Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness

1997 ◽  
Vol 83 (1) ◽  
pp. 25-31 ◽  
Author(s):  
Gene L. Colice ◽  
Nicholas Hill ◽  
Yan-Jie Lee ◽  
Hongkai Du ◽  
James Klinger ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Single Dose ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Minute Ventilation ◽  
Chronic Mountain Sickness ◽  
Pulmonary Vascular Remodeling ◽  
Increased Sensitivity ◽  
Pulmonary Arterial ◽  
Mountain Sickness

Colice, Gene L., Nicholas Hill, Yan-Jie Lee, Hongkai Du, James Klinger, James C. Leiter, and Lo-Chang Ou. Exaggerated pulmonary hypertension with monocrotaline in rats susceptible to chronic mountain sickness. J. Appl. Physiol. 83(1): 25–31, 1997.—Hilltop (H) strain Sprague-Dawley rats are more susceptible to chronic mountain sickness than are the Madison (M) strain rats. It is unclear what role pulmonary vascular remodeling, polycythemia, and hypoxia-induced vasoconstriction play in mediating the more severe pulmonary hypertension that develops in the H rats during chronic hypoxia. It is also unclear whether the increased sensitivity of the H rats to chronic mountain sickness is specific for a hypoxia effect or, instead, reflects a general propensity toward the development of pulmonary hypertension. Monocrotaline (MCT) causes pulmonary vascular remodeling and pulmonary hypertension. We hypothesized that the difference in the pulmonary vascular response to chronic hypoxia between H and M rats reflects an increased sensitivity of the H rats to any pulmonary hypertensive stimuli. Consequently, we expected the two strains to also differ in their susceptibility to MCT-induced pulmonary hypertension. Pulmonary arterial pressures in conscious H and M rats were measured 3 wk after a single dose of MCT, exposure to a simulated high altitude of 18,000 ft (barometric pressure = 380 mmHg), and administration of a single dose of saline as a placebo. The H rats had significantly higher pulmonary arterial pressures and right ventricular weights after MCT and chronic hypoxia than did the M rats. The H rats also had more pulmonary vascular remodeling, i.e., greater wall thickness as a percentage of vessel diameter, after MCT and chronic hypoxia than did the M rats. The H rats had significantly lower arterial[Formula: see text] than did the M rats after MCT, but the degree of hypoxemia was mild [arterial[Formula: see text] of 72.5 ± 0.8 (SE) Torr for H rats vs. 77.4 ± 0.8 Torr for M rats after MCT]. The H rats had lower arterial [Formula: see text] and larger minute ventilation values than did the M rats after MCT. These ventilatory differences suggest that MCT caused more severe pulmonary vascular damage in the H rats than in the M rats. These data support the hypothesis that the H rats have a general propensity to develop pulmonary hypertension and suggest that differences in pulmonary vascular remodeling account for the increased susceptibility of H rats, compared with M rats, to both MCT and chronic hypoxia-induced pulmonary hypertension.

Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

2006 ◽  
Vol 291 (5) ◽  
pp. L912-L922 ◽  
Author(s):  
Crystal Kantores ◽  
Patrick J. McNamara ◽  
Lilian Teixeira ◽  
Doreen Engelberts ◽  
Prashanth Murthy ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Antioxidant Properties ◽  
Ventricular Performance ◽  
Pulmonary Vascular Remodeling ◽  
Beneficial Effects ◽  
Arterial Resistance ◽  
Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

scholarly journals 55th Bowditch Lecture: Effects of chronic hypoxia on the pulmonary circulation: Role of HIF-1

2012 ◽  
Vol 113 (9) ◽  
pp. 1343-1352 ◽  
Author(s):  
Larissa A. Shimoda
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Inducible Factor 1 ◽  
Pulmonary Arterial ◽  
Expression And Activity

When exposed to chronic hypoxia (CH), the pulmonary circulation responds with enhanced contraction and vascular remodeling, resulting in elevated pulmonary arterial pressures. Our work has identified CH-induced alterations in the expression and activity of several ion channels and transporters in pulmonary vascular smooth muscle that contribute to the development of hypoxic pulmonary hypertension and uncovered a critical role for the transcription factor hypoxia-inducible factor-1 (HIF-1) in mediating these responses. Current work is focused on the regulation of HIF in the chronically hypoxic lung and evaluation of the potential for pharmacological inhibitors of HIF to prevent, reverse, or slow the progression of pulmonary hypertension.

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)

scholarly journals Curcumin Improves Pulmonary Hypertension Rats by Regulating Mitochondrial Function

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jing Chen ◽  
Wen Jiang ◽  
Fei Zhu ◽  
Qiong Wang ◽  
Haiyan Yang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Mitochondrial Function ◽  
Vascular Remodeling ◽  
Control Group ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Sprague Dawley Rats ◽  
Pulmonary Arterial ◽  
Toxicological Mechanism ◽  
And Function

Objective. To investigate the role of curcumin in regulating pathogenesis of pulmonary arterial smooth muscle cells (PASMCs) derived from pulmonary arterial hypertension (PAH) model. Methods. Male Sprague Dawley rats were injected with monocrotaline (MCT) to establish the PAH experimental model. The rats were divided into control group, MCT group, and curcumin group. At the end of the study, hemodynamic data were measured to determine pulmonary hypertension. Proliferation ability of PASMCs, a remodeling indicator of pulmonary artery and right ventricle, was detected. In addition, the morphology and function of mitochondria, antiglycolysis and antiproliferation pathways, and genes were also analyzed. Results. Curcumin may function by reversing MCT-mediated pulmonary vascular remodeling in rats. Curcumin effectively improved pulmonary vascular remodeling, promoted PASMC apoptosis, and protected mitochondrial function. In addition, curcumin treatment suppressed the PI3K/AKT pathway in PASMCs and regulated the expression of antiproliferative genes. Conclusion. Curcumin can improve energy metabolism and reverse the process of PAHS. However, there were side effects of curcumin in MCT-induced rats, suggesting that the dosage should be treated with caution and its toxicological mechanism should be further studied and evaluated.

Evidence that hypoxic pulmonary vascular remodeling in rats is polyamine dependent

1987 ◽  
Vol 62 (4) ◽  
pp. 1562-1568 ◽  
Author(s):  
J. E. Atkinson ◽  
J. W. Olson ◽  
R. J. Altiere ◽  
M. N. Gillespie
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Right Ventricular Hypertrophy ◽  
Polyamine Biosynthesis ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

This study tested the hypothesis that the polyamines, a family of low-molecular-weight organic cations with documented regulatory roles in cell growth and differentiation, are mediators of chronic hypoxia-induced pulmonary vascular remodeling. Relative to room air controls, chronically hypoxic animals (inspired O2 fraction = 0.1; 21 days) exhibited higher pulmonary arterial pressures (measured in room air), thicker medial layers in pulmonary arteries of 50–100 microns diam, increased hematocrits, and right ventricular hypertrophy. In addition, lung contents of the polyamines, putrescine, spermidine, and spermine were greater in hypoxic animals than in controls. alpha-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, attenuated the hypoxia-induced elevations in lung putrescine and spermidine content and blunted the increases in pulmonary arterial pressure and medial thickness. Neither the increased hematocrit nor right ventricular hypertrophy associated with chronic hypoxia were abrogated by DFMO. In addition, DFMO failed to influence vasoconstrictor responses provoked by acute hypoxic ventilation in isolated, buffer-perfused rat lungs. These observations suggest that depression of polyamine biosynthesis with DFMO blunts the sustained increase in pulmonary arterial pressure by attenuating hypoxia-induced medial thickening.

p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

2011 ◽  
Vol 300 (5) ◽  
pp. L753-L761 ◽  
Author(s):  
Shiro Mizuno ◽  
Herman J. Bogaard ◽  
Donatas Kraskauskas ◽  
Aysar Alhussaini ◽  
Jose Gomez-Arroyo ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Left Ventricle ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Hypoxic Exposure ◽  
Arterial Remodeling ◽  
Pulmonary Arterial ◽  
The Right

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling

2000 ◽  
Vol 278 (2) ◽  
pp. H331-H338 ◽  
Author(s):  
Henry Ooi ◽  
Elaine Cadogan ◽  
Michèle Sweeney ◽  
Katherine Howell ◽  
R. G. O'Regan ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O2 fraction ([Formula: see text]) = 0.10], chronic hypercapnia (inspiratory CO2 fraction = 0.10), hypoxia-hypercapnia ([Formula: see text]= 0.10, inspiratory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone ( P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk ( P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 ± 1.8 mmHg) was significantly ( P < 0.01, ANOVA) elevated compared with control conditions (12.1 ± 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 ± 0.9 mmHg) or hypercapnia (11.8 ± 1.3 mmHg). HPV ([Formula: see text] = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control ( P < 0.05, ANOVA). Addition of N ω-nitro-l-arginine methyl ester (10−4 M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.

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