Pulmonary vascular dysfunction in preterm lambs with chronic lung disease

2003 ◽  
Vol 285 (1) ◽  
pp. L76-L85 ◽  
Author(s):  
Richard D. Bland ◽  
Con Yee Ling ◽  
Kurt H. Albertine ◽  
David P. Carlton ◽  
Amy J. MacRitchie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mechanical Ventilation ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Lung Disease ◽  
Chronic Lung Disease ◽  
Soluble Guanylate Cyclase ◽  
Prolonged Mechanical Ventilation ◽  
Pulmonary Arteries ◽  
Human Infants

Chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and leads to structural abnormalities of the lung circulation in newborn sheep. Compared with normal lambs born at term, chronically ventilated preterm lambs have increased pulmonary arterial smooth muscle and elastin, fewer lung microvessels, and reduced abundance of endothelial nitric oxide synthase. These abnormalities may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). Nitric oxide inhalation (iNO) reduces PVR in human infants and lambs with persistent pulmonary hypertension. We wondered whether iNO might have a similar effect in lambs with CLD. We therefore studied the effect of iNO on PVR in lambs that were delivered prematurely at ∼125 days of gestation (term = 147 days) and mechanically ventilated for 3 wk. All of the lambs had chronically implanted catheters for measurement of pulmonary vascular pressures and blood flow. During week 2 of mechanical ventilation, iNO at 15 parts/million for 1 h decreased PVR by ∼20% in 12 lambs with evolving CLD. When the same study was repeated in eight lambs at the end of week 3, iNO had no significant effect on PVR. To see whether this loss of iNO effect on PVR might reflect dysfunction of lung vascular smooth muscle, we infused 8-bromo-guanosine 3′,5′-cyclic monophosphate (cGMP; 150 μg · kg-1 · min-1 iv) for 15–30 min in four of these lambs at the end of week 3. PVR consistently decreased by 30–35%. Lung immunohistochemistry and immunoblot analysis of excised pulmonary arteries from lambs with CLD, compared with control term lambs, showed decreased soluble guanylate cyclase (sGC). These results suggest that loss of pulmonary vascular responsiveness to iNO in preterm lambs with CLD results from impaired signaling, possibly related to deficient or defective activation of sGC, the intermediary enzyme through which iNO induces increased vascular smooth muscle cell cGMP and resultant vasodilation.

Abstract 107: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide in Vascular Smooth Muscle

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Adam C Straub ◽  
Anh T Nguyen ◽  
Mizanur Rahaman ◽  
Stephanie M Mutchler ◽  
Megan Miller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Cytochrome B5 Reductase ◽  
Arterial Blood

The inability nitric oxide (NO) to stimulate soluble guanylate cyclase (sGC) has been linked to numerous cardiovascular diseases (CVD) including hypertension. While several studies have defined the importance of sGC expression in the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Here, we report for the first time that sGC heme iron redox state, which is essential for NO-induced sGC activation, is regulated by cytochrome B5 reductase 3 (CyB5R3). Genetic knockdown and pharmacological inhibition of CyB5R3 in primary rat vascular smooth muscle cells resulted in a 60% loss in cGMP production. Conversely, the sGC activator Bay 58-2667, which activates oxidized or heme free sGC, reversed these effects. Consistent with our cell culture work, purified protein studies demonstrate that CyB5R3 can directly reduce oxidized sGC heme iron and sensitize sGC to NO. To test the functional importance of Cyb5R3 activity, we cultured mouse thoracodorsal arteries with a pharmacological inhibitor of Cyb5R3 (ZINC 747) and performed vascular reactivity studies using pressure myography. Arteries treated with ZINC 747 showed decreased responsiveness the NO donor DETA-NONOate but increase sensitivity to Bay 58-2667. We then treated mice with 10mg/kg/day of ZINC 747 using osmotic mini pumps, which caused an increase in mean arterial blood pressure (107.5±3.4 vs 131±13.16) measured via radio telemetry. Lastly, translational studies reveal that the CyB5R3 T116S polymorphism with allele frequency 0.23 only in African Americans is unable to reduce sGC and correlates with increased blood pressure. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to NO therapies and new classes of sGC activator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (T117S SNP based drug selection).

scholarly journals Augmented dilation to nitric oxide in uterine arteries from rats with type 2 diabetes: implications for vascular adaptations to pregnancy

2014 ◽  
Vol 306 (4) ◽  
pp. H610-H618 ◽  
Author(s):  
Styliani Goulopoulou ◽  
Johanna L. Hannan ◽  
Takayuki Matsumoto ◽  
Adviye Ergul ◽  
R. Clinton Webb
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Vascular Dysfunction ◽  
Late Pregnancy ◽  
Gk Rats ◽  
Uterine Arteries

Pre-existing diabetes increases the risk of maternal and fetal complications during pregnancy, which may be due to underlying maternal vascular dysfunction and impaired blood supply to the uteroplacental unit. Endothelial dysfunction and reduced vascular smooth muscle responsiveness to nitric oxide (NO) are common vascular impairments in type 2 diabetes (T2D). We hypothesized that uterine arteries from diabetic rats would have reduced vascular smooth muscle sensitivity to NO compared with nondiabetic rats due to impairment in the NO/soluble guanylate cyclase (sGC)/cGMP signaling pathway. Uterine arteries from pregnant Goto-Kakizaki (GK; model of T2D) and Wistar (nondiabetic) rats were studied in a wire myograph. GK nonpregnant uterine arteries had reduced responses to ACh and sodium nitroprusside (SNP) but increased responses to propylamine propylamine NONOate and greater sensitivity to sildenafil compared with Wistar nonpregnant arteries. In late pregnancy, Wistar rats had reduced uterine vascular smooth muscle responsiveness to SNP, but GK rats failed to show this adaptation and had reduced expression of sGC compared with the nonpregnant state. GK rats had a smaller litter size (13.9 ± 0.48 vs. 9.8 ± 0.75; P < 0.05) and a greater number of resorptions compared with Wistar controls (0.8 ± 0.76% vs. 19.9 ± 6.06%; P < 0.05). These results suggest that uterine arteries from rats with T2D show reduced sensitivity of uterine vascular smooth muscle sGC to NO. During pregnancy, the GK uterine vascular smooth muscle fails to show relaxation responses similar to those of arteries from nondiabetic rats.

Incidence and risk factors for postoperative pulmonary complications in elective intracranial surgery

2008 ◽  
Vol 109 (2) ◽  
pp. 222-227 ◽  
Author(s):  
Luciana Carrupt Machado Sogame ◽  
Milena Carlos Vidotto ◽  
José Roberto Jardim ◽  
Sonia Maria Faresin
Keyword(s):  
Risk Factors ◽  
Mechanical Ventilation ◽  
Lung Disease ◽  
Chronic Lung Disease ◽  
Prolonged Mechanical Ventilation ◽  
Pulmonary Complications ◽  
Postoperative Pulmonary Complications ◽  
Duration Of Surgery ◽  
Level Of Consciousness ◽  
Type Of Surgery

Object It has been shown that craniotomy may lead to a decrease in lung volumes and arterial blood gas tensions as well as a change in the respiratory pattern. The purpose of this study was to determine the incidence of postoperative pulmonary complications (PPCs) and the mortality rate in patients who have undergone elective craniotomy and to evaluate the associations between preoperative and postoperative variables and PPCs in this population. Methods Two hundred thirty-six patients were followed up based on a protocol including a clinical questionnaire, physical examination and observation of clinical characteristics in the preoperative period, type of surgery performed, duration of surgery, time spent in the intensive care unit (ICU) and hospital, and the occurrence of any PPCs. Results Postoperative pulmonary complications occurred in 58 patients (24.6%) and 23 other patients (10%) died. Predicting factors for PPCs according to multivariate analyses were as follows: type of surgery performed (p < 0.0001), prolonged mechanical ventilation ≥ 48 hours (p < 0.0001), time spent in the ICU > 3 days (p < 0.0001), decrease in level of consciousness (p < 0.002), duration of surgery ≥ 300 minutes (p < 0.01), and previous chronic lung disease (p < 0.04). Conclusions The incidence from March 2003 to March 2005 of PPCs in patients who had undergone craniotomy was 25% and death occurred in 10%. Some risk factors for PPCs may be predicted such as the type of surgery performed, prolonged mechanical ventilation, a longer time in the ICU, a decreased level of consciousness, duration of surgery, and previous chronic lung disease.

scholarly journals Interleukin 1 activates soluble guanylate cyclase in human vascular smooth muscle cells through a novel nitric oxide-independent pathway.

1994 ◽  
Vol 179 (1) ◽  
pp. 71-80 ◽  
Author(s):  
D Beasley ◽  
M McGuiggin
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Interleukin 1 ◽  
No Synthase ◽  
Guanylate Cyclase Activation

Recent demonstration of cytokine-inducible production of nitric oxide (NO) in vascular smooth muscle cells (VSMC) from rat aorta has implicated VSMC-derived NO as a key mediator of hypotension in septic shock. Our studies to determine whether an inducible NO pathway exists in human VSMC have revealed a novel cytokine-inducible, NO-independent pathway of guanylate cyclase activation in VSMC from human saphenous vein (HSVSMC). Interleukin 1 (IL-1), tumor necrosis factor (TNF), interferon gamma (IFN-gamma) and Escherichia coli lipopolysaccharide (LPS) increased cGMP at 24 h, whereas IL-2 and IL-6 were ineffective. The effect of IL-1 on cyclic guanosine 3',5'-monophosphate (cGMP) was delayed, occurring after 6 h of exposure, and was maximal after 10 h. Methylene blue and LY83583 reversed the IL-1-induced increase in cGMP, suggesting that it was mediated by activation of soluble guanylate cyclase. However, IL-1-induced cGMP in HSVSMC was not inhibited by extracellular hemoglobin. Also, the effect of IL-1 on cGMP was not reversed by nitro- or methyl-substituted L-arginine analogs, aminoguanidine, or diphenyleneiodonium, all of which inhibit IL-1-induced NO synthase in rat aortic VSMC (RAVSMC). IL-1-induced cGMP in HSVSMC was also independent of tetrahydrobiopterin and extracellular L-arginine, as it was not affected by 2,4-diamino-6-hydroxyprytimidine, an inhibitor of tetrahydrobiopterin biosynthesis, and was similar in L-arginine-free and L-arginine-containing media. Analysis of NO synthase mRNA with the use of polymerase chain reaction indicates that levels of mRNA for inducible NO synthase are several orders of magnitude lower in IL-1-treated human HSVSMC than in IL-1-treated RAVSMC. IL-1-induced cGMP was also NO independent in human umbilical artery VSMC, and NO dependent in rat vena cava VSMC. Together these results indicate that IL-1 activates a novel NO-independent pathway of soluble guanylate cyclase activation in human VSMC.

Prediction of Abnormal Pulmonary Follow-up in Premature Infants

PEDIATRICS ◽  
1988 ◽  
Vol 82 (4) ◽  
pp. 670-671
Author(s):  
EDUARDO BANCALARI
Keyword(s):  
Mechanical Ventilation ◽  
Respiratory Failure ◽  
Lung Disease ◽  
Premature Infants ◽  
Chronic Lung Disease ◽  
Oxygen Therapy ◽  
Prolonged Mechanical Ventilation ◽  
Respiratory Outcome ◽  
Definition Of

The article by Shennan and collaborators1 raises some interesting questions concerning the diagnosis of chronic lung disease and the predictability of respiratory outcome in early infancy. The first question addressed by the authors relates to the definition of bronchopulmonary dysplasia. This term was introduced by Northway et al2 in 1967 to describe a group of infants in whom severe chronic lung changes developed after prolonged mechanical ventilation and oxygen therapy. Most of these were infants with birth weights greater than 1000 g in whom chronic respiratory failure developed and whose chest radiographs appeared abnormal. In recent years, there has been an increase in the survival rate of infants with birth weights less than 1000 g, which has resulted in an increase in the population at risk for the development of chronic lung disease.

Free nitric oxide diffusion in the bronchial microcirculation

2002 ◽  
Vol 283 (6) ◽  
pp. H2660-H2670 ◽  
Author(s):  
Peter Condorelli ◽  
Steven C. George
Keyword(s):  
Nitric Oxide ◽  
Mass Transfer ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Soluble Guanylate Cyclase ◽  
Vascular Endothelial Cells ◽  
Surrounding Tissue ◽  
No Production ◽  
Transfer Rates

Theoretical mass transfer rates and concentration distributions were determined for transient diffusion of free nitric oxide (NO) generated in vivo from vascular endothelial cells. Our analytical framework is typical of the bronchial circulation in the human pulmonary system but is applicable to the microvascular circulation in general. We characterized mass transfer rates in terms of the fractional mass flux across a boundary relative to the total endothelial NO production rate. NO concentration in the tissue surrounding blood vessels was expressed in terms of fractional soluble guanylate cyclase (sGC) activity. Our results suggest that endothelium-derived free NO is capable of vascular smooth muscle dilation despite its rapid consumption by hemoglobin in blood. An optimal blood vessel radius of 20 μm was estimated for NO signaling. We hypothesize intermittent generation of endothelial NO as a possible mechanism for sGC activation in vascular smooth muscle. This mechanism enhances the efficacy of NO-modulated vascular smooth muscle dilation while minimizing NO losses to blood and surrounding tissue.

Thrombin Prevents the Expression of Inducible Nitric Oxide Synthase in Vascular Smooth Muscle Cells by a Proteolytically-Activated Thrombin Receptor

1995 ◽  
Vol 74 (03) ◽  
pp. 980-986 ◽  
Author(s):  
Valérie B Schini-Kerth ◽  
Beate Fißithaler ◽  
Thomas T Andersen ◽  
John W Fenton ◽  
Paul M Vanhoutte ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Inducible Nitric Oxide Synthase ◽  
Muscle Cells ◽  
Thrombin Receptor ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

SummaryProteolytically active forms of thrombin (α- and γ-thrombin) and thrombin receptor peptides inhibited the release of nitrite, a stable endproduct of nitric oxide, evoked by interleukin-1 β(IL-1 β) in cultured vascular smooth muscle cells while proteolytically inactive forms [D-Phe-Pro-Arg chloromethyl ketone-α-thrombin (PPACK-α- thrombin) and diisopropylphosphoryl-α-thrombin (DIP-α-thrombin)] had either no or only minimal inhibitory effects. Under bioassay conditions, perfusates from columns containing IL-1 β-activated vascular smooth muscle cells or cells treated with IL-1βplus PPACK-α-thrombin relaxed detector blood vessels. These relaxations were abolished by the inhibitor of nitric oxide synthesis, NG-nitro-L arginine. No relaxations were obtained with untreated cells or IL-1 β-treated cells in the presence of α-thrombin. The expression of inducible nitric oxide synthase mRNA and protein in vascular smooth muscle cells by IL-1 β was impaired by α-thrombin. These results demonstrate that thrombin regulates the expression of the inducible nitric oxide synthase at a transcriptional level via the proteolytic activation of the thrombin receptor in vascular smooth muscle cells

Endothelin-1 Enhances Nitric Oxide–Induced Cytotoxicity in Vascular Smooth Muscle

Hypertension ◽  
1995 ◽  
Vol 25 (4) ◽  
pp. 744-747 ◽  
Author(s):  
Takeshi Nakahashi ◽  
Keisuke Fukuo ◽  
Takuo Inoue ◽  
Shigeto Morimoto ◽  
Shigeki Hata ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Endothelin 1
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