Changes In Pulmonary Circulation Research Articles

Effects of vasoactive substances on changes of pulmonary circulation in barium sulfate-induced pulmonary microembolism in the dog (author's transl)

Effects of vasoactive substances on changes of pulmonary circulation in barium sulfate-induced pulmonary microembolism in the dog (author's transl)

Pulmonary Vascular Involvement in COPD

Alterations in pulmonary vessel structure and function are highly prevalent in patients with COPD. Vascular abnormalities impair gas exchange and may result in pulmonary hypertension, which is one of the principal factors associated with reduced survival in COPD patients. Changes in pulmonary circulation have been identified at initial disease stages, providing new insight into their pathogenesis. Endothelial cell damage and dysfunction produced by the effects of cigarette smoke products or inflammatory elements is now considered to be the primary alteration that initiates the sequence of events resulting in pulmonary hypertension. Cellular and molecular mechanisms involved in this process are being extensively investigated. Progress in the understanding of the pathobiology of pulmonary hypertension associated with COPD may provide the basis for a new therapeutic approach addressed to correct the imbalance between endothelium-derived vasoactive agents. The safety and efficacy of endothelium-targeted therapy in COPD-associated pulmonary hypertension warrants further investigation in randomized clinical trials.

Effect of sildenafil on hypoxia-induced changes in pulmonary circulation and right ventricular function

Hypoxia leads to pulmonary vasoconstriction in healthy men. However, the consequences on right ventricular function are not known. The effects of hypoxia on systolic pulmonary artery pressure (sPAP) and right ventricular function index (TEI) were assessed by Doppler echocardiography. Fourteen members of a Mount Everest expedition were monitored during acute hypoxic challenge at sea level, environmental hypoxia exposure at altitudes of 3440 m and 5245 m and 2 weeks after return to sea level. Subjects received either placebo or 50mg sildenafil in a double-blind randomised cross-over design. Under normoxia at baseline, mean sPAP was 17.1(S.E.M. 1.3) mm Hg, and TEI was 0.13(0.004). Both increased during acute hypoxia: sPAP 29.6(2.6) mm Hg, and TEI 0.35(0.06) (each p<0.01). At 5245 m sPAP was 29.1(1.7) and TEI was 0.43(0.05) in the placebo group, while in the sildenafil group, both sPAP and TEI were reduced to 22(1.5) mm Hg and 0.23(0.03) (each p<0.005), respectively. We conclude that in healthy individuals, exposure to acute hypoxia and sojourns at high altitude result in a small but significant increase in sPAP accompanied by an impairment of right ventricular function. Sildenafil significantly decreases sPAP and improves right ventricular function.

Effect of pulmonary artery pressure on extravascular lung water in an experimental model of acute lung injury

Lung edema can be influenced by hemodynamic changes in pulmonary circulation. The aim of this study was to evaluate, in an experimental model of acute lung injury, the effect on extravascular lung water (EVLW) of an increase in pulmonary artery pressure (Ppa) without changes in cardiac output and wedge pressure. Lung edema was produced by an intravenous oleic acid infusion in mixed-breed pigs weighing 25-31 kg, which, after 20 min, were randomly assigned to a control group (100% FiO(2)) (n = 6) or a high Ppa group (21% FiO(2)) (n = 7). An increase in pulmonary artery pressure of at least 40% over baseline was produced in the high Ppa group by alveolar hypoxia. Hemodynamic, ventilatory and gas exchange parameters were collected at regular intervals. Pulmonary, wedge and capillary pressures were measured with a pulmonary artery catheter and the occlusion technique. EVLW was calculated gravimetrically. At 240 min, both gravimetric-measured EVLW and mean pulmonary artery pressures were significantly higher (P < 0.05) in high Ppa animals vs. controls (12.06 +/- 4.21 vs. 7.98 +/- 2.46 ml/kg and 39.0 +/- 1.3 vs. 26.6 +/- 4.7 mmHg, respectively). Cardiac output (6.8 +/- 2.5 vs. 7.3 +/- 1.3) and pulmonary wedge pressures (9.2 +/- 1.7 vs. 9.4 +/- 2.8 mmHg) were similar. A difference was detected in pulmonary capillary pressures [17.0 +/- 3.3 (high Ppa) vs. 13.8 +/- 2.7 mmHg (controls)] but did not reach statistical significance. In this model, an increase in pulmonary artery pressure by alveolar hypoxia produces an increase in extravascular lung water, probably related to changes in pulmonary capillary pressures.

Vd/Vt test in the detection of pulmonary dysfunction in sepsis

Dyspnea and tachypnea are the leading signs of pulmonary dysfunction in sepsis. With regards to present knowledge of pathophysiology and pathogenesis of the pulmonary dysfunction, the real reasons for this phenomena are still not researched enough. It is our assumption that one of the underlying causes is in the increased ventilation of the physiological dead space due to the mismatch of the pulmonary ventilation and perfusion. In sepsis, equal to change in systemic, there are changes in pulmonary circulation, often with pulmonary hypotension and decreased pulmonary vascular resistance. To investigate this we used a simple test to measure the ventilation of the dead space using the Vd/Vt test.

Pulmonary hypertension in chronic obstructive pulmonary disease.

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). Its presence is associated with shorter survival and worse clinical evolution. In COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. However, transitory increases of pulmonary artery pressure may occur during exacerbations, exercise and sleep. Right ventricular function is only mildly impaired with preservation of the cardiac output. Structural and functional changes of pulmonary circulation are apparent at the initial stages of COPD. Recent investigations have shown endothelial dysfunction and changes in the expression of endothelium-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease. Some of these changes are also present in smokers with normal lung function. Accordingly, it has been postulated that the initial event in the natural history of pulmonary hypertension in COPD could be the lesion of pulmonary endothelium by cigarette-smoke products. Long-term oxygen administration is the only treatment that slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease. Nevertheless, with this treatment pulmonary artery pressure rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Vasodilators are not recommended on the basis of their minimal clinical efficacy and because they impair pulmonary gas exchange. Recognition of the role of endothelial dysfunction in the physiopathology of pulmonary hypertension in chronic obstructive pulmonary disease opens new perspectives for the treatment of this complication.

Changes in pulmonary circulation during liver transplantation

Changes in pulmonary circulation during liver transplantation

Tissue Lipid Peroxidation and Reduced Glutathione Depletion in Hypochlorite-Induced Lung Injury

Neutrophils are involved in acute lung injury during ARDS via several mechanisms. This study focuses on neutrophil-derived oxidative stress. Hypochlorite is a major neutrophil-derived oxidant. This study characterizes hypochlorite-induced acute changes in pulmonary circulation and the involvement of tissue lipid peroxidation (LPO) and reduced glutathione (rGSH) depletion. Hypochlorite (500, 1,000, and 2,000 nmol/min) or buffer (control) were infused into isolated rabbit lungs. Pulmonary artery pressure (PAP), capillary filtration coefficient (Kf,c) [10(4)/mL/s/cm H(2)O/g], and lung weight were measured. Experiments were terminated after 105 min or when fluid retention was > 50 g. Lung tissue was frozen immediately after termination of the experiments and analyzed for LPO products and rGSH (nanomoles per milligram of protein). Baseline PAP and Kf,c values averaged from 6.1 to 6.5 mm Hg and from 0.97 to 1.23, respectively, in all groups. Hypochlorite infusion of 500, 1,000, and 2,000 nmol/min (n = 5 to 7 per group) evoked an increase (mean +/- SEM) in maximum PAP (PAPmax) [12.9 +/- 2.1, 14.3 +/- 1.7, and 13.3 +/- 2.2 mm Hg], in maximum Kf,c (Kf,cmax) [1.9 +/- 1.2, 6.34 +/- 1.2, and >10.0], and in tissue LPO products (1.7 +/- 0.06, 2.1 +/- 0.06, and 2.3 +/- 0.11 vs 1.4 +/- 0.04 in controls), and a decrease in tissue rGSH (73.4 +/- 8.7, 43.0 +/- 9.6, and 50.4 +/- 7.2 vs 139 +/- 12.6 in controls). Parameters of lung injury (PAPmax and Kf,cmax) of each single experiment were closely correlated with tissue rGSH but did not correlate with tissue LPO products. All changes are significant (p < 0.05) vs control. The neutrophil-specific oxidant hypochlorite induces acute lung injury, rGSH depletion, and LPO in isolated rabbit lungs. The lung injury correlates with rGSH depletion, suggesting an important mechanistic role in hypochlorite-induced acute lung injury.

A maturational shift in pulmonary K+ channels, from Ca2+ sensitive to voltage dependent.

The mechanism responsible for the abrupt decrease in resistance of the pulmonary circulation at birth may include changes in the activity of O2-sensitive K+ channels. We characterized the electrophysiological properties of fetal and adult ovine pulmonary arterial (PA) smooth muscle cells (SMCs) using conventional and amphotericin B-perforated patch-clamp techniques. Whole cell K+ currents of fetal PASMCs in hypoxia were small and characteristic of spontaneously transient outward currents. The average resting membrane potential (RMP) was -36 +/- 3 mV and could be depolarized by charybdotoxin (100 nM) or tetraethylammonium chloride (5 mM; both blockers of Ca2+-dependent K+ channels) but not by 4-aminopyridine (4-AP; 1 mM; blocker of voltage-gated K+ channels) or glibenclamide (10 microM; blocker of ATP-dependent K+ channels). In hypoxia, chelation of intracellular Ca2+ by 5 mM 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid further reduced the amplitude of the whole cell K+ current and prevented spontaneously transient outward current activity. Under these conditions, the remaining current was partially inhibited by 1 mM 4-AP. K+ currents of fetal PASMCs maintained in normoxia were not significantly reduced by acute hypoxia. In normoxic adult PASMCs, whole cell K+ currents were large and RMP was -49 +/- 3 mV. These 4-AP-sensitive K+ currents were partially inhibited by exposure to acute hypoxia. We conclude that the K+ channel regulating RMP in the ovine pulmonary circulation changes after birth from a Ca2+-dependent K+ channel to a voltage-dependent K+ channel. The maturational-dependent differences in the mechanism of the response to acute hypoxia may be due to this difference in K+ channels.

Inhibition of PMN- and HOCl-induced vascular injury in isolated rabbit lungs by acetylsalicylic acid: a possible link between neutrophil-derived oxidative stress and eicosanoid metabolism?

Neutrophils are involved in the pathogenesis of acute lung injury. The neutrophil-derived enzyme myeloperoxidase (MPO) catalyzes the formation of the oxidant hypochlorous acid (HOCl). This study characterizes the effects of (A) continuous HOCl infusion, and (B) stimulated neutrophils on pulmonary circulation in an isolated rabbit lung model. Furthermore, the effect of cyclooxygenase inhibition by acetylsalicylic acid (ASA, 0.5 mM) on these effects was investigated. (A) Infusion of HOCl (in nmol min −1, groups: 0, 0+ASA, 1000, 1000+ASA, 2000, and 2000+ASA) into the isolated organ was started after a 45-min steady-state period ( t=0). (B) Neutrophils (PMN group: 1480±323 and ASA group 1294±320 μl −1) were added into the perfusate between ( t=−45 min) and stimulated with FMLP (1 μM) after two 45-min steady-state periods ( t=0). Perfusate MPO activity was measured at t=−90, −45, 0, 1, 2, 3, 5, 10, 15, 30, 60, and 90 min. For both groups, pulmonary artery pressure (PAP) and lung weight were continuously recorded and the capillary filtration coefficient ( K f,c in 10 −4 cm 3 s −1 cm H 2O −1 g −1) was calculated from the slope of weight gain after a hydrostatic challenge at t=−45, −15, 30, 60 and 90 min. (A) Continuous HOCl infusion (1000/2000 nmol min −1) evoked a significant increase in ΔPAP and an up to 10-fold increase in K f,c reaching the maximum extent of the observed effects significant earlier in the 2000 nmol min −1 group. ASA reduced ΔPAP max significantly to about 50% in corresponding groups and the increase in PAP and K f,c occurred later in the ASA groups. (B) Neutrophil stimulation (PMN group/ASA group) evoked a rapid increase in ΔPAP and MPO activity, while the changes in vascular permeability were rather moderate, but still significant. The release of MPO activity was similar in both groups. ASA significantly reduced the increase in ΔPAP without affecting the release of MPO activity. Compared to baseline values, the preventive effects on vascular permeability increase reached level of significance as well. In summary, the described changes in pulmonary circulation caused by HOCl infusion or by neutrophil stimulation are significantly reduced by ASA. An involvement of cyclooxygenase products in the mediation of neutrophil-derived oxidative stress could be concluded.

Resting potentials and potassium currents during development of pulmonary artery smooth muscle cells.

The pulmonary circulation changes rapidly at birth to adapt to extrauterine life. The neonate is at high risk of developing pulmonary hypertension, a common cause being perinatal hypoxia. Smooth muscle K+ channels have been implicated in hypoxic pulmonary vasoconstriction in adults and O2-induced vasodilation in the fetus, channel inhibition being thought to promote Ca2+ influx and contraction. We investigated the K+ currents and membrane potentials of pulmonary artery myocytes during development, in normal pigs and pigs exposed for 3 days to hypoxia, either from birth or from 3 days after birth. The main finding is that cells were depolarized at birth and hyperpolarized to the adult level of -40 mV within 3 days. Hypoxia prevented the hyperpolarization when present from birth and reversed it when present from the third postnatal day. The mechanism of hyperpolarization is unclear but may involve a noninactivating, voltage-gated K+ channel. It is not caused by increased Ca2+-activated or delayed rectifier current. These currents were small at birth compared with adults, declined further over the next 2 wk, and were suppressed by exposure to hypoxia from birth. Hyperpolarization could contribute to the fall in pulmonary vascular resistance at birth, whereas the low K+-current density, by enhancing membrane excitability, would contribute to the hyperreactivity of neonatal vessels. Hypoxia may hinder pulmonary artery adaptation by preventing hyperpolarization and suppressing K+ current.

Hemodynamic Profile of Submaximal Constant Workload Exercise in Patients With Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

Constant workload exercise on an upright bicycle at submaximal levels of exercise intensity is frequently used in physical training programs. Nevertheless, only a few data are currently available on the hemodynamic changes induced by constant workload exercise in patients with heart failure. The aim of this study was to assess the hemodynamic response during submaximal constant-workload exercise at 2 different work rates in patients with heart failure. The hemodynamic profile was assessed by means of right-sided cardiac catheterization in 21 men with moderate heart failure during submaximal-constant workload exercise performed on an upright bicycle for 15 minutes. The intensity of constant work rate exercise was selected during a previous symptom-limited or maximal test. The first submaximal test was performed at the level of the anaerobic threshold workload, corresponding to 64% of peak work rate, and the other test at 70% of anaerobic threshold workload (42% of peak work rate). During both submaximal tests, a marked increase in right heart pressure was observed as compared with baseline. The increase in systolic pulmonary artery pressure was statistically not different between the 2 tests (from 40 ± 18 to 66 ± 20 mm Hg during exercise at the anaerobic threshold workload, and from 39 ± 16 to 63 ± 21 mm Hg during exercise under anaerobic threshold). The increase in pulmonary arterial wedge pressure was similar (from 20 ± 10 to 35 ± 13 mm Hg during exercise at the anaerobic threshold, and from 19 ± 9 to 32 ± 12 mm Hg during the other test). Cardiac output and heart rate were significantly higher during submaximal exercise at a higher workload, paralleling the behavior of oxygen uptake. Finally, the hemodynamic profile during submaximal exercise at the anaerobic threshold workload was quite similar to that observed during symptom-limited exercise. Thus, in patients with heart failure, submaximal exercise performed at a constant workload, even at low exercise intensity, may determine relevant pressure changes in pulmonary circulation.

Increased plasma adrenomedullin levels in chronic congestive heart failure

Adrenomedullin is a potent vasodilator peptide and occurs in circulating blood of human beings and experimental animals. Because it is produced in intact aorta of rats and in cultured vascular endothelial cells, adrenomedullin seems to participate in regulation of local vascular tone. To determine the pathophysiological roles of adrenomedullin, we investigated its plasma concentrations in 49 patients with heart failure. Plasma adrenomedullin levels increased significantly with advancing severity of the disease (New York Heart Association functional class I, 4.1 ± 1.0; II, 5.6 ± 1.6; III, 6.4 ± 0.8; IV, 13.2 ± 6.8 (fmol/I)). Plasma adrenomedullin was correlated with pulmonary artery pressure ( r = 0.44, p = 0.0114) and pulmonary capillary wedge pressure ( r = 0.53, p = 0.0002). These findings indicate that adrenomedullin may play some important role in the pathophysiologic makeup of heart failure by its vasodilating effects against the concomitant exaggeration of humor pressor agents such as catecholamine and the renin-angiotensin system. Hemodynamic changes in pulmonary circulation may have some influence on the increased synthesis and secretion of plasma adrenomedullin in chronic congestive heart failure.

Changes in pulmonary circulation during the early postoperative period following single lung transplantation.

This study examines the pulmonary hemodynamics during reimplantation and rejection following unilateral lung transplantation in dogs. Nineteen mongrel dogs were divided into three groups according to the method of treatment used: group 1 (n = 6) underwent modified autotransplantation of the left lung; group 2 (n = 6), allotransplantation without immunosuppression; and group 3 (n = 7), allotransplantation with immunosuppression. The pulmonary arterial blood flow and ventilation scores, assessed by chest X-rays, were measured for 2 weeks postoperatively. Pulmonary blood flow to the transplanted lung decreased slightly in group 1, whereas in group 2, it decreased sharply from the 3rd postoperative day (POD) and was almost completely absent by the 14th POD. In group 3, it decreased by 28% on the 1st POD but recovered gradually to 37% by the 14th POD. Ventilation scores were the same among the three groups on the 1st POD but in group 2, they decreased rapidly from the 3rd POD. This change correlated well with that of the pulmonary arterial (PA) flow, although the ventilation score changed after the PA flow did. In conclusion, rejection was reflected earlier and more distinctly by the changes in PA flow than by chest X-rays.

Hemodynamic changes in pulmonary circulation induced by effort in the elderly

Age-related changes in vascular tissue were previously reported. 1,2 Moreover, mild diffuse connective tissue proliferation of the aging lung can contribute to reduced reserve of the pulmonary vascular bed. 3 These morphologic changes may induce some hemodynamic impairment of the aging pulmonary circulation. Unlike the systemic circulation, relatively little is known regarding the effects of effort on pulmonary hemodynamics in healthy, elderly subjects. Difficulties in selecting elderly subjects without pulmonary vascular, cardiac and lung disease, and the absence of an effective, noninvasive method for the measurement of pulmonary hemodynamics are the causes for this poor knowledge. 4 In the present study, we evaluated the pulmonary hemodynamics in an elderly cohort, free of cardiovascular and lung disease, at rest and during submaximal supine exercise.

COR Pulmonale Is Caused by Monocrotaline and Dehydromonocrotaline, but Not by Glutathione or Cysteine Conjugates of Dihydropyrrolizine

Monocrotaline (MCT) produces pulmonary hypertension and right ventricular hypertrophy in rats. It is generally believed that MCI must undergo hepatic metabolism to reactive metabolites that are subsequently transported to the lungs to induce a pneumotoxic response. Several studies suggest that dehydromonocrotaline (MCTP) is the reactive intermediate that initiates pulmonary toxicity. We recently identified two other MCI metabolites, the glutathione and N-acetylcysteine conjugates of 6,7-dihydro-7-hydroxy-I-hydromethyl-5 H -pyrrolizine (DHP). To determine the potential pulmonary toxicity of the glutathione conjugate (DHP-GSH) and the unacetylated cysteine conjugate precursor (DHP-Cys) of the N-acetylated excretion product, we conducted parallel in vivo toxicity studies with DHP-GSI. DHP-Cys, MCI, and MCTP. Relative pneumotoxicity was evaluated by measurements of right ventricular pressure (RVP), ventricular weight ratio (RV/LV + S), subjective histopathology, and measurements of components of the arteriolar wall. Animals given a single injection of MCI (60 mg/kg) developed pulmonary hypertension at the end of 3 weeks, as indicated by significant elevation in RVP when compared to the controls (22.1 ± 2.4 mm Hg vs 13.2 ± 0.8 mm Hg). A parallel and significant increase in RVI LV + S was also evident: 0.37 ± 0.021 (MCI) vs 0.299 ± 0.011 (control). Histopathology showed marked alterations in both pulmonary vasculature and parenchyma in MCI- and MCIP-treated animals. MCIP (1 mg/kg) caused a significantly elevated RVP (MCIP vs control: 28.1 ± 3.4 mm Hg vs 16.8 ± 0.97 mm Hg) and an increased RV/LV + S (MCIP vs control: 0.445 ± 0.051 vs 0.284 ± 0.026). Both MCI- and MCIP-treated rats had increased arteriolar medial thickness and decreased lumen diameter, but MCIP-treated rats had a milder vascular inflammatory response and less parenchymal lesions. Neither DHP-GSH (24 or 12 mg/kg) nor DHP-Cys (12 mg/kg) caused detectable changes in pulmonary circulation and no structural alteration in the lung was observed in these treatment groups. Although they are all pyrrolic metabolites of MCI, these studies demonstrate that only MCIP but not the glutathione or cysteine conjugates, is pneumotoxic at the doses tested.

Regional effects and clearance of endothelin-1 across pulmonary and splanchnic circulation.

To determine the impact of i.v. endothelin-1 on systemic, pulmonary and splanchnic circulation, as well as the peptide's regional clearance, hepatic venous and right heart catheterization was performed in healthy volunteers. During the peptide's continuous i.v. administration (0.4 pmol x kg-1 x min-1, 60 min) its plasma concentration rose from 2.1 +/- 0.5 to 9.5 +/- 5.3 pmol/l (pulmonary artery), from 2.1 +/- 0.9 to 5.0 +/- 1.6 pmol/l (femoral artery), and from 1.5 +/- 0.6 to 2.9 +/- 1.2 pmol/l (hepatic vein). This was accompanied by an increase in mean systolic arterial pressure from 127 +/- 14 to 131 +/- 12 mmHg (P less than 0.05). Concomitantly, cardiac output and heart rate decreased from 7.0 +/- 1.1 to 5.8 +/- 1.0 l/min and from 63 +/- 6 to 56 +/- 5 beats/min, respectively, while total vascular resistance increased from 964 +/- 273 to 1204 +/- 338 dyn x cm x s-5 (P less than 0.01). No major changes in pulmonary circulation were observed, while splanchnic vascular resistance increased from 4472 +/- 1056 to 5361 +/- 1420 dyn x cm x s-5 (P less than 0.01) and estimated hepatic blood flow decreased from 1403 +/- 218 to 1218 +/- 219 ml min-1 (P less than 0.01). During endothelin-1 infusion the pulmonary vascular bed accounted for approximately 53% of the peptide's overall disposal.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in pulmonary circulation in severe bronchopulmonary dysplasia.

Eight patients with severe bronchopulmonary dysplasia underwent cardiac catheterisation. Seven had a pulmonary vascular resistance greater than 3 mm Hg.l-1 min.m2 (mean 8.9, range 2.2-13.8). All had raised intrapulmonary shunts (mean 25.6%, range 5.4-50%, normal less than 5%). Two had a high alveolar dead space, and two had unsuspected congenital heart disease. Epoprostenol (prostacyclin), but not 100% oxygen, caused a significant fall in pulmonary vascular resistance. Death was associated with a high pulmonary vascular resistance and a high shunt. Morphometric studies in three cases showed normal numbers of airways, but increased thickness of bronchial muscle. The numbers of alveoli were reduced and the walls thickened. There was increased medial thickness in small pulmonary arteries with distal extension of muscle. In the oldest child some vessels were obliterated by fibrosis. We speculate that measurements of pulmonary vascular resistance and shunt may have prognostic value; that a trial of pulmonary vasodilators other than oxygen might be worthwhile in patients with poor prognosis; and that abnormalities of the pulmonary circulation contribute to the difficulties of managing patients with bronchopulmonary dysplasia.

Effects of corticosteroid treatment on pulmonary haemodynamics in patients with sarcoidosis

Effects of 12 months steroid treatment on pulmonary haemodynamics in 24 patients with pulmonary sarcoidosis, stage II and III, were investigated. All patients had a chest radiograph, lung function tests, and pulmonary haemodynamics (measured at rest and during submaximal exercise) prior to the treatment. Resting pulmonary hypertension was found in 3 patients. In 18 an abnormal increase in pulmonary arterial mean pressure (PAP) on exercise was observed. All investigations were repeated after a year of treatment. In almost all patients (22) a regression of radiological changes in the lungs and improvement of pulmonary function were observed. The changes in pulmonary circulation were less uniform. In only half of the patients studied was regression of the disease seen on chest X-ray and improvement in lung function accompanied by improvement in pulmonary haemodynamics.

A fetal-instrumented model to study age-specific responses to leukotriene D4 and prostaglandin D2 in unsedated newborn lambs.

Sequential studies of the pulmonary vascular response to leukotriene D4 (LTD4) and prostaglandin D2 (PGD2) in the immediate newborn period were performed in lambs, instrumented in utero and delivered vaginally. Compounds were tested in fully conscious 1.5-day-old lambs and the study was repeated 1 week later. Bolus injections of PGD2 (0.05-2.0 micrograms/kg) or LTD4 (0.01-1.0 micrograms/kg) were made into the main pulmonary artery or aorta while pulmonary blood flow and aortic, pulmonary artery, and left and right atrial pressures were monitored continuously. PGD2 was a systemic constrictor regardless of age. In lambs 1.5 days of age, it decreased pulmonary vascular pressure and resistance by 6% (p less than 0.05) and 15% (p less than 0.05), respectively, while 1 week later it increased pulmonary vascular resistance by 18% (p less than 0.05). In contrast, LTD4 was a pulmonary and systemic vasoconstrictor in both the early and late newborn, the threshold dose being between 0.01 and 0.05 micrograms/kg at either age. The decrease in pulmonary blood flow and the increase in pressure and resistance were greater in older animals. In lambs 1.5 days of age, LTD4 (1 micrograms/kg) increased pulmonary vascular resistance by 66.1% (p less than 0.05) and 1 week later by 210% (p less than 0.001). These sequential observations in the same animal indicate that unlike PGD2, LTD4 is a pulmonary vasoconstrictor regardless of age, and its effectiveness increases significantly with age. These results support previous reports that PGD2 action in the pulmonary circulation changes shortly after birth from dilation to constriction.