Increased pulmonary vascular resistance and defective pulmonary artery filling in caveolin-1−/− mice

2008 ◽  
Vol 294 (5) ◽  
pp. L865-L873 ◽  
Author(s):  
Nikolaos A. Maniatis ◽  
Vasily Shinin ◽  
Dean E. Schraufnagel ◽  
Shigenori Okada ◽  
Stephen M. Vogel ◽  
...  
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Type I Collagen ◽  
Pulmonary Arteries ◽  
Lung Parenchyma ◽  
Negative Regulator ◽  
Pulmonary Vasculature ◽  
Type I ◽  
Caveolin 1 ◽  
Pulmonary Vasodilation

Caveolin-1, the structural and signaling protein of caveolae, is an important negative regulator of endothelial nitric oxide synthase (eNOS). We observed that mice lacking caveolin-1 ( Cav1−/−) had twofold increased plasma NO levels but developed pulmonary hypertension. We measured pulmonary vascular resistance (PVR) and assessed alterations in small pulmonary arteries to determine the basis of the hypertension. PVR was 46% greater in Cav1−/− mice than wild-type (WT), and increased PVR in Cav1−/− mice was attributed to precapillary sites. Treatment with NG-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS activity raised PVR by 42% in WT but 82% in Cav1−/− mice, indicating greater NO-mediated pulmonary vasodilation in Cav1−/− mice compared with WT. Pulmonary vasculature of Cav1−/− mice was also less reactive to the vasoconstrictor thromboxane A2 mimetic (U-46619) compared with WT. We observed redistribution of type I collagen and expression of smooth muscle α-actin in lung parenchyma of Cav1−/− mice compared with WT suggestive of vascular remodeling. Fluorescent agarose casting also showed markedly decreased density of pulmonary arteries and artery filling defects in Cav1−/− mice. Scanning electron microscopy showed severely distorted and tortuous pulmonary precapillary vessels. Thus caveolin-1 null mice have elevated PVR that is attributed to remodeling of pulmonary precapillary vessels. The elevated basal plasma NO level in Cav1−/− mice compensates partly for the vascular structural abnormalities by promoting pulmonary vasodilation.

Vagal control of pulmonary vascular resistance in the turtle Chrysemys scripta

1977 ◽  
Vol 55 (2) ◽  
pp. 359-367 ◽  
Author(s):  
William K. Milsom ◽  
B. Lowell Langille ◽  
David R. Jones
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Sympathetic Innervation ◽  
Pulmonary Arteries ◽  
Lung Parenchyma ◽  
Distal Segment ◽  
Cholinergic Innervation ◽  
Pulmonary Flow ◽  
Induced Changes

We have directly examined the control of pulmonary vascular resistance in the turtle Chrysemys scripta to determine the way in which pulmonary vasoregulation is achieved. The pulmonary circulation of the turtle Chrysemys scripta receives a strong excitatory cholinergic innervation from the vagus nerve. The major site of vasoconstrictor activity is in the extrinsic pulmonary artery proximal to the lung with only weak constrictor activity evident in the intrinsic arteries and arterioles within the lung parenchyma. No cholinergic innervation is evident in the segment of the extrinsic pulmonary artery proximal to the origin of the arterial ligament (ligamentum Botalli) and all vagally induced changes in flow resistance reside in the much narrower segment distal to this site. Vagal stimulation in an intact preparation produces sufficient constriction in the distal segment of extrinsic pulmonary artery to totally occlude pulmonary flow. The pulmonary arteries appear to be devoid of sympathetic innervation.

Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct 

1998 ◽  
Vol 88 (1) ◽  
pp. 190-195 ◽  
Author(s):  
Christophe Adrie ◽  
Mona W. Hirani ◽  
Alexandra Holzmann ◽  
Larry Keefer ◽  
Warren M. Zapol ◽  
...  
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Circulation ◽  
Half Life ◽  
Pulmonary Vasculature ◽  
Prostaglandin F2alpha ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Healthy Sheep ◽  
Inhaled No

Background PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension. Methods In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized. Results Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled). Conclusions The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.

Influence of bronchial arterial PO2 on pulmonary vascular resistance

1991 ◽  
Vol 70 (1) ◽  
pp. 405-415 ◽  
Author(s):  
B. E. Marshall ◽  
C. Marshall ◽  
M. Magno ◽  
P. Lilagan ◽  
G. G. Pietra
Keyword(s):  
Vascular Resistance ◽  
Bronchial Artery ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Arteries ◽  
Vasa Vasorum ◽  
Pulmonary Vasculature ◽  
Mechanically Ventilated ◽  
Bronchial Circulation ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasoconstriction

In six anesthetized and mechanically ventilated adult sheep, the bronchial artery was perfused with blood from an oxygenator-pump circuit. When the lungs were ventilated with 100% O2 and the bronchial O2 tension (PbrO2) was approximately 600 Torr, the mean of the pulmonary vascular resistances (PVR) measured at the beginning (3.32 +/- 0.29 units) and end (3.17 +/- 0.13 units) of the experiment was 3.24 +/- 0.20 units. When the PbrO2 was changed to 58 +/- 1 Torr, the PVR (2.99 +/- 0.14 units) did not change significantly. However, when the lungs were ventilated with air as PbrO2 was decreased to 91 +/- 4, 77 +/- 3, 56 +/- 2, and 42 +/- 1 Torr, the PVR increased to 3.67 +/- 0.18, 4.03 +/- 0.16, 4.79 +/- 0.19, and 4.71 +/- 0.35 units, respectively. However, when the PbrO2 was decreased further to 26 +/- 1 and 13 +/- 1 Torr, the PVR decreased to 3.77 +/- 0.28 and 3.91 +/- 0.30 units, respectively. In contrast, the bronchial vascular resistance decreased monotonically as PbrO2 decreased. The bronchial circulation supplies vasa vasorum to the walls of all but the smallest pulmonary arteries, and it is therefore suggested that the PO2 of the bronchial circulation is responsible for the bimodal response of the pulmonary vasculature, with stimulation of hypoxic pulmonary vasoconstriction at moderate hypoxemia and of hypoxic pulmonary vasodilation at profound hypoxemia. The physiological and pathophysiological significance of the influence of systemic PO2 on pulmonary vascular tone is discussed.

Pulmonary Vascular Versus Right Ventricular Function Changes During Targeted Therapies of Pulmonary Hypertension – An Argument for Upfront Combination Therapy?

2012 ◽  
Vol 8 (3) ◽  
pp. 209
Author(s):  
Wouter Jacobs ◽  
Anton Vonk-Noordegraaf ◽  
◽  
Keyword(s):  
Combination Therapy ◽  
Right Ventricle ◽  
Right Ventricular ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Meta Analysis ◽  
Right Heart Failure ◽  
Functional Class ◽  
Pulmonary Vasculature ◽  
The Right

Pulmonary arterial hypertension is a progressive disease of the pulmonary vasculature, ultimately leading to right heart failure and death. Current treatment is aimed at targeting three different pathways: the prostacyclin, endothelin and nitric oxide pathways. These therapies improve functional class, increase exercise capacity and improve haemodynamics. In addition, data from a meta-analysis provide compelling evidence of improved survival. Despite these treatments, the outcome is still grim and the cause of death is inevitable – right ventricular failure. One explanation for this paradox of haemodynamic benefit and still worse outcome is that the right ventricle does not benefit from a modest reduction in pulmonary vascular resistance. This article describes the physiological concepts that might underlie this paradox. Based on these concepts, we argue that not only a significant reduction in pulmonary vascular resistance, but also a significant reduction in pulmonary artery pressure is required to save the right ventricle. Haemodynamic data from clinical trials hold the promise that these haemodynamic requirements might be met if upfront combination therapy is used.

Trabecular Bone is Increased in a Rat Model of Polycystic Ovary Syndrome

2020 ◽  
Author(s):  
Lady Katerine Serrano Mujica ◽  
Werner Giehl Glanzner ◽  
Amanda Luiza Prante ◽  
Vitor Braga Rissi ◽  
Gabrielle Rebeca Everling Correa ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Bone Formation ◽  
Type I Collagen ◽  
Polycystic Ovary ◽  
Osteoclast Differentiation ◽  
Bone Volume ◽  
Negative Regulator ◽  
Type I ◽  
Ovary Syndrome ◽  
The Impact

AbstractPolycystic ovary syndrome (PCOS) in an intricate disorder characterized by reproductive and metabolic abnormalities that may affect bone quality and strength along with the lifespan. The present study analysed the impact of postnatal androgenization (of a single dose of testosterone propionate 1.25 mg subcutaneously at day 5 of life) on bone development and markers of bone metabolism in adult female Wistar rats. Compared with healthy controls, the results of measurements of micro-computed tomography (microCT) of the distal femur of androgenized rats indicated an increased cortical bone volume voxel bone volume to total volume (VOX BV/TV) and higher trabecular number (Tb.n) with reduced trabecular separation (Tb.sp). A large magnitude effect size was observed in the levels of circulating bone formation Procollagen I N-terminal propeptide (P1NP) at day 60 of life; reabsorption cross-linked C-telopeptide of type I collagen (CTX) markers were similar between the androgenized and control rats at days 60 and 110 of life. The analysis of gene expression in bone indicated elements for an increased bone mass such as the reduction of the Dickkopf-1 factor (Dkk1) a negative regulator of osteoblast differentiation (bone formation) and the reduction of Interleukin 1-b (Il1b), an activator of osteoclast differentiation (bone reabsorption). Results from this study highlight the possible role of the developmental programming on bone microarchitecture with reference to young women with PCOS.

Pressure-induced smooth muscle cell depolarization in pulmonary arteries from control and chronically hypoxic rats does not cause myogenic vasoconstriction

2005 ◽  
Vol 98 (3) ◽  
pp. 1119-1124 ◽  
Author(s):  
Jay S. Naik ◽  
Scott Earley ◽  
Thomas C. Resta ◽  
Benjimen R. Walker
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arteries ◽  
Barometric Pressure ◽  
Cell Membrane Potential ◽  
Intraluminal Pressure ◽  
Dose Dependent

Chronic obstructive pulmonary diseases, as well as prolonged residence at high altitude, can result in generalized airway hypoxia, eliciting an increase in pulmonary vascular resistance. We hypothesized that a portion of the elevated pulmonary vascular resistance following chronic hypoxia (CH) is due to the development of myogenic tone. Isolated, pressurized small pulmonary arteries from control (barometric pressure ≅ 630 Torr) and CH (4 wk, barometric pressure = 380 Torr) rats were loaded with fura 2-AM and perfused with warm (37°C), aerated (21% O2-6% CO2-balance N2) physiological saline solution. Vascular smooth muscle (VSM) intracellular Ca2+ concentration ([Ca2+]i) and diameter responses to increasing intraluminal pressure were determined. Diameter and VSM cell [Ca2+]i responses to KCl were also determined. In a separate set of experiments, VSM cell membrane potential responses to increasing luminal pressure were determined in arteries from control and CH rats. VSM cell membrane potential in arteries from CH animals was depolarized relative to control at each pressure step. VSM cells from both groups exhibited a further depolarization in response to step increases in intraluminal pressure. However, arteries from both control and CH rats distended passively to increasing intraluminal pressure, and VSM cell [Ca2+]i was not affected. KCl elicited a dose-dependent vasoconstriction that was nearly identical between control and CH groups. Whereas KCl administration resulted in a dose-dependent increase in VSM cell [Ca2+]i in arteries taken from control animals, this stimulus elicited only a slight increase in VSM cell [Ca2+]i in arteries from CH animals. We conclude that the pulmonary circulation of the rat does not demonstrate pressure-induced vasoconstriction.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus

2009 ◽  
Vol 297 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Marc Chester ◽  
Pierre Tourneux ◽  
Greg Seedorf ◽  
Theresa R. Grover ◽  
Jason Gien ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Left Pulmonary Artery ◽  
Flow Transducer ◽  
Pulmonary Vasodilation

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 ± 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1–100 μg over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.

Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats

1978 ◽  
Vol 234 (4) ◽  
pp. H346-H351 ◽  
Author(s):  
C. W. Leffler ◽  
T. L. Tyler ◽  
S. Cassin
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Fetal Lung ◽  
Rapid Decrease ◽  
Vascular Response ◽  
Pulmonary Vasodilation ◽  
Prostaglandin Synthase ◽  
Perfused Lung ◽  
Lung Preparation ◽  
Indomethacin Treatment

The effect of indomethacin treatment of the pulmonary vasodilation caused by ventilation of the fetal lung with air was evaluated in anesthetized, exteriorized, fetal goats by means of an open-chest, pump-perfused lung preparation. The decrease in pulmonary vascular resistance that occurs when the fetal lung is ventilated with air consists of two components: 1) a rapid decrease in pulmonary vascular resistance during the first 30 s of ventilation; 2) a slower decline, which continues through the first 10-20 min or more of ventilation. Indomethacin has no effect on the first component. The second component is absent following indomethacin pretreatment. The effect of indomethacin treatment is more pronounced in immature fetuses (less than 90% gestation) than in mature fetuses. Prostaglandin synthase activity appears to be important in the pulmonary vasodilation caused by ventilation of the fetal lungs with air.

A bronchial epithelium-derived factor reduces pulmonary vascular tone in the newborn rat

2004 ◽  
Vol 96 (4) ◽  
pp. 1399-1405 ◽  
Author(s):  
J. Belik ◽  
J. Pan ◽  
R. P. Jankov ◽  
A. K. Tanswell
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Arteries ◽  
Bronchial Epithelium ◽  
Force Generation ◽  
Phosphatidylinositol 3 Kinase ◽  
Newborn Rat ◽  
No Release ◽  
Phosphatidylinositol 3

The factors accounting for the maintenance of a low pulmonary vascular resistance postnatally are not completely understood. The aim of this study was to test the hypothesis that bronchial epithelium produces a factor capable of relaxing adjacent pulmonary arterial smooth muscle. We studied fourth-generation intralobar pulmonary arteries and bronchi of 4- to 8-day-old rats. Arteries were mounted on a wire myograph, alone or with the adjacent bronchus. The presence of the attached bronchus significantly reduced pulmonary artery force generation induced by the thromboxane analog (U-46619) or KCl whether the endothelium was present or absent ( P < 0.01). The converse was not true in that bronchial force generation was not affected when studied with the adjacent pulmonary artery. Mechanical removal of the bronchial epithelium or addition of the nitric oxide (NO) synthase (NOS) nonspecific ( NG-monomethyl-l-arginine) or the specific neuronal NOS (7-nitroindazole) inhibitors increased arterial force generation to levels comparable to the isolated artery preparation. Wortmannin, a phosphatidylinositol 3-kinase inhibitor, significantly decreased ( P < 0.01) NO release of pulmonary arteries only when the adjacent bronchus was present. We conclude that bronchial epithelium in the newborn rat produces a factor capable of lowering pulmonary vascular muscle tone. This relaxant effect can be suppressed by NOS and phosphatidylinositol 3-kinase kinase inhibition, suggesting an action via NOS phosphorylation and NO release. We speculate that such a mechanism may be operative in vivo and plays an important role in control of pulmonary vascular resistance in the early postnatal period.

scholarly journals Contractile properties of EDL and soleus muscles of myostatin-deficient mice

2006 ◽  
Vol 101 (3) ◽  
pp. 898-905 ◽  
Author(s):  
Christopher L. Mendias ◽  
James E. Marcin ◽  
Daniel R. Calerdon ◽  
John A. Faulkner
Keyword(s):  
Type I Collagen ◽  
Contractile Properties ◽  
Negative Regulator ◽  
Type I ◽  
Lengthening Contractions ◽  
Tetanic Force ◽  
The Difference ◽  
The Impact ◽  
Deficient Mice

Myostatin is a negative regulator of muscle mass. The impact of myostatin deficiency on the contractile properties of healthy muscles has not been determined. We hypothesized that myostatin deficiency would increase the maximum tetanic force (Po), but decrease the specific Po(sPo) of muscles and increase the susceptibility to contraction-induced injury. The in vitro contractile properties of extensor digitorum longus (EDL) and soleus muscles from wild-type ( MSTN+/+), heterozygous-null ( MSTN+/−), and homozygous-null ( MSTN−/−) adult male mice were determined. For EDL muscles, the Poof both MSTN+/−and MSTN−/−mice were greater than the Poof MSTN+/+mice. For soleus muscles, the Poof MSTN−/−mice was greater than that of MSTN+/+mice. The sPoof EDL muscles of MSTN−/−mice was less than that of MSTN+/+mice. For soleus muscles, however, no difference in sPowas observed. Following two lengthening contractions, EDL muscles from MSTN−/−mice had a greater force deficit than that of MSTN+/+or MSTN+/−mice, whereas no differences were observed for the force deficits of soleus muscles. Myostatin-deficient EDL muscles had less hydroxyproline, and myostatin directly increased type I collagen mRNA expression and protein content. The difference in the response of EDL and soleus muscles to myostatin may arise from differences in the levels of a myostatin receptor, activin type IIB. Compared with the soleus, the amount of activin type IIB receptor was approximately twofold greater in EDL muscles. The results support a significant role for myostatin not only in the mass of muscles but also in the contractility and the composition of the extracellular matrix of muscles.

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