scholarly journals 2-Aminoethyldiphenylborinate modifies the pulmonary circulation in pulmonary hypertensive newborn lambs partially gestated at high altitude

2016 ◽  
Vol 311 (4) ◽  
pp. L788-L799 ◽  
Author(s):  
S. Castillo-Galán ◽  
S. Quezada ◽  
F. Moraga ◽  
G. Ebensperger ◽  
E. A. Herrera ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Pressure ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Vasoconstrictor Response ◽  
End Of Treatment ◽  
Vehicle Treatment ◽  
Pulmonary Arterial ◽  
Phosphodiesterase 5

Calcium signaling through store-operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, six of them received a 2-APB treatment and the other six received vehicle treatment for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure between the 3rd and 10th days, cardiac output between the 4th and 8th days, and pulmonary vascular resistance at the 10th day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-bromoguanosine 3′,5′-cyclic monophosphate (8-BrcGMP). The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil, respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin, and the percentage of Ki67-positive nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses, and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension; however, further testing of specific blockers is needed.

scholarly journals Role of the RhoA/ROCK pathway in high-altitude associated neonatal pulmonary hypertension in lambs

2016 ◽  
Vol 310 (11) ◽  
pp. R1053-R1063 ◽  
Author(s):  
Nandy C. Lopez ◽  
German Ebensperger ◽  
Emilio A. Herrera ◽  
Roberto V. Reyes ◽  
Gloria Calaf ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Daily Administration ◽  
Rock Inhibitor ◽  
Pulmonary Arterial ◽  
Neonatal Lambs

Exposure to high-altitude chronic hypoxia during pregnancy may cause pulmonary hypertension in neonates, as a result of vasoconstriction and vascular remodeling. We hypothesized that susceptibility to pulmonary hypertension, due to an augmented expression and activity of the RhoA/Rho-kinase (ROCK) pathway in these neonates, can be reduced by daily administration of fasudil, a ROCK inhibitor. We studied 10 highland newborn lambs with conception, gestation, and birth at 3,600 m in Putre, Chile. Five highland controls (HLC) were compared with 5 highland lambs treated with fasudil (HL-FAS; 3 mg·kg−1·day−1 iv for 10 days). Ten lowland controls were studied in Lluta (50 m; LLC). During the 10 days of fasudil daily administration, the drug decreased pulmonary arterial pressure (PAP) and resistance (PVR), basally and during a superimposed episode of acute hypoxia. HL-FAS small pulmonary arteries showed diminished muscular area and a reduced contractile response to the thromboxane analog U46619 compared with HLC. Hypoxia, but not fasudil, changed the protein expression pattern of the RhoA/ROCKII pathway. Moreover, HL-FAS lungs expressed less pMYPT1T850 and pMYPT1T696 than HLC, with a potential increase of the myosin light chain phosphatase activity. Finally, hypoxia induced RhoA, ROCKII, and PKG mRNA expression in PASMCs of HLC, but fasudil reduced them (HL-FAS) similarly to LLC. We conclude that fasudil decreases the function of the RhoA/ROCK pathway, reducing the PAP and PVR in chronically hypoxic highland neonatal lambs. The inhibition of ROCKs by fasudil may offer a possible therapeutic tool for the pulmonary hypertension of the neonates.

scholarly journals Caveolar peroxynitrite formation impairs endothelial TRPV4 channels and elevates pulmonary arterial pressure in pulmonary hypertension

2021 ◽  
Vol 118 (17) ◽  
pp. e2023130118
Author(s):  
Zdravka Daneva ◽  
Corina Marziano ◽  
Matteo Ottolini ◽  
Yen-Lin Chen ◽  
Thomas M. Baker ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Endothelial Cell ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Lung Edema ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Pulmonary Arterial ◽  
Trpv4 Channel

Recent studies have focused on the contribution of capillary endothelial TRPV4 channels to pulmonary pathologies, including lung edema and lung injury. However, in pulmonary hypertension (PH), small pulmonary arteries are the focus of the pathology, and endothelial TRPV4 channels in this crucial anatomy remain unexplored in PH. Here, we provide evidence that TRPV4 channels in endothelial cell caveolae maintain a low pulmonary arterial pressure under normal conditions. Moreover, the activity of caveolar TRPV4 channels is impaired in pulmonary arteries from mouse models of PH and PH patients. In PH, up-regulation of iNOS and NOX1 enzymes at endothelial cell caveolae results in the formation of the oxidant molecule peroxynitrite. Peroxynitrite, in turn, targets the structural protein caveolin-1 to reduce the activity of TRPV4 channels. These results suggest that endothelial caveolin-1–TRPV4 channel signaling lowers pulmonary arterial pressure, and impairment of endothelial caveolin-1–TRPV4 channel signaling contributes to elevated pulmonary arterial pressure in PH. Thus, inhibiting NOX1 or iNOS activity, or lowering endothelial peroxynitrite levels, may represent strategies for restoring vasodilation and pulmonary arterial pressure in PH.

Correlation of acute with chronic hypoxic pulmonary hypertension in cattle

1975 ◽  
Vol 38 (3) ◽  
pp. 495-498 ◽  
Author(s):  
D. H. Will ◽  
J. L. Hicks ◽  
C. S. Card ◽  
J. T. Reeves ◽  
A. F. Alexander
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
Acute Hypoxia ◽  
Common Mechanism ◽  
Mean Pulmonary Arterial Pressure ◽  
Pressor Responses ◽  
Pulmonary Arterial ◽  
Highly Correlated

We investigated acute and chronic hypoxic pulmonary pressor responses in two groups of calves, one bred to be susceptible, the other resistant to high-altitude pulmonary hypertension. Twelve 5-mo-old susceptible calves residing at 1,524 m increased their mean pulmonary arterial pressure from 26 +/- 2 (SE) to 55 +/- 4 mmHg during 2 h at a simulated altitude of 4,572 m. In 10 resistant calves pressure increased from 22 +/- 1 to 37 +/- 2 mmHg. Five calves were selected from each group for further study. When 9 mo old, the 5 susceptible calves again showed a greater pressor response to acute hypoxia (27 +/- 1 to 55 +/- 4 mmHg) than did 5 resistant calves (23 +/- 1 to 41 +/- 3 mmHg). When 12 mo old, the 5 susceptible calves also developed a greater increase in pulmonary arterial pressure (21 +/- 2 to 9 +/- 4 mmHg) during 18 days at 4,572 m than did the 5 resistant calves (21 +/- 1 to 64 +/- 4 mmHg). Acute and chronic hypoxic pulmonary pressor responses were highly correlated (r = 0.91; P less than 0.001) indicating that they were probably produced through a common mechanism.

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)

Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats

2003 ◽  
Vol 285 (5) ◽  
pp. H2125-H2131 ◽  
Author(s):  
Noritoshi Nagaya ◽  
Hiroyuki Okumura ◽  
Masaaki Uematsu ◽  
Wataru Shimizu ◽  
Fumiaki Ono ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Systemic Arterial Pressure ◽  
Inhalation Therapy ◽  
Rank Test ◽  
Pulmonary Resistance ◽  
Mean Pulmonary Arterial Pressure ◽  
Pulmonary Arterial

Adrenomedullin (AM) is a potent vasodilator peptide. We investigated whether inhalation of aerosolized AM ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Male Wistar rats given MCT (MCT rats) were assigned to receive repeated inhalation of AM ( n = 8) or 0.9% saline ( n = 8). AM (5 μg/kg) or saline was inhaled as an aerosol using an ultrasonic nebulizer for 30 min four times a day. After 3 wk of inhalation therapy, mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with AM than in those given saline [mean pulmonary arterial pressure: 22 ± 2 vs. 35 ± 1 mmHg (–37%); total pulmonary resistance: 0.048 ± 0.004 vs. 0.104 ± 0.006 mmHg · ml–1 · min–1 · kg–1 (–54%), both P < 0.01]. Neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in MCT rats. Kaplan-Meier survival curves demonstrated that MCT rats treated with aerosolized AM had a significantly higher survival rate than those given saline (70% vs. 10% 6-wk survival, log-rank test, P < 0.01). In conclusion, repeated inhalation of AM inhibited MCT-induced pulmonary hypertension without systemic hypotension and thereby improved survival in MCT rats.

scholarly journals Analysis of responses to the Rho-kinase inhibitor Y-27632 in the pulmonary and systemic vascular bed of the rat

2010 ◽  
Vol 299 (1) ◽  
pp. H184-H192 ◽  
Author(s):  
David B. Casey ◽  
Adeleke M. Badejo ◽  
Jasdeep S. Dhaliwal ◽  
James L. Sikora ◽  
Alex Fokin ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Guanylate Cyclase ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Rho Kinase ◽  
Hypoxic Exposure ◽  
Intravenous Injections ◽  
Vasoconstrictor Response ◽  
Rho Kinase Inhibitor ◽  
Pulmonary Arterial

Responses to the Rho kinase inhibitor Y-27632 were investigated in the anesthetized rat. Under baseline conditions intravenous injections of Y-27632 decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressures were enhanced when baseline tone was increased with U-46619, and under elevated tone conditions Y-27632 produced similar percent decreases in pulmonary and systemic arterial pressures. Injections of Y-27632 prevented and reversed the hypoxic pulmonary vasoconstrictor response. The increase in pulmonary arterial pressure in response to ventilation with a 10% O2-90% N2 gas mixture was not well maintained during the period of hypoxic exposure. Treatment with the nitric oxide (NO) synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME) increased pulmonary arterial pressure and prevented the decline or fade in the hypoxic pulmonary vasoconstrictor response. The hypoxic pulmonary vasoconstrictor response was reversed by Y-27632 in control and in l-NAME-treated animals. The Rho kinase inhibitor attenuated increases in pulmonary arterial pressures in response to intravenous injections of serotonin, angiotensin II, and Bay K 8644. Y-27632, sodium nitrite, and BAY 41-8543, a guanylate cyclase stimulator, decreased pulmonary and systemic arterial pressures and vascular resistances in monocrotaline-treated rats. These data suggest that Rho kinase is involved in the regulation of baseline tone and in the mediation of pulmonary vasoconstrictor responses. The present data suggest that the hypoxic pulmonary vasoconstrictor response is modulated by the release of NO that mediates the nonsustained component of the response in the anesthetized rat. These data suggest that Rho kinase and NOS play important roles in the regulation of vasoconstrictor tone in physiological and pathophysiological states and that monocrotaline-induced pulmonary hypertension can be reversed by agents that inhibit Rho kinase, generate NO, or stimulate soluble guanylate cyclase.

The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat

2012 ◽  
Vol 90 (7) ◽  
pp. 825-835 ◽  
Author(s):  
Edward A. Pankey ◽  
Ryuk J. Byun ◽  
William B. Smith ◽  
Manish Bhartiya ◽  
Franklin R. Bueno ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Kinase Inhibitor ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Rock Inhibitor ◽  
Vasodilator Activity ◽  
Pulmonary Arterial ◽  
Vascular Beds

Responses to a selective azaindole-based Rho kinase (ROCK) inhibitor (azaindole-1) were investigated in the rat. Intravenous injections of azaindole-1 (10–300 µg/kg), produced small decreases in pulmonary arterial pressure and larger decreases in systemic arterial pressure without changing cardiac output. Responses to azaindole-1 were slow in onset and long in duration. When baseline pulmonary vascular tone was increased with U46619 or L-NAME, the decreases in pulmonary arterial pressure in response to the ROCK inhibitor were increased. The ROCK inhibitor attenuated the increase in pulmonary arterial pressure in response to ventilatory hypoxia. Azaindole-1 decreased pulmonary and systemic arterial pressures in rats with monocrotaline-induced pulmonary hypertension. These results show that azaindole-1 has significant vasodilator activity in the pulmonary and systemic vascular beds and that responses are larger, slower in onset, and longer in duration when compared with the prototypical agent fasudil. Azaindole-1 reversed hypoxic pulmonary vasoconstriction and decreased pulmonary and systemic arterial pressures in a similar manner in rats with monocrotaline-induced pulmonary hypertension. These data suggest that ROCK is involved in regulating baseline tone in the pulmonary and systemic vascular beds, and that ROCK inhibition will promote vasodilation when tone is increased by diverse stimuli including treatment with monocrotaline.

Drug action on pulmonary circulation of unanesthetized dogs

1964 ◽  
Vol 206 (6) ◽  
pp. 1201-1206 ◽  
Author(s):  
Abraham M. Rudolph ◽  
Emile M. Scarpelli
Keyword(s):  
Pulmonary Blood Flow ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Drug Action ◽  
Test Lung ◽  
Local Effects ◽  
Amino Butyric Acid ◽  
Vasoconstrictor Response ◽  
Pulmonary Arterial ◽  
Pharmacologic Agents

A preparation is described which overcomes most of the difficulties previously encountered in the assessment of vasomotor responses of the pulmonary vessels to pharmacologic agents. The use of electromagnetic flow transducers on the main and left pulmonary arteries allows for the observation of immediate local effects following unilateral drug administration before general systemic effects occur. The opposite lung serves as a control, since it is subjected to the same changes of left artrial pressure, pulmonary arterial pressure, and pulmonary blood flow as the test lung. Our studies have demonstrated a direct pulmonary vasoconstrictor response to 5-hydroxytryptamine and acetylcholine in both the conscious and anesthetized dog. Epinephrine was also shown to have a direct pulmonary vasoconstrictor activity, but this could be elicited in only three of the eight dogs studied. Isoproterenol, methoxamine, aminophylline, phenylephrine, γ-amino butyric acid and pentobarbital had no apparent direct pulmonary vasomotor effect.

Severe VA/Q mismatch in perfused lungs evoked by sequential challenge with endotoxin and E. coli hemolysin

1994 ◽  
Vol 76 (3) ◽  
pp. 1020-1030 ◽  
Author(s):  
D. Walmrath ◽  
J. Pilch ◽  
M. Scharmann ◽  
F. Grimminger ◽  
W. Seeger
Keyword(s):  
Pulmonary Hypertension ◽  
Gas Exchange ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Low Doses ◽  
Edema Formation ◽  
Shunt Flow ◽  
E Coli ◽  
Vasoconstrictor Response ◽  
Pulmonary Arterial

Escherichia coli hemolysin (ECH), an important pathogenicity factor in extraintestinal E. coli infections, provokes pulmonary hypertension and microvascular leakage in buffer-perfused rabbit lungs. We investigated gas exchange abnormalities in response to low doses of ECH, lipopolysaccharides (LPS), and sequential and combined application of these bacterial agents by using the multiple inert gas elimination technique. In control lungs and after admixture of 100 ng/ml of LPS, unimodal narrow distribution of perfusion and ventilation to midrange ventilation-perfusion (VA/Q) areas was noted. ECH [0.08 hemolytic units (HU)/ml] caused a moderate increase in pulmonary arterial pressure (< 10 mmHg), progressive lung edema formation (approximately 10 g within 20 min), and a broadening of perfusate and gas flow dispersion. Application of 0.08 HU/ml of ECH in lungs “primed” with 100 ng/ml of LPS in a preceding 125-min perfusion period provoked a large increase in pulmonary arterial pressure (> 50 mmHg within 5 min), rapid edema formation (approximately 10 g within 10 min), and severe VA/Q mismatch with predominance of shunt flow. Vasoconstrictor response and VA/Q mismatch, but not edema formation, were largely inhibited by pretreatment of lungs with acetylsalicylic acid or the thromboxane receptor antagonist BM-13.505. In addition, “rescue” application of BM-13.505 rapidly reversed pressure rise and shunt flow due to sequential LPS and/or ECH stimulation, whereas edema formation was not affected. We conclude that the marked pulmonary hypertension in response to low doses of ECH in LPS-primed lungs is paralleled by severe gas exchange abnormalities with predominance of shunt flow. Both the vasoconstrictor response and the development of shunt are closely related to toxin-induced thromboxane generation.

Three-week neonatal hypoxia reduces blood CGRP and causes persistent pulmonary hypertension in rats

2000 ◽  
Vol 279 (4) ◽  
pp. H1571-H1578 ◽  
Author(s):  
I. M. Keith ◽  
S. Tjen-A-Looi ◽  
H. Kraiczi ◽  
R. Ekman
Keyword(s):  
Pulmonary Hypertension ◽  
Ventricular Hypertrophy ◽  
Pulmonary Arterial Pressure ◽  
Pulmonary Arteries ◽  
Left Ventricular ◽  
Persistent Pulmonary Hypertension ◽  
Perinatal Exposure ◽  
Calcitonin Gene ◽  
Potent Vasodilator ◽  
Pulmonary Arterial

To increase understanding of persistent pulmonary hypertension, we examined chronic pulmonary effects of hypoxia at birth and their relationships with immunoreactive levels of the potent vasodilator, calcitonin gene-related peptide (CGRP). Rats were born in 10% hypobaric hypoxia, where they remained for 1–2 days, or in 15% hypoxia, where they remained for 21 days. All were then reared in normoxia for 3 mo followed by reexposure to 10% hypoxia for 7 days (H→H) or continued normoxia (H→N); age-matched normoxic rats were hypoxic for the last 7 days (N→H) or normoxic throughout (N→N). Results are as follows. Pulmonary arterial pressure (PPA) in 10% H→N rats was normal at the end of the experiment (13 wk), but in rats reexposed to hypoxia (H→H), pressure rose to 19% above N→H controls. In 15% H→N rats, PPA remained high, similar to that of N→H rats, and increased further by 40% on reexposure (H→H). Medial thickness of small pulmonary arteries in 10% H→H rats also increased by 40% over N→H controls and was equally high in 15% H→N and H→H rats. In N→H rats from both experiments, right ventricular hypertrophy index (RVH) was increased after hypoxia at 15–16 wk. Also, in the 15% study, RVH remained elevated in H→N rats and increased in H→H rats by 19% above N→H controls. Blood CGRP was reduced by neonate and adult hypoxia, and hypoxic reexposure (H→H) further lowered blood CGRP in the 15% but not 10% study. Declining left ventricular blood CGRP correlated highly with logarithmically increasing PPA in the 15% study ( r = −0.81, P = 0.000). In conclusion, 1) short perinatal exposure to 10% O2 exacerbated pulmonary hypertension with hypoxia later in life, 2) 15% O2 at birth and for 21 days caused persistent pulmonary hypertension and exacerbation with reexposure, and 3) PPA correlated highly with declining blood CGRP levels in the 15% study.

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