods: Hemodynam-ic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (3 weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPTec-/- mice were exposed to 10% hypoxia (3 weeks). Bio-chemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Results: Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (RVSP, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF-a were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPTec-/- KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. Conclusions: These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.

Abstract 508: TNFα Downregulates DNA Methylation and Increases Pulmonary Arterial Smooth Muscle Cell (PASMC) Proliferation

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Patrick Crosswhite ◽  
Zhongjie Sun
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Dna Methyltransferase ◽  
Pulmonary Arteries ◽  
Cell Number ◽  
Superoxide Production ◽  
Tnf Alpha ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial

Background: Chronic cold exposure triggers robust TNFα production in the lungs and pulmonary arteries (PAs) and causes PA remodeling in rats. A hallmark of the PA remodeling is the over-proliferation of PASMCs. The purpose of this experiment was to investigate potential mechanisms of TNF-alpha induced PASMC proliferation. Methods and Results: PASMCs were isolated from 8-week-old male Sprague Dawley rats and treated with 0, 20 or 200 ng/ml TNFα for 24 or 48 hours. After treatment, cell number, superoxide production, histone acetylation and DNA methylation were assessed. TNFα treatment significantly increased the number of PASMCs, indicating excessive proliferation. TNFα also increased NADPH oxidase activity and superoxide production compared with untreated controls. TNFα treatment however did not affect histone acetylation at either dose. Interestingly, DNA methylation was significantly decreased by TNFα treatment compared to controls. Unexpectedly, the activity of DNA methyltransferase-1, the major enzyme for DNA methylation, was not altered by TNFα treatment. Further investigation using QRT-RT-PCR revealed that TNFα upregulated several factors including Gadd45α that regulate DNA de-methylation. Conclusions: Our results show that TNFα treatment induced cell proliferation and increased superoxide production in PASMCs. TNFα decreased DNA methylation and upregulated mediators of de-methylation in PASMCs. These findings suggest that TNF-alpha induced PASMCs proliferation may involve the DNA methylation mechanism. (Supported by NIH HL077490 and AHA 11PRE7830040).

scholarly journals Huang Qi Jian Zhong Pellet Attenuates TNBS-Induced Colitis in Rats via Mechanisms Involving Improvement of Energy Metabolism

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Duan-Yong Liu ◽  
Chun-Shui Pan ◽  
Yu-Ying Liu ◽  
Xiao-Hong Wei ◽  
Chang-Man Zhou ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Inflammatory Responses ◽  
Mucosal Injury ◽  
Underlying Mechanism ◽  
Trinitrobenzene Sulfonic Acid ◽  
Sprague Dawley ◽  
Colonic Injury ◽  
Sprague Dawley Rats ◽  
Microcirculatory Disturbances

Huang Qi Jian Zhong Pellet (HQJZ) is a famous Chinese medicine formula for treatment of various gastrointestinal tract diseases. This study investigated the role of HQJZ in 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced colitis and its underlying mechanism. Colonic mucosal injury was induced by TNBS in the Sprague-Dawley rats. In the HQJZ treatment group, HQJZ was administered (2 g/kg) for 14 days starting from day 1 after TNBS infusion. Colonic mucosal injury occurred obviously 1 day after TNBS challenge and did not recover distinctively until day 15, including an increase in macro- and microscopic scores, a colonic weight index, a decrease in colonic length, a number of functional capillaries, and blood flow. Inverted intravital microscopy and ELISA showed colonic microcirculatory disturbances and inflammatory responses after TNBS stimulation, respectively. TNBS decreased occludin, RhoA, and ROCK-I, while increasing Rac-1, PAK-1, and phosphorylated myosin light chain. In addition, ATP content and ATP5D expression in colonic mucosa decreased after TNBS challenge. Impressively, treatment with HQJZ significantly attenuated all of the alterations evoked by TNBS, promoting the recovery of colonic injury. The present study demonstrated HQJZ as a multitargeting management for colonic mucosal injury, which set in motion mechanisms involving improvement of energy metabolism.

EDHF contributes to strain-related differences in pulmonary arterial relaxation in rats

2001 ◽  
Vol 280 (3) ◽  
pp. L458-L464 ◽  
Author(s):  
M. R. Karamsetty ◽  
J. M. Nakashima ◽  
L.-C. Ou ◽  
J. R. Klinger ◽  
N. S. Hill
Keyword(s):  
Pulmonary Arteries ◽  
Relaxation Response ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Sprague Dawley Rats ◽  
Enos Mrna ◽  
Pulmonary Arterial ◽  
Relaxation Responses ◽  
And Function ◽  
Endothelial Nitric Oxide

Pulmonary arteries from the Madison (M) strain relax more in response to acetylcholine (ACh) than those from the Hilltop (H) strain of Sprague-Dawley rats. We hypothesized that differences in endothelial nitric oxide (NO) synthase (eNOS) expression and function, metabolism of ACh by cholinesterases, release of prostacyclin, or endothelium-derived hyperpolarizing factor(s) (EDHF) from the endothelium would explain the differences in the relaxation response to ACh in isolated pulmonary arteries. eNOS mRNA and protein levels as well as the NO-dependent relaxation responses to thapsigargin in phenylephrine (10−6 M)-precontracted pulmonary arteries from the M and H strains were identical. The greater relaxation response to ACh in M compared with H rats was also observed with carbachol, a cholinesterase-resistant analog of ACh, a response that was not modified by pretreatment with meclofenamate (10−5M). N ω-nitro-l-arginine (10−4 M) completely abolished carbachol-induced relaxation in H rat pulmonary arteries but not in M rat pulmonary arteries. Precontraction with KCl (20 mM) blunted the relaxation response to carbachol in M rat pulmonary arteries and eliminated differences between the M and H rat pulmonary arteries. NO-independent relaxation present in the M rat pulmonary arteries was significantly reduced by 17-octadecynoic acid (2 μM) and was completely abolished by charybdotoxin plus apamin (100 nM each). These findings suggest that EDHF, but not NO, contributes to the strain-related differences in pulmonary artery reactivity. Also, EDHF may be a metabolite of cytochrome P-450 that activates Ca2+-dependent K+ channels.

Hypoxic constriction of porcine distal pulmonary arteries: endothelium and endothelin dependence

2001 ◽  
Vol 280 (5) ◽  
pp. L856-L865 ◽  
Author(s):  
Q. Liu ◽  
J. S. K. Sham ◽  
L. A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Bronchial Arteries ◽  
Pulmonary Vasoconstriction ◽  
Endothelial Denudation ◽  
Basal Release ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

To determine the role of endothelium in hypoxic pulmonary vasoconstriction (HPV), we measured vasomotor responses to hypoxia in isolated seventh-generation porcine pulmonary arteries < 300 μm in diameter with (E+) and without endothelium. In E+ pulmonary arteries, hypoxia decreased the vascular intraluminal diameter measured at a constant transmural pressure. These constrictions were complete in 30–40 min; maximum at Po 2 of 2 mmHg; half-maximal at Po 2 of 40 mmHg; blocked by exposure to Ca2+-free conditions, nifedipine, or ryanodine; and absent in E+ bronchial arteries of similar size. Hypoxic constrictions were unaltered by indomethacin, enhanced by indomethacin plus N G-nitro-l-arginine methyl ester, abolished by BQ-123 or endothelial denudation, and restored in endothelium-denuded pulmonary arteries pretreated with 10−10 M endothelin-1 (ET-1). Given previous demonstrations that hypoxia caused contractions in isolated pulmonary arterial myocytes and that ET-1 receptor antagonists inhibited HPV in intact animals, our results suggest that full in vivo expression of HPV requires basal release of ET-1 from the endothelium to facilitate mechanisms of hypoxic reactivity in pulmonary arterial smooth muscle.

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