Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension

1989 ◽  
Vol 66 (4) ◽  
pp. 1662-1673 ◽  
Author(s):  
S. L. Archer ◽  
G. J. Johnson ◽  
R. L. Gebhard ◽  
W. L. Castleman ◽  
A. S. Levine ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Fish Oil ◽  
Chronic Hypoxia ◽  
Corn Oil ◽  
Pulmonary Arteries ◽  
Hypoxic Pulmonary Hypertension ◽  
Dietary Fish ◽  
Lung Lipid ◽  
Pulmonary Arterial ◽  
Fish Oil Diet

The effects of dietary polyunsaturated fats on chronic hypoxic pulmonary hypertension were assessed in rats fed fish oil, corn oil, or a lower fat, “high-carbohydrate” diet (regular) beginning 1 mo before the start of hypoxia (0.4 atm, n = 30 for each). Mean pulmonary arterial pressures were lower in the chronically hypoxic rats fed fish oil (19.7 +/- 1.8 mm Hg) than in the rats fed corn oil (25.3 +/- 1.6 mm Hg) or regular diets (27.5 +/- 1.5 mm Hg, P less than 0.05). The fish oil diet increased lung eicosapentaenoic acid 50-fold and depleted lung arachidonic acid 60% (P less than 0.0001 for each). Lung thromboxane B2 and 6-ketoprostaglandin F1 alpha levels were lower, and platelet aggregation, in response to collagen, was reduced in rats fed fish oil. Chronically hypoxic rats fed fish oil had lower mortality rates than the other hypoxic rats. They also had lower blood viscosity, as well as less right ventricular hypertrophy and less peripheral extension of vascular smooth muscle to intra-acinar pulmonary arteries (P less than 0.05 for each). The mechanism by which dietary fish oil decreases pulmonary hypertension and vascular remodeling during chronic hypoxia remains uncertain. The finding that a fish oil diet can reduce the hemodynamic and morphological sequelae of chronic hypoxia may have therapeutic significance.

Thromboxane inhibition reduces an early stage of chronic hypoxia-induced pulmonary hypertension in piglets

2005 ◽  
Vol 99 (2) ◽  
pp. 670-676 ◽  
Author(s):  
Candice D. Fike ◽  
Yongmei Zhang ◽  
Mark R. Kaplowitz
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Early Stage ◽  
Pulmonary Arteries ◽  
Pulmonary Wedge Pressure ◽  
Thromboxane Synthase Inhibitor ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor ◽  
Air Control ◽  
Arterial Responses

The pulmonary vasoconstrictor, thromboxane, may contribute to the development of pulmonary hypertension. Our objective was to determine whether a combined thromboxane synthase inhibitor-receptor antagonist, terbogrel, prevents pulmonary hypertension and the development of aberrant pulmonary arterial responses in newborn piglets exposed to 3 days of hypoxia. Piglets were maintained in room air (control) or 11% O2 (hypoxic) for 3 days. Some hypoxic piglets received terbogrel (10 mg/kg po bid). Pulmonary arterial pressure, pulmonary wedge pressure, and cardiac output were measured in anesthetized animals. A cannulated artery technique was used to measure responses to acetylcholine. Pulmonary vascular resistance for terbogrel-treated hypoxic piglets was almost one-half the value of untreated hypoxic piglets but remained greater than values for control piglets. Dilation to acetylcholine in preconstricted pulmonary arteries was greater for terbogrel-treated hypoxic than for untreated hypoxic piglets, but it was less for pulmonary arteries from both groups of hypoxic piglets than for control piglets. Terbogrel may ameliorate pulmonary artery dysfunction and attenuate the development of chronic hypoxia-induced pulmonary hypertension in newborns.

Polycythemia and vascular remodeling in chronic hypoxic pulmonary hypertension in guinea pigs

1991 ◽  
Vol 71 (6) ◽  
pp. 2218-2223 ◽  
Author(s):  
S. P. Janssens ◽  
B. T. Thompson ◽  
C. R. Spence ◽  
C. A. Hales
Keyword(s):  
Pulmonary Hypertension ◽  
Guinea Pigs ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Similar Degree ◽  
Similar Tendency ◽  
Pulmonary Arterial ◽  
Medial Thickening

Chronic hypoxia increases pulmonary arterial pressure (PAP) as a result of vasoconstriction, polycythemia, and vascular remodeling with medial thickening. To determine whether preventing the polycythemia with repeated bleeding would diminish the pulmonary hypertension and remodeling, we compared hemodynamic and histological profiles in hypoxic bled (HB, n = 6) and hypoxic polycythemic guinea pigs (H, n = 6). After 10 days in hypoxia (10% O2), PAP was increased from 10 +/- 1 (SE) mmHg in room air controls (RA, n = 5) to 20 +/- 1 mmHg in H (P less than 0.05) but was lower in HB (15 +/- 1 mmHg, P less than 0.05 vs. H). Cardiac output and pulmonary artery vasoreactivity did not differ among groups. Total pulmonary vascular resistance increased from 0.072 +/- 0.011 mmHg.ml-1.min in RA to 0.131 mmHg.ml-1.min in H but was significantly lower in HB (0.109 +/- 0.006 mmHg.ml-1.min). Hematocrit increased with hypoxia (57 +/- 3% in H vs. 42 +/- 1% in RA, P less than 0.05), and bleeding prevented the increase (46 +/- 4% in HB, P less than 0.05 vs. H only). The proportion of thick-walled peripheral pulmonary vessels (53.2 +/- 2.9% in HB and 50.6 +/- 4.8% in H vs. 31.6 +/- 2.6% in RA, P less than 0.05) and the percent medial thickness of pulmonary arteries adjacent to alveolar ducts (7.2 +/- 0.6% in HB and 7.0 +/- 0.4% in H vs. 5.2 +/- 0.4% in RA, P less than 0.05) increased to a similar degree in both hypoxic groups. A similar tendency was present in larger bronchiolar vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m

1993 ◽  
Vol 265 (6) ◽  
pp. H2175-H2183 ◽  
Author(s):  
A. G. Durmowicz ◽  
E. C. Orton ◽  
K. R. Stenmark
Keyword(s):  
Pulmonary Hypertension ◽  
Chronic Exposure ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Barometric Pressure ◽  
Hypoxic Conditions ◽  
Progressive Loss ◽  
Vessel Structure ◽  
Pulmonary Arterial ◽  
Neonatal Calves

Severe neonatal pulmonary hypertension (PH) may have both reversible (vasoconstrictive) and “fixed” (vasodilator unresponsive) components. To assess when and to what degree vasodilator unresponsive PH developed in the neonate, pulmonary arterial pressures (PAP) and cardiac outputs (CO) were measured, and total pulmonary resistances (TPR) were calculated in neonatal calves exposed to chronic hypoxia (CH) (barometric pressure of 430 mmHg = 4,570 m) for 1, 3, 7, and 14 days under both normoxic (barometric pressure of 640 mmHg = 1,500 m) and hypoxic conditions with and without an infusion of the vasodilator acetylcholine (ACh). Studies were done at 4 h and at 2, 4, 8, and 15 days of life in both control and CH animals. The fixed component of PH was defined as that PAP or TPR above the control baseline value which remained in CH animals after an infusion ACh at 1,500 m. Small pulmonary arteries were also examined histologically in an attempt to correlate relative changes in the reversible and fixed elements of PH with alterations in vessel structure. Chronic exposure to 4,570 m altitude prevented the normal postnatal fall in PAP and TPR observed in control animals. Instead, PAP, TPR, and the structure of small pulmonary arteries initially remained similar to those of the 4-h-old newborn. By 7 days exposure to 4,570 m, a significant element of fixed PH developed, which increased dramatically between the 7- and 14-day exposure periods and appeared to correlate with a narrowed pulmonary artery lumen and increased medial and adventitial thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclooxygenase-2 and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs

2005 ◽  
Vol 98 (3) ◽  
pp. 1111-1118 ◽  
Author(s):  
Candice D. Fike ◽  
Mark R. Kaplowitz ◽  
Yongmei Zhang ◽  
Sandra L. Pfister
Keyword(s):  
Pulmonary Hypertension ◽  
Arachidonic Acid ◽  
Chronic Hypoxia ◽  
Early Stage ◽  
Pulmonary Arteries ◽  
Intact Control ◽  
Pulmonary Arterial ◽  
Cox 2 ◽  
Air Control ◽  
Arterial Responses

Our objective was to determine whether cyclooxygenase (COX)-2-dependent metabolites contribute to the altered pulmonary vascular responses that manifest in piglets with chronic hypoxia-induced pulmonary hypertension. Piglets were raised in either room air (control) or hypoxia for 3 days. The effect of the COX-2 selective inhibitor NS-398 on responses to arachidonic acid or acetylcholine (ACh) was measured in endothelium-intact and denuded pulmonary arteries (100- to 400-μm diameter). Pulmonary arterial production of the stable metabolites of thromboxane and prostacyclin was assessed in the presence and absence of NS-398. Dilation to arachidonic acid was greater for intact control than for intact hypoxic arteries, was unchanged by NS-398 in intact arteries of either group, and was augmented by NS-398 in denuded hypoxic arteries. ACh responses, which were dilation in intact control arteries but constriction in intact and denuded hypoxic arteries, were diminished by NS-398 treatment of all arteries. NS-398 reduced prostacyclin production by control pulmonary arteries and reduced thromboxane production by hypoxic pulmonary arteries. COX-2-dependent contracting factors, such as thromboxane, contribute to aberrant pulmonary arterial responses in piglets exposed to 3 days of hypoxia.

HIF-1 regulates hypoxic induction of NHE1 expression and alkalinization of intracellular pH in pulmonary arterial myocytes

2006 ◽  
Vol 291 (5) ◽  
pp. L941-L949 ◽  
Author(s):  
Larissa A. Shimoda ◽  
Michele Fallon ◽  
Sarah Pisarcik ◽  
Jian Wang ◽  
Gregg L. Semenza
Keyword(s):  
Pulmonary Hypertension ◽  
Intracellular Ph ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Ex Vivo ◽  
Ph Homeostasis ◽  
Hypoxic Pulmonary Hypertension ◽  
Hypoxic Induction ◽  
Alkaline Shift ◽  
Pulmonary Arterial

Vascular remodeling resulting from altered pulmonary arterial smooth muscle cell (PASMC) growth is a contributing factor to the pathogenesis of hypoxic pulmonary hypertension. PASMC growth requires an alkaline shift in intracellular pH (pHi) and we previously showed that PASMCs isolated from mice exposed to chronic hypoxia exhibited increased Na+/H+ exchanger (NHE) expression and activity, which resulted in increased pHi. However, the mechanism by which hypoxia caused these changes was unknown. In this study we tested the hypothesis that hypoxia-induced changes in PASMC pH homeostasis are mediated by the transcriptional regulator hypoxia-inducible factor 1 (HIF-1). Consistent with previous results, increased NHE isoform 1 (NHE1) mRNA and protein, enhanced NHE activity, and an alkaline shift in pHi were observed in PASMCs isolated from wild-type mice exposed to chronic hypoxia (3 wk at 10% O2). In contrast, these changes were absent in PASMCs isolated from chronically hypoxic mice with partial deficiency for HIF-1. Exposure of PASMCs to hypoxia ex vivo (48 h at 4% O2) or overexpression of HIF-1 in the absence of hypoxia also increased NHE1 mRNA and protein expression. Our results indicate that full expression of HIF-1 is essential for hypoxic induction of NHE1 expression and changes in PASMC pH homeostasis and suggest a novel mechanism by which HIF-1 mediates pulmonary vascular remodeling during the pathogenesis of hypoxic pulmonary hypertension.

scholarly journals Functional and molecular factors associated with TAPSE in hypoxic pulmonary hypertension

2016 ◽  
Vol 311 (1) ◽  
pp. L59-L73 ◽  
Author(s):  
Slaven Crnkovic ◽  
Albrecht Schmidt ◽  
Bakytbek Egemnazarov ◽  
Jochen Wilhelm ◽  
Leigh M. Marsh ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Plasma Levels ◽  
Molecular Mechanisms ◽  
Chronic Hypoxia ◽  
Systolic Function ◽  
Hypoxic Pulmonary Hypertension ◽  
Interleukin 22 ◽  
Pulmonary Arterial ◽  
The Right ◽  
And Function

Adaptation of the right ventricle (RV) to increased afterload is crucial for survival in pulmonary hypertension (PH), but it is challenging to assess RV function and identify associated molecular mechanisms. The aim of the current study was to analyze the relationship between invasive and noninvasive parameters of RV morphology and function and associated molecular changes. The response of mice to normobaric hypoxia was assessed by hechocardiography, invasive hemodynamics, and histological and molecular analyses. Plasma levels of possibly novel markers of RV remodeling were measured by ELISA in patients with idiopathic pulmonary arterial hypertension (IPAH) and matched healthy controls. Chronic hypoxia-induced PH was accompanied by significantly decreased tricuspid annular plane systolic excursion (TAPSE) and unchanged RV contractility index and tau. RV hypertrophy was present without an increase in fibrosis. There was no change in α- and β-major histocompatibility class or natriuretic peptides expression. Comparative microarray analysis identified two soluble factors, fibroblast growth factor-5 (FGF5) and interleukin-22 receptor alpha-2 (IL22RA2), as being possibly associated with RV remodeling. We observed significantly higher plasma levels of IL22RA2, but not FGF5, in patients with IPAH. Hypoxic pulmonary hypertension in a stage of RV remodeling with preserved systolic function is associated with decreased pulmonary vascular compliance, mild diastolic RV dysfunction, and significant decrease in TAPSE. Subtle gene expression changes in the RV vs. the left ventricle upon chronic hypoxia suggest that the majority of changes are due to hypoxia and not due to changes in afterload. Increased IL22RA2 levels might represent a novel RV adaptive mechanism.

scholarly journals Chronic hypoxia limits H2O2-induced inhibition of ASIC1-dependent store-operated calcium entry in pulmonary arterial smooth muscle

2014 ◽  
Vol 307 (5) ◽  
pp. L419-L430 ◽  
Author(s):  
Danielle R. Plomaritas ◽  
Lindsay M. Herbert ◽  
Tracylyn R. Yellowhair ◽  
Thomas C. Resta ◽  
Laura V. Gonzalez Bosc ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Inhibitory Effect ◽  
Alternative Mechanism ◽  
Arterial Smooth Muscle ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle ◽  
Expression And Activity

Our laboratory shows that acid-sensing ion channel 1 (ASIC1) contributes to the development of hypoxic pulmonary hypertension by augmenting store-operated Ca2+ entry (SOCE) that is associated with enhanced agonist-induced vasoconstriction and arterial remodeling. However, this enhanced Ca2+ influx following chronic hypoxia (CH) is not dependent on an increased ASIC1 protein expression in pulmonary arterial smooth muscle cells (PASMC). It is well documented that hypoxic pulmonary hypertension is associated with changes in redox potential and reactive oxygen species homeostasis. ASIC1 is a redox-sensitive channel showing increased activity in response to reducing agents, representing an alternative mechanism of regulation. We hypothesize that the enhanced SOCE following CH results from removal of an inhibitory effect of hydrogen peroxide (H2O2) on ASIC1. We found that CH increased PASMC superoxide (O2·−) and decreased rat pulmonary arterial H2O2 levels. This decrease in H2O2 is a result of decreased Cu/Zn superoxide dismutase expression and activity, as well as increased glutathione peroxidase (GPx) expression and activity following CH. Whereas H2O2 inhibited ASIC1-dependent SOCE in PASMC from control and CH animals, addition of catalase augmented ASIC1-mediated SOCE in PASMC from control rats but had no further effect in PASMC from CH rats. These data suggest that, under control conditions, H2O2 inhibits ASIC1-dependent SOCE. Furthermore, H2O2 levels are decreased following CH as a result of diminished dismutation of O2·− and increased H2O2 catalysis through GPx-1, leading to augmented ASIC1-dependent SOCE.

scholarly journals Hypercapnia attenuates hypoxic pulmonary hypertension by inhibiting lung radical injury

2009 ◽  
pp. S79-S86 ◽  
Author(s):  
M Chovanec ◽  
J Novotná ◽  
J Wilhelm ◽  
V Hampl ◽  
M Vízek ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Male Rats ◽  
Pulmonary Vasculature ◽  
Hypoxic Pulmonary Hypertension ◽  
Hypoxic Injury ◽  
Arterial Blood ◽  
Hypoxic Environment ◽  
Pulmonary Arterial ◽  
The Right

Chronic lung hypoxia results in hypoxic pulmonary hypertension. Concomitant chronic hypercapnia partly inhibits the effect of hypoxia on pulmonary vasculature. Adult male rats exposed to 3 weeks hypoxia (Fi02=0.1) combined with hypercapnia (FiC02=0.04-0.05) had lower pulmonary arterial blood pressure, increased weight of the right heart ventricle, and less pronounced structural remodeling of the peripheral pulmonary arteries compared with rats exposed only to chronic hypoxia (Fi02=0.1). According to our hypothesis, hypoxic pulmonary hypertension is triggered by hypoxic injury to the walls of the peripheral pulmonary arteries. Hypercapnia inhibits release of both oxygen radicals and nitric oxide at the beginning of exposure to the hypoxic environment. The plasma concentration of nitrotyrosine, the marker of peroxynitrite activity, is lower in hypoxic rats exposed to hypercapnia than in those exposed to hypoxia alone. Hypercapnia blunts hypoxia-induced collagenolysis in the walls of prealveolar pulmonary arteries. We conclude that hypercapnia inhibits the development of hypoxic pulmonary hypertension by the inhibition of radical injury to the walls of peripheral pulmonary arteries.

scholarly journals RhoA increases ASIC1a plasma membrane localization and calcium influx in pulmonary arterial smooth muscle cells following chronic hypoxia

2018 ◽  
Vol 314 (2) ◽  
pp. C166-C176 ◽  
Author(s):  
Lindsay M. Herbert ◽  
Thomas C. Resta ◽  
Nikki L. Jernigan
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Plasma Membrane ◽  
Ion Channel ◽  
Chronic Hypoxia ◽  
Membrane Localization ◽  
Hypoxic Pulmonary Hypertension ◽  
Plasma Membrane Localization ◽  
Pulmonary Arterial ◽  
Pulmonary Arterial Smooth Muscle

Increases in pulmonary arterial smooth muscle cell (PASMC) intracellular Ca2+ levels and enhanced RhoA/Rho kinase-dependent Ca2+ sensitization are key determinants of PASMC contraction, migration, and proliferation accompanying the development of hypoxic pulmonary hypertension. We previously showed that acid-sensing ion channel 1a (ASIC1a)-mediated Ca2+ entry in PASMC is an important constituent of the active vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic pulmonary hypertension. However, the enhanced ASIC1a-mediated store-operated Ca2+ entry in PASMC from pulmonary hypertensive animals is not dependent on an increase in ASIC1a protein expression, suggesting that chronic hypoxia (CH) stimulates ASIC1a function through other regulatory mechanism(s). RhoA is involved in ion channel trafficking, and levels of activated RhoA are increased following CH. Therefore, we hypothesize that activation of RhoA following CH increases ASIC1a-mediated Ca2+ entry by promoting ASIC1a plasma membrane localization. Consistent with our hypothesis, we found greater plasma membrane localization of ASIC1a following CH. Inhibition of RhoA decreased ASIC1a plasma membrane expression and largely diminished ASIC1a-mediated Ca2+ influx, whereas activation of RhoA had the opposite effect. A proximity ligation assay revealed that ASIC1a and RhoA colocalize in PASMC and that the activation state of RhoA modulates this interaction. Together, our findings show a novel interaction between RhoA and ASIC1a, such that activation of RhoA in PASMC, both pharmacologically and via CH, promotes ASIC1a plasma membrane localization and Ca2+ entry. In addition to enhanced RhoA-mediated Ca2+ sensitization following CH, RhoA can also activate a Ca2+ signal by facilitating ASIC1a plasma membrane localization and Ca2+ influx in pulmonary hypertension.

C-type natriuretic peptide expression and pulmonary vasodilation in hypoxia-adapted rats

1998 ◽  
Vol 275 (4) ◽  
pp. L645-L652 ◽  
Author(s):  
James R. Klinger ◽  
Farjaad M. Siddiq ◽  
Richard A. Swift ◽  
Cynthia Jackson ◽  
Linda Pietras ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricle ◽  
Natriuretic Peptide ◽  
Right Atrium ◽  
Chronic Hypoxia ◽  
Right Atrial ◽  
Mrna Levels ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
The Right

Atrial and brain natriuretic peptides (ANP and BNP, respectively) are potent pulmonary vasodilators that are upregulated in hypoxia-adapted rats and may protect against hypoxic pulmonary hypertension. To test the hypothesis that C-type natriuretic peptide (CNP) also modulates pulmonary vascular responses to hypoxia, we compared the vasodilator effect of CNP with that of ANP on pulmonary arterial rings, thoracic aortic rings, and isolated perfused lungs obtained from normoxic and hypoxia-adapted rats. We also measured CNP and ANP levels in heart, lung, brain, and plasma in normoxic and hypoxia-adapted rats. Steady-state CNP mRNA levels were quantified in the same organs by relative RT-PCR. CNP was a less potent vasodilator than ANP in preconstricted thoracic aortic and pulmonary arterial rings and in isolated lungs from normoxic and hypoxia-adapted rats. Chronic hypoxia increased plasma CNP (15 ± 2 vs. 6 ± 1 pg/ml; P < 0.05) and decreased CNP in the right atrium (35 ± 14 vs. 65 ± 17 pg/mg protein; P < 0.05) and in the lung (3 ± 1 vs. 14 ± 3 pg/mg protein; P < 0.05) but had no effect on CNP in brain or right ventricle. Chronic hypoxia increased ANP levels fivefold in the right ventricle (49 ± 5 vs. 11 ± 2 pg/mg protein; P < 0.05) but had no effect on ANP in lung or brain. There was a trend toward decreased ANP levels in the right atrium (2,009 ± 323 vs. 2,934 ± 397 pg/mg protein; P = not significant). No differences in CNP transcript levels were observed between the two groups of rats except that the right atrial CNP mRNA levels were lower in hypoxia-adapted rats. We conclude that CNP is a less potent pulmonary vasodilator than ANP in normoxic and hypoxia-adapted rats and that hypoxia raises circulating CNP levels without increasing cardiopulmonary CNP expression. These findings suggest that CNP may be less important than ANP or BNP in protecting against hypoxic pulmonary hypertension in rats.

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