scholarly journals Caveolae are involved in mechanotransduction during pulmonary hypertension

2016 ◽  
Vol 310 (11) ◽  
pp. L1078-L1087 ◽  
Author(s):  
Guillaume Gilbert ◽  
Thomas Ducret ◽  
Jean-Pierre Savineau ◽  
Roger Marthan ◽  
Jean-François Quignard
Keyword(s):  
Pulmonary Hypertension ◽  
Plasma Membrane ◽  
Sarcoplasmic Reticulum ◽  
Osmotic Shock ◽  
Ryanodine Receptors ◽  
Membrane Microdomains ◽  
Mechanical Stimuli ◽  
Membrane Stretch ◽  
Arterial Blood ◽  
Pulmonary Arterial

Caveolae are stiff plasma membrane microdomains implicated in various cell response mechanisms like Ca2+ signaling and mechanotransduction. Pulmonary arterial smooth muscle cells (PASMC) transduce mechanical stimuli into Ca2+ increase via plasma membrane stretch-activated channels (SAC). This mechanotransduction process is modified in pulmonary hypertension (PH) during which stretch forces are increased by the increase in arterial blood pressure. We propose to investigate how caveolae are involved in the pathophysiology of PH and particularly in mechanotransduction. PASMC were freshly isolated from control rats (Ctrl rats) and rats suffering from PH induced by 3 wk of chronic hypoxia (CH rats). Using a caveolae disrupter (methyl-β-cyclodextrin), we showed that SAC activity measured by patch-clamp, stretch-induced Ca2+ increase measured with indo-1 probe and pulmonary arterial ring contraction to osmotic shock are enhanced in Ctrl rats when caveolae are disrupted. In CH rats, SAC activity, Ca2+, and contraction responses to stretch are all higher compared with Ctrl rats. However, in contrast to Ctrl rats, caveolae disruption in CH-PASMC, reduces SAC activity, Ca2+ responses to stretch and arterial contractions. Furthermore, by means of immunostainings and transmission electron microscopy, we observed that caveolae and caveolin-1 are expressed in PASMC from both Ctrl and CH rats and localize close to subplasmalemmal sarcoplasmic reticulum (ryanodine receptors) and mitochondria, thus facilitating Ca2+ exchanges, particularly in CH. In conclusion, caveolae are implicated in mechanotransduction in Ctrl PASMC by buffering mechanical forces. In PH-PASMC, caveolae form a distinct Ca2+ store facilitating Ca2+ coupling between SAC and sarcoplasmic reticulum.

Endothelial Upregulation of Mechanosensitive Channel Piezo1 in Pulmonary Hypertension

2021 ◽  
Author(s):  
Ziyi Wang ◽  
Jiyuan Chen ◽  
Aleksandra Babicheva ◽  
Pritesh P. Jain ◽  
Marisela Rodriguez ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cyclic Stretch ◽  
Mechanosensitive Channel ◽  
Pathogenic Role ◽  
Membrane Stretch ◽  
Mrna And Protein Expression ◽  
Resultant Increase ◽  
Pulmonary Arterial ◽  
Arterial Endothelial Cells ◽  
Notch Ligands

Piezo is a mechanosensitive cation channel responsible for stretch-mediated Ca2+ and Na+ influx in multiple types of cells. Little is known about the functional role of Piezo1 in the lung vasculature and its potential pathogenic role in pulmonary arterial hypertension (PAH). Pulmonary arterial endothelial cells (PAECs) are constantly under mechanic stretch and shear stress that are sufficient to activate Piezo channels. Here we report that Piezo1 is significantly upregulated in PAECs from patients with idiopathic PAH and animals with experimental pulmonary hypertension (PH) compared to normal controls. Membrane stretch by decreasing extracellular osmotic pressure or by cyclic stretch (18% CS) increases Ca2+-dependent phosphorylation (p) of AKT and ERK, and subsequently upregulates expression of Notch ligands, Jagged1/2 (Jag1 and Jag-2), and Delta like-4 (DLL4) in PAECs. siRNA-mediated downregulation of Piezo1 significantly inhibited the stretch-mediated pAKT increase and Jag-1 upregulation, while downregulation of AKT by siRNA markedly attenuated the stretch-mediated Jag1 upregulation in human PAECs. Furthermore, the mRNA and protein expression level of Piezo1 in the isolated pulmonary artery, which mainly contains pulmonary arterial smooth muscle cells (PASMCs), from animals with severe PH was also significantly higher than that from control animals. Taken together, our study suggests that membrane stretch-mediated Ca2+ influx through Piezo1 is an important trigger for pAKT-mediated upregulation of Jag-1 in PAECs. Upregulation of the mechanosensitive channel Piezo1 and the resultant increase in the Notch ligands (Jag-1/2 and DLL4) in PAECs may play a critical pathogenic role in the development of pulmonary vascular remodeling in PAH and PH.

P6480Asymmetric dimethylarginine (ADMA) predicts altitude-associated hypoxic pulmonary arterial hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
R H Boeger ◽  
P Siques ◽  
J Brito ◽  
E Schwedhelm ◽  
E Pena ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Logistic Regression ◽  
Oxygen Saturation ◽  
High Altitude ◽  
Sea Level ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Arterial Blood ◽  
Pulmonary Arterial

Abstract Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) is an important regulator of systemic and pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis that increases in hypoxia, we aimed to investigate whether ADMA predicts the incidence of HAPH among Chilean frontiers personnel exposed to six months of CIH. We performed a prospective study of 123 healthy male subjects who were subjected to CIH (5 days at appr. 3,550 m, followed by 2 days at sea level) for six months. ADMA, SDMA, L-arginine, arterial oxygen saturation, systemic arterial blood pressure, and haematocrit were measured at baseline and at months 1, 4, and 6 at high altitude. Acclimatization to high altitude was determined using the Lake Louise Score and the presence of acute mountain sickness (AMS). Echocardiography was performed after six months of CIH in a subgroup of 43 individuals with either good (n=23) or poor (n=20) aclimatization to altitude, respectively. Logistic regression was used to assess the association of biomarkers with HAPH. 100 study participants aged 18.3±1.3 years with complete data sets were included in the final analysis. Arterial oxygen saturation decreased upon the first ascent to altitude and plateaued at about 90% during the further course of the study. Haematocrit increased to about 47% after one month and remained stable thereafter. ADMA continuously increased and SDMA decreased during the study course, whilst L-arginine levels showed no distinct pattern. The incidence of AMS and the Lake Louise Score were high after the first ascent (53 and 3.1±2.4, respectively) and at one month of CIH (47 and 3.0±2.6, respectively), but decreased to 20 and 1.4±2.0 at month 6, respectively (both p<0.001 for trend). In echocardiography, 18 participants (42%) showed a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg (mean ± SD, 30.4±3.9 mm Hg), out of which 9 (21%) were classified as HAPH (mPAP ≥30 mm Hg; mean ± SD, 33.9±2.2 mm Hg). Baseline ADMA, but not SDMA, was significantly associated with mPAP at month 6 in univariate logistic regression analysis (R = 0.413; p=0.007). In ROC analysis, a cut-off for baseline ADMA of 0.665 μmol/l was determined as the optimal cut-off level to predict HAPH (mPAP >30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. ADMA concentration increases during long-term CIH. It is an independent predictive biomarker for the incidence of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of high altitude pulmonary hypertension. Acknowledgement/Funding CONICYT/FONDEF/FONIS Sa 09I20007; FIC Tarapaca BIP 30477541-0; BMBF grant 01DN17046 (DECIPHER); Georg & Jürgen Rickertsen Foundation, Hamburg

Pulmonary hypertension induced by repeated pulmonary inflammation in the rat

1981 ◽  
Vol 51 (3) ◽  
pp. 755-761 ◽  
Author(s):  
J. Herget ◽  
F. Palecek ◽  
P. Preclik ◽  
M. Cermakova ◽  
M. Vizek ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Pulmonary Hypertension ◽  
Lung Inflammation ◽  
Pulmonary Inflammation ◽  
Control Group ◽  
Arterial Blood ◽  
The Media ◽  
Pulmonary Arterial ◽  
The Mean ◽  
And Control

The effect of repeated lung inflammation on the pulmonary vascular bed was studied in rats. Nonbacterial lung inflammation was induced by repeated carrageenan instillations into the lungs. Three days after the single carrageenan injection, the mean pulmonary arterial blood pressure was only slightly raised [16.3 +/- 0.6 (mean +/- SE) Torr in controls and 19.5 +/- 0.5 Torr in rats with lung inflammation, P less than 0.001]. A substantial pulmonary hypertension was found in rats 3 days after the sixth lung inflammation (24.6 +/- 1 Torr). In this group, arterial hypoxemia, hypercapnia, and right-heart hypertrophy were found. In the 14th day of recovery after the last injection of carrageenan, the mean pulmonary artery blood pressure decreased (18.5 +/- 0.9 Torr) but remained higher than in the control group. There was no difference in cardiac output measured by dye-dilution technique between the experimental and control groups. After repeated inflammation, the media of distal pulmonary vessels thickened and the number of pulmonary arterioles with distinct media increased.

Thromboxane does not mediate pulmonary hypertension in phorbol ester-induced acute lung injury in dogs

1990 ◽  
Vol 69 (1) ◽  
pp. 345-352 ◽  
Author(s):  
A. H. Stephenson ◽  
R. S. Sprague ◽  
T. E. Dahms ◽  
A. J. Lonigro
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Pressor Response ◽  
H2 Receptor Antagonist ◽  
Arterial Blood ◽  
Pulmonary Arterial ◽  
The Relationship

Thromboxane (Tx) has been suggested to mediate the pulmonary hypertension of phorbol myristate acetate- (PMA) induced acute lung injury. To test this hypothesis, the relationship between Tx and pulmonary arterial pressure was evaluated in a model of acute lung injury induced with PMA in pentobarbital sodium-anesthetized male mongrel dogs. Sixty minutes after administration of PMA (20 micrograms/kg iv, n = 10), TxB2 increased 10-fold from control in both systemic and pulmonary arterial blood and 8-fold in bronchoalveolar lavage (BAL) fluid. Concomitantly, pulmonary arterial pressure (Ppa) increased from 14.5 +/- 1.0 to 36.2 +/- 3.5 mmHg, and pulmonary vascular resistance (PVR) increased from 5.1 +/- 0.4 to 25.9 +/- 2.9 mmHg.l-1.min. Inhibition of Tx synthase with OKY-046 (10 mg/kg iv, n = 6) prevented the PMA-induced increase in Tx concentrations in blood and BAL fluid but did not prevent or attenuate the increase in Ppa. OKY-046 pretreatment did, however, attenuate but not prevent the increase in PVR 60 min after PMA administration. Pretreatment with the TxA2/prostaglandin H2 receptor antagonist ONO-3708 (10 micrograms.kg-1.min-1 iv, n = 7) prevented the pressor response to bolus injections of 1-10 micrograms U-46619, a Tx receptor agonist, but did not prevent or attenuate the PMA-induced increase in Ppa. ONO-3708 also attenuated but did not prevent the increase in PVR. These results suggest that Tx does not mediate the PMA-induced pulmonary hypertension but may augment the increases in PVR in this model of acute lung injury.

Aberrant cytoplasmic sequestration of eNOS in endothelial cells after monocrotaline, hypoxia, and senescence: live-cell caveolar and cytoplasmic NO imaging

2007 ◽  
Vol 292 (3) ◽  
pp. H1373-H1389 ◽  
Author(s):  
Somshuvra Mukhopadhyay ◽  
Fang Xu ◽  
Pravin B. Sehgal
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Plasma Membrane ◽  
Live Cell ◽  
Caveolin 1 ◽  
Protein Levels ◽  
Pulmonary Arterial ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
Arterial Endothelial Cells

We previously reported the disruption of caveolae/rafts, dysfunction of Golgi tethers, N-ethylmaleimide-sensitive factor-attachment protein (SNAP) receptor proteins (SNAREs), and SNAPs, and inhibition of anterograde trafficking in endothelial cells in culture and rat lung exposed to monocrotaline pyrrole (MCTP) as a prelude to the development of pulmonary hypertension. We have now investigated 1) whether this trafficking block affects subcellular localization and function of endothelial nitric oxide (NO) synthase (eNOS) and 2) whether Golgi blockade and eNOS sequestration are observed after hypoxia and senescence. Immunofluorescence data revealed that MCTP-induced “megalocytosis” of pulmonary arterial endothelial cells (PAEC) was accompanied by a loss of eNOS from the plasma membrane, with increased accumulation in the cytoplasm. This cytoplasmic eNOS was sequestered in heterogeneous compartments and partially colocalized with Golgi and endoplasmic reticulum (ER) markers, caveolin-1, NOSTRIN, and ER Tracker, but not Lyso Tracker. Hypoxia and senescence also produced enlarged PAEC, with dysfunctional Golgi and loss of eNOS from the plasma membrane, with sequestration in the cytoplasm. Live-cell imaging of caveolar and cytoplasmic NO with 4,5-diaminofluorescein diacetate (DAF-2DA) as probe showed a marked loss of caveolar NO after MCTP, hypoxia, and senescence. Although ionomycin stimulated DAF-2DA fluorescence in control PAEC, this ionophore decreased DAF-2DA fluorescence in MCTP-treated and senescent PAEC, suggesting localization of eNOS in an aberrant cytoplasmic compartment that was readily discharged by Ca2+-induced exocytosis. Thus monocrotaline, hypoxia, and senescence produce a Golgi blockade in PAEC, leading to sequestration of eNOS away from its functional caveolar location and providing a mechanism for the often-reported reduction in pulmonary arterial NO levels in experimental pulmonary hypertension, despite sustained eNOS protein levels.

Physiologic response to two endotracheal suctioning techniques in newborn lambs with and without acute pulmonary hypertension

1995 ◽  
Vol 4 (6) ◽  
pp. 453-459 ◽  
Author(s):  
BB Daicoff ◽  
Langham MRJr ◽  
TW Mullet ◽  
HN Yarandi
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Repeated Measures ◽  
Pulmonary Arterial Pressure ◽  
Endotracheal Suctioning ◽  
Repeated Measures Design ◽  
Arterial Blood ◽  
Acute Pulmonary Hypertension ◽  
Pulmonary Arterial ◽  
Physiologic Responses

BACKGROUND: Endotracheal suctioning may cause sudden increases in pulmonary arterial pressure, which can result in hypoxia secondary to right ventricular failure and/or increased right-to-left shunting. An adaptor that allows suctioning without disconnecting the ventilator has been proposed to prevent these problems; however, its efficacy has not been rigorously studied. OBJECTIVE: To examine the physiologic responses to two endotracheal suctioning techniques in newborn lambs with and without acute pulmonary hypertension. METHODS: A repeated-measures design was used to compare two endotracheal suctioning techniques in seven newborn lambs with and without acute pulmonary hypertension. An adaptor was used in the ventilator-controlled technique, making disconnection of the ventilator during suctioning unnecessary. In the bag-controlled technique, the ventilator was disconnected and ventilation was done with a manual resuscitation bag. Physiologic variables, pulmonary and mean arterial pressure, peak inspiratory pressure, mixed venous oxygen saturation, cardiac index, and arterial blood gas values were recorded before, during, and after endotracheal suctioning. RESULTS: Endotracheal suctioning caused a statistically significant systemic hypertensive response in lambs with and without acute pulmonary hypertension, regardless of which suctioning technique was used. No statistically significant changes occurred in pulmonary arterial pressure using either technique. CONCLUSIONS: Use of an adaptor resulted in no differences in the physiologic responses to endotracheal suctioning. However, endotracheal suctioning was easier to perform using an adaptor because no extra equipment or person was needed.

scholarly journals Oxidation of Ryanodine Receptors Promotes Ca 2+ Leakage and Contributes to Right Ventricular Dysfunction in Pulmonary Hypertension

Hypertension ◽  
2021 ◽  
Vol 77 (1) ◽  
pp. 59-71
Author(s):  
Yongfa Huang ◽  
Chuxiang Lei ◽  
Wenjun Xie ◽  
Li Yan ◽  
Yanru Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Ryanodine Receptors ◽  
Right Ventricular Dysfunction ◽  
Protein Levels ◽  
Intracellular Ca ◽  
Pulmonary Arterial

Right ventricular (RV) failure is a major cause of death in patients with pulmonary arterial hypertension, and the mechanism of RV failure remains unclear. While the malfunction of RyR2 (ryanodine receptor type 2) on sarcoplasmic reticulum (SR) and aberrant Ca 2+ cycling in cardiomyocytes have been recognized in some cardiovascular diseases, their roles in RV failure secondary to pulmonary arterial hypertension require further investigation. In a monocrotaline-induced rat model of pulmonary arterial hypertension, the RV remodeling process was divided into normal, compensated, and decompensated stages according to the hemodynamic and morphological parameters. In both compensated and decompensated stages, significant diastolic SR Ca 2+ leakage was detected along with reduced intracellular Ca 2+ transient amplitude and SR Ca 2+ contents in RV myocytes. RyR2 protein levels decreased progressively during the process, and the thiol oxidation proportions of RyR2 were higher in compensated and decompensated stages than in normal stage. Inhibition of RyR2 oxidation by dithiothreitol or repairing RyR2 directly by dantrolene could restore Ca 2+ homeostasis in RV myocytes. Daily intraperitoneal injection of dantrolene delayed decompensation progression and significantly improved the survival rate of pulmonary hypertension rats in decompensated stage (79.3% versus 55.9%; P =0.026). Our findings suggest that diastolic SR Ca 2+ leakage via oxidized RyR2 facilitates the development of RV failure. Dantrolene can inhibit diastolic SR Ca 2+ leakage in RV cardiomyocytes, delay right cardiac dysfunction, and improve the survival of rats with pulmonary arterial hypertension.

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.

Increased vasoreactivity and chronic pulmonary hypertension following thoracic irradiation in sheep

1986 ◽  
Vol 61 (5) ◽  
pp. 1875-1881 ◽  
Author(s):  
E. A. Perkett ◽  
K. L. Brigham ◽  
B. Meyrick
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Reactivity ◽  
Structural Changes ◽  
Blood Gases ◽  
Base Line ◽  
External Diameter ◽  
Thoracic Irradiation ◽  
Arterial Blood ◽  
Chronic Pulmonary Hypertension ◽  
Pulmonary Arterial

Six chronically catheterized sheep were exposed to 1,500-rad whole-lung irradiation and followed for a four-week period. Pulmonary arterial, left atrial and systemic arterial pressures, cardiac output, arterial blood gases, and pH were measured at base line and biweekly following radiation. Pulmonary vasoreactivity to 12% O2, 100% O2, and an analogue of prostaglandin H2 (PGH2-A) was also assessed. Five nonirradiated sheep served as controls. By the 2nd wk following irradiation, pulmonary vascular resistance had doubled. Final pulmonary arterial pressure was increased 50% over the base-line value (base line = 14 +/- 1 cm H2O; final 22 +/- 2; mean +/- SE; P less than 0.05). Arterial PO2 was decreased to approximately 70 Torr throughout the study. In addition, pulmonary vasoreactivity to PGH2-A, but not to breathing 12 or 100% O2, was significantly increased above base line in the irradiated animals (P less than 0.05). Morphometric techniques applied to the lungs in which the pulmonary arterial circulation was distended with barium gelatin mixture, showed extension of muscle into the distal intra-acinar arteries, and a reduction in both the external diameter and the number of barium-filled peripheral arteries in the irradiated animals. Thus thoracic irradiation results in functional and structural changes of chronic pulmonary hypertension and increased pulmonary vasoreactivity to PGH2-A. The structural changes in the peripheral pulmonary arterial bed may contribute to the increased pulmonary vascular reactivity following thoracic irradiation.

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