scholarly journals Selective estrogen receptor-α and estrogen receptor-β agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism

2008 ◽  
Vol 295 (5) ◽  
pp. R1486-R1493 ◽  
Author(s):  
Tim Lahm ◽  
Paul R. Crisostomo ◽  
Troy A. Markel ◽  
Meijing Wang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Organ Bath ◽  
Sprague Dawley ◽  
Response Curves ◽  
Vascular Effects ◽  
M 10 ◽  
Dependent Mechanism

Both endogenous and exogenous estrogen decrease pulmonary artery (PA) vasoconstriction. Whether these effects are mediated via estrogen receptor (ER)-α or ER-β, and whether the contribution of ERs is stimulus-dependent, remains unknown. We hypothesized that administration of the selective ER-α agonist propylpyrazole triol (PPT) and/or the selective ER-β agonist diarylpropiolnitrile (DPN) rapidly decreases PA vasoconstriction induced by pharmacologic and hypoxic stimuli via a nitric oxide (NO)-dependent mechanism. PA rings ( n = 3–10/group) from adult male Sprague-Dawley rats were suspended in physiologic organ baths. Force displacement was measured. Vasoconstrictor responses to phenylephrine (10−8M − 10−5M) and hypoxia (Po2 35–45 mmHg) were determined. Endothelium-dependent and -independent vasorelaxation were measured by generating dose-response curves to acetylcholine (10−8M − 10−4M) and sodium nitroprusside (10−9M − 10−5M). PPT or DPN (10−9M − 5 × 10−5M) were added to the organ bath in the presence and absence of the NO-synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) (10−4M). Selective ER-α activation (PPT, 5 × 10−5M) rapidly (<20 min) decreased phenylephrine-induced vasoconstriction. This effect, as well as PPT's effects on endothelium-dependent vasorelaxation, were neutralized by l-NAME. In contrast, selective ER-β activation (DPN, 5 × 10−5M) rapidly decreased phase II of hypoxic pulmonary vasoconstriction (HPV). l-NAME eliminated this phenomenon. Lower PPT or DPN concentrations were less effective. We conclude that both ER-α and ER-β decrease PA vasoconstriction. The immediate onset of effect suggests a nongenomic mechanism. The contribution of specific ERs appears to be stimulus specific, with ER-α primarily modulating phenylephrine-induced vasoconstriction, and ER-β inhibiting HPV. NO inhibition eliminates these effects, suggesting a central role for NO in mediating the pulmonary vascular effects of both ER-α and ER-β.

Endogenous estrogen attenuates pulmonary artery vasoreactivity and acute hypoxic pulmonary vasoconstriction: the effects of sex and menstrual cycle

2007 ◽  
Vol 293 (3) ◽  
pp. E865-E871 ◽  
Author(s):  
Tim Lahm ◽  
Ketan M. Patel ◽  
Paul R. Crisostomo ◽  
Troy A. Markel ◽  
Meijing Wang ◽  
...  
Keyword(s):  
Menstrual Cycle ◽  
Pulmonary Artery ◽  
Isometric Force ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Organ Bath ◽  
Sprague Dawley ◽  
Hypoxic Conditions ◽  
Pulmonary Vasoconstriction ◽  
Vasoconstrictor Response ◽  
Endogenous Estrogen

Sex differences exist in a variety of cardiovascular disorders. Sex hormones have been shown to mediate pulmonary artery (PA) vasodilation. However, the effects of fluctuations in physiological sex hormone levels due to sex and menstrual cycle on PA vasoreactivity have not been clearly established yet. We hypothesized that sex and menstrual cycle affect PA vasoconstriction under both normoxic and hypoxic conditions. Isometric force displacement was measured in isolated PA rings from proestrus females (PF), estrus and diestrus females (E/DF), and male (M) Sprague-Dawley rats. The vasoconstrictor response under normoxic conditions (organ bath bubbled with 95% O2-5% CO2) was measured after stimulation with 80 mmol/l KCl and 1 μmol/l phenylephrine. Hypoxia was generated by changing the gas to 95% N2-5% CO2. PA rings from PF demonstrated an attenuated vasoconstrictor response to KCl compared with rings from E/DF (75.58 ± 3.2% vs. 92.43 ± 4.24%, P < 0.01). Rings from M also exhibited attenuated KCl-induced vasoconstriction compared with E/DF (79.34 ± 3.2% vs. 92.43 ± 4.24%, P < 0.05). PA rings from PF exhibited an attenuated vasoconstrictor response to phenylephrine compared with E/DF (59.61 ± 2.98% vs. 70.03 ± 4.61%, P < 0.05). While the maximum PA vasodilation during hypoxia did not differ between PF, E/DF, and M, phase II of hypoxic pulmonary vasoconstriction was markedly diminished in the PA from PF (64.10 ± 7.10% vs. 83.91 ± 5.97% in M, P < 0.05). We conclude that sex and menstrual cycle affect PA vasoconstriction in isolated PA rings. Even physiological increases in circulating estrogen levels attenuate PA vasoconstriction under both normoxic and hypoxic conditions.

SELECTIVE ESTROGEN RECEPTOR AGONISTS ATTENUATE PULMONARY ARTERY VASOCONSTRICTION BY A NITRIC OXIDE-DEPENDENT MECHANISM

CHEST Journal ◽  
2008 ◽  
Vol 134 (4) ◽  
pp. 25S
Author(s):  
Tim Lahm ◽  
Paul R. Crisostomo ◽  
Troy A. Markel ◽  
Meijing Wang ◽  
Yue Wang ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Pulmonary Artery ◽  
Receptor Agonists ◽  
Dependent Mechanism

Glutathione enhances endothelium-mediated control of coronary vascular resistance via a ROS- and NO intermediate-dependent mechanism

2012 ◽  
Vol 113 (2) ◽  
pp. 246-254 ◽  
Author(s):  
Andrew S. Levy ◽  
Chris Vigna ◽  
James W. E. Rush
Keyword(s):  
Vascular Resistance ◽  
Dose Response ◽  
Vascular Function ◽  
Soluble Guanylate Cyclase ◽  
Threshold Concentration ◽  
Coronary Vascular Resistance ◽  
Sprague Dawley ◽  
Response Curves ◽  
Physiological Relevance ◽  
Dependent Mechanism

The purpose of this investigation was to determine the effects of acute physiological GSH administration on endothelium-mediated reduction in coronary vascular resistance (CVR) using isolated perfused Sprague-Dawley rat hearts. A dose-response curve to GSH was conducted to determine a threshold concentration of GSH. We demonstrate that 30 μM GSH was sufficient to reduce CVR, and maximal dilation was achieved with 1 mM. In subsequent experiments, GSH was administered at concentrations of 0 [control (CON)], 1 μM, or 10 μM (GSH10), and dose-response curves to the endothelial agonist bradykinin (BK) were constructed. These GSH concentrations were chosen because of the physiological relevance and because the effects of GSH on BK action could be assessed independent of baseline differences in CVR. Sensitivity to BK (EC50) was enhanced in GSH10 vs. CON ( P < 0.05). This enhancement remained in the presence of nitric oxide (NO) synthase inhibition l-ωnitro-l-arginine (lNAME) and/or soluble guanylate cyclase (sGC) inhibition. Treatment with 4-hydroxy (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPOL) enhanced the sensitivity to BK in CON, similar to the effects of GSH10 and GSH10 + TEMPOL. However, the GSH10-dependent enhancement of EC50 observed in the presence of lNAME did not occur in the presence of lNAME + TEMPOL or in the presence of lNAME + sGC inhibition and NO scavenging. Collectively, these results suggest that GSH enhances BK-mediated dilation and reduction in CVR through an antioxidant-dependent mechanism that involves a NO intermediate but is unrelated to acute production of NO and GC-dependent effects of NO. These results suggest a mechanism whereby physiologically relevant levels of GSH modulate the endogenous reactive oxygen species and NO control of endothelium-dependent coronary vascular function.

Loss of hypoxic pulmonary vasoconstriction in chronic pneumonia is not mediated by nitric oxide

1993 ◽  
Vol 265 (5) ◽  
pp. H1523-H1528 ◽  
Author(s):  
D. G. McCormack ◽  
N. A. Paterson
Keyword(s):  
Nitric Oxide ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Sprague Dawley ◽  
Absolute Increase ◽  
Pulmonary Vasoconstriction ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Inflammatory Processes ◽  
The Difference

In pulmonary inflammatory processes such as pneumonia there is diminished hypoxic pulmonary vasoconstriction (HPV). We investigated whether the attenuated HPV in pneumonia is a due to excess nitric oxide (NO) release. Sprague-Dawley rats were anesthetized, and a slurry (0.06 ml) of infected agar beads (containing 6 x 10(5) Pseudomonas aeruginosa organisms) or control (sterile) beads was then injected into a distal bronchus through a tracheotomy. After the establishment of a chronic P. aeruginosa pneumonia (7-10 days later) animals were instrumented for hemodynamic monitoring, and the response to exposure to hypoxic gas (fraction of inspired O2 = 0.08) was recorded before and after the administration of NG-monomethyl-L-arginine (L-NMMA; 50 mg/kg), an inhibitor of NO synthesis. The hypoxic pressor response, as assessed by the absolute increase in pulmonary arterial pressure (PAP) and total pulmonary resistance (TPR), was reduced in infected animals compared with control animals. The change in PAP and TPR was 8.5 +/- 0.7 and 0.053 +/- 0.007, respectively, in control animals compared with 5.9 +/- 0.5 and 0.041 +/- 0.011 in infected animals. After L-NMMA the increase in PAP and TPR during hypoxia was greater in both control and infected animals. However, treatment with L-NMMA did not affect the difference between control and infected animals. We conclude that excess release of NO does not account for the attenuated hypoxic pressor response in pneumonia.

Vascular endothelial function is improved by oral glycine treatment in aged rats

2015 ◽  
Vol 93 (6) ◽  
pp. 465-473 ◽  
Author(s):  
Jaime H. Gómez-Zamudio ◽  
Rebeca García-Macedo ◽  
Martha Lázaro-Suárez ◽  
Maximiliano Ibarra-Barajas ◽  
Jesús Kumate ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mrna Expression ◽  
Interleukin 1 ◽  
Aged Rats ◽  
Sprague Dawley ◽  
Response Curves ◽  
Proinflammatory Mediators ◽  
Nadph Oxidase 4 ◽  
Tnf Α ◽  
Cox 2

Glycine has been used to reduce oxidative stress and proinflammatory mediators in some metabolic disorders; however, its effect on the vasculature has been poorly studied. The aim of this work was to explore the effect of glycine on endothelial dysfunction in aged rats. Aortic rings with intact or denuded endothelium were obtained from untreated or glycine-treated male Sprague–Dawley rats at 5 and 15 months of age. Concentration–response curves to phenylephrine (PHE) were obtained from aortic rings incubated with NG-nitro-l-arginine methyl ester (l-NAME), superoxide dismutase (SOD), indomethacin, SC-560, and NS-398. Aortic mRNA expression of endothelial nitric oxide synthase (eNOS), NADPH oxidase 4 (NOX-4), cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2), tumour necrosis factor (TNF)-α, and interleukin-1 β was measured by real time RT–PCR. The endothelial modulation of the contraction by PHE was decreased in aortic rings from aged rats. Glycine treatment improved this modulator effect and increased relaxation to acetylcholine. Glycine augmented the sensitivity for PHE in the presence of l-NAME and SOD. It also reduced the contraction by incubation with indomethacin, SC-560, and NS-398. Glycine increased the mRNA expression of eNOS and decreased the expression of COX-2 and TNF-α. Glycine improved the endothelium function in aged rats possibly by enhancing eNOS expression and reducing the role of superoxide anion and contractile prostanoids that increase the nitric oxide bioavailability.

scholarly journals CYP-epoxygenases contribute to A2A receptor-mediated aortic relaxation via sarcolemmal KATP channels

2012 ◽  
Vol 303 (10) ◽  
pp. R1003-R1010 ◽  
Author(s):  
Dovenia S. Ponnoth ◽  
Mohammed A. Nayeem ◽  
Stephen L. Tilley ◽  
Catherine Ledent ◽  
S. Jamal Mustafa
Keyword(s):  
Nitric Oxide ◽  
Relaxation Effect ◽  
Katp Channels ◽  
Induced Response ◽  
Organ Bath ◽  
Response Curves ◽  
Nitric Oxide Synthase Inhibitor ◽  
Signaling Mechanism ◽  
Cgs 21680 ◽  
Synthase Inhibitor

Previously, we have shown that A2A adenosine receptor (A2AAR) mediates aortic relaxation via cytochrome P-450 (CYP)-epoxygenases. However, the signaling mechanism is not understood properly. We hypothesized that ATP-sensitive K+ (KATP) channels play an important role in A2AAR-mediated relaxation. Organ bath and Western blot experiments were done using isolated aorta from A2AKO and corresponding wild-type (WT) mice. Aortic rings from WT and A2A knockout (KO) mice were precontracted with submaximal dose of phenylephrine (PE, 10−6 M), and concentration-response curves for pinacidil, cromakalim (nonselective KATP openers), and diazoxide (mitochondrial KATP opener) were obtained. Diazoxide did not have any relaxation effect on PE-precontracted tissues, whereas relaxation to pinacidil (48.09 ± 5.23% in WT vs. 25.41 ± 2.73% in A2AKO; P < 0.05) and cromakalim (51.19 ± 2.05% in WT vs. 38.50 ± 2.26% in A2AKO; P < 0.05) was higher in WT than A2AKO aorta. This suggested the involvement of sarcolemmal rather than mitochondrial KATP channels. Endothelium removal, treatment with SCH 58651 (A2AAR antagonist; 10−6 M), NG-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor) and methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH, CYP-epoxygenases inhibitor; 10−5 M) significantly reduced pinacidil-induced relaxation in WT compared with controls, whereas these treatments did not have any effect in A2AKO aorta. Glibenclamide (KATP channel inhibitor, 10−5 M) blocked 2- p-(2-carboxyethyl)phenethylamino-5′ N-ethylcarboxamido adenosine hydrochloride (CGS 21680, A2AAR agonist)-induced relaxation in WT and changed 5′- N-ethylcarboxamide (NECA) (nonselective adenosine analog)-induced response to higher contraction in WT and A2AKO. 5-Hydroxydecanoate (5-HD, mitochondrial KATP channel inhibitor, 10−4 M) had no effect on CGS 21680-mediated response in WT aorta. Our data suggest that A2AAR-mediated vasorelaxation occurs through opening of sarcolemmal KATP channels via CYP-epoxygenases and possibly, nitric oxide, contributing to pinacidil-induced responses.

scholarly journals Raloxifene Acutely Relaxes Rabbit Coronary Arteries In Vitro by an Estrogen Receptor–Dependent and Nitric Oxide–Dependent Mechanism

Circulation ◽  
1999 ◽  
Vol 100 (10) ◽  
pp. 1095-1101 ◽  
Author(s):  
Gemma A. Figtree ◽  
Ying-qing Lu ◽  
Carolyn M. Webb ◽  
Peter Collins
Keyword(s):  
Nitric Oxide ◽  
Estrogen Receptor ◽  
Coronary Arteries ◽  
Dependent Mechanism

scholarly journals Use of Almitrine and Inhaled Nitric Oxide in ARDS Due to COVID-19

2021 ◽  
Vol 8 ◽  
Author(s):  
Driss Laghlam ◽  
Ghilas Rahoual ◽  
Julien Malvy ◽  
Philippe Estagnasié ◽  
Alain Brusset ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Pulmonary Artery Hypertension ◽  
Inhaled Nitric Oxide ◽  
Pulmonary Artery Systolic Pressure ◽  
Open Label ◽  
Paris Area ◽  
Fraction Of Inspired Oxygen

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is manifested by an acute respiratory distress syndrome (ARDS) with intense inflammation and endothelial dysfunction leading to particularly severe hypoxemia. We hypothesized that an impaired hypoxic pulmonary vasoconstriction aggravates hypoxemia. The objective of the study was to test the effect of two pulmonary vasoactive drugs on patient oxygenation.Methods: Observational, single-center, open-label study in one intensive care unit (ICU) of the Paris area, realized in April 2020. Eligible patients had coronavirus disease 2019 (COVID-19) and moderate to severe ARDS [arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) &lt;200 mmHg] despite conventional protective ventilation. Exclusion criteria included pulmonary artery hypertension defined by a pulmonary artery systolic pressure (PAPs) &gt;45 mmHg. The assessment of oxygenation was based on PaO2/FiO2 at (1) baseline, then after (2) 30 min of inhaled nitric oxide (iNO) 10 ppm alone, then (3) 30 min combination of iNO + almitrine infusion 8 μg/kg/min, then (4) 30 min of almitrine infusion alone.Results: Among 20 patients requiring mechanical ventilation during the study period, 12 met the inclusion criteria. Baseline PaO2/FiO2 was 146 ± 48 mmHg. When iNO was combined with almitrine, PaO2/FiO2 rose to 255 ± 90 mmHg (+80 ± 49%, p = 0.005), also after almitrine alone: 238 ± 98 mmHg (+67 ± 75%, p = 0.02), but not after iNO alone: 185 ± 73 mmHg (+30 ± 5%, p = 0.49). No adverse events related to almitrine infusion or iNO was observed.Conclusion: Combining iNO and infused almitrine improved the short-term oxygenation in patients with COVID-19-related ARDS. This combination may be of interest when first-line therapies fail to restore adequate oxygenation. These findings argue for an impaired pulmonary hypoxic vasoconstriction in these patients.

Abstract P405: Cardioprotective Actions Of Nitroxyl Donor Angeli's Salt Are Preserved In The Diabetic Heart And Vasculature In The Face Of Nitric Oxide Resistance

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Anida Velagic ◽  
Jasmin Chendi Li ◽  
Chengxue Helena Qin ◽  
Mandy Li ◽  
Minh Deo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Potential ◽  
Left Ventricular ◽  
Maximal Rate ◽  
Sprague Dawley ◽  
Response Curves ◽  
No Donor ◽  
Coronary Vasculature ◽  
Acute Ischaemia ◽  
Angeli's Salt

Introduction: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. Nitroxyl (HNO) induces positive inotropic and lusitropic effects in healthy and failing hearts. Hypothesis: We hypothesised that in a rodent model, T2DM will promote, and HNO will circumvent, NO• resistance in the myocardium and coronary vasculature. Methods: At 8 weeks of age, male Sprague-Dawley rats commenced a high-fat diet. After two weeks, the rats received low-dose streptozotocin (two intraperitoneal injections, 35 mg/kg, over two consecutive days), and continued the diet. Twelve weeks later, hearts were Langendorff-perfused to assess responses to the NO• donor diethylamine NONOate (DEA/NO) and the HNO donor Angeli’s salt. Results: Inotropic, lusitropic and coronary vasodilator responses to DEA/NO were impaired, and responses to Angeli’s salt were preserved or enhanced, in T2DM hearts compared with non-diabetic hearts. Conclusions: This is the first evidence that inotropic and lusitropic responses are preserved, and NO• resistance in the coronary vasculature is circumvented, by the HNO donor Angeli’s salt in T2DM. These findings highlight the cardiovascular therapeutic potential of HNO donors, especially in cardiac emergencies such as acute ischaemia or heart failure. Figure 1. Dose-response curves and maximal responses to DEA/NO or Angeli's salt in diabetic or non-diabetic hearts. (A-C) LV+dP/dt, (D-F) LV-dP/dt and (G-I) coronary flow rate. Data expressed as change from baseline (denoted by Δ), mean ± SEM. Data analysed by two-way RM ANOVA with Sidak's post-hoc test. *P<0.05 vs. non-diabetic. LV, left ventricular; LV+dP/dt, maximal rate of rise in LV pressure; LV-dP/dt, maximal rate of fall in LV pressure.

Synchronous detection of vascular tension and nitric oxide release in pulmonary artery: A combined application of confocal wire myograph with confocal laser scanning microscopy

Vascular ◽  
2020 ◽  
Vol 28 (5) ◽  
pp. 619-628
Author(s):  
Xiao-Ling Zhuang ◽  
Zhuang-Li Zhu ◽  
Jie-Ling Zhu ◽  
Su-Mei Lai ◽  
Long-Xin Gui ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Artery ◽  
Confocal Laser Scanning Microscopy ◽  
Laser Scanning ◽  
Laser Scanning Microscopy ◽  
Confocal Laser Scanning ◽  
Confocal Laser ◽  
Combined Application ◽  
M 10 ◽  
No Release

Objectives To detect the vascular tension and nitric oxide (NO) release synchronously in mice pulmonary artery, we perform two experiments and present a novel application of confocal wire myograph coupled with the confocal laser scanning microscopy. Methods In the first experiment, viable endothelium-intact mouse pulmonary artery (outer diameter 100–300 μM) rings underwent a one-hour preincubation with a NO-specific fluorescent dye, 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate Calbiochem (2.5 μM), and then precontracted with phenylephrine (Phen, 10−6 M), and subsequently dilated in acetylcholine (ACh, 10−6 M – 10−4 M). The endothelium-dependent vasorelaxation and NO generation in pulmonary artery rings were simultaneously recorded. In the second experiment, after 30-min incubation with the former NO fluorescent dye, the qualified pulmonary artery rings were co-incubated for another 30 min with a nitric oxide synthase inhibitor, 10−4 M Nω-nitro-L-arginine-methyl-ester (L-NAME), and then pretreated with Phen (10−6 M) followed by ACh (10−5 M). The Ach-induced vasodilation and NO release were recorded simultaneously. Results ACh (10−6 M – 10−4 M) promoted pulmonary artery relaxation and intracellular NO release in a dose-dependent manner. Additionally, L-NAME (10−4 M) significantly attenuated the vasodilatation and the intracellular NO release. Conclusions This combined application visually confirms that the synchronous changes in Ach induced vasodilation and NO release, which provides a new method for cardiovascular research.

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