Cardiotrophin-1 is a prophylactic against the development of chronic hypoxic pulmonary hypertension in rats

BACKGROUND: Cardiotrophin-1 (CT-1) reduces arterial blood pressure by activating nitric oxide synthesis. This study attempted to elucidate the effect of CT-1 on pulmonary arteries of pulmonary hypertensive rats. METHODS: Pulmonary hypertension was induced in rats in a hypoxic chamber containing 10% to 11% oxygen. Rats kept in the hypoxic environment received either recombinant mouse CT-1 at a concentration of 50 micro g/kg (CT-1+hypoxia group, n = 21) or phosphate-buffered saline (hypoxia group, n = 30) once per day. Control rats housed in room air also received either the equivalent concentration of CT-1 (CT-1+normoxia group, n = 18) or phosphate-buffered saline (normoxia group, n = 39). Pulmonary arterial pressure, pulmonary vasorelaxation, and ventricular hypertrophy were measured. RESULTS: The mean pulmonary arterial pressures were as follows (from lowest to highest; p values are relative to the hypoxia group): normoxia group (20.3 +/- 4.0 mm Hg, p < 0.0001), CT-1+normoxia group (21.1 +/- 2.4 mm Hg, p < 0.0001), CT-1+hypoxia group (27.9 +/- 4.1 mm Hg, p = 0.0019), and hypoxia group (33.9 +/- 6.6 mm Hg). The endothelium-dependent vasorelaxation value was largest in the normoxia group (59.5% +/- 17.4%, p < 0.0001), with it decreasing in the other groups in the following order (p values are relative to the hypoxia group): CT-1+normoxia group (52.8% +/- 15.5%, p = 0.0005), CT-1+hypoxia group (42.3% +/- 14.8%, p = 0.0061), and hypoxia group (17.4% +/- 4.8%). Right ventricular hypertrophy was significant only in the hypoxia group. CONCLUSIONS: Our results demonstrate that treatment with CT-1 in a chronic hypoxic pulmonary hypertension model protects the endothelial function of the pulmonary artery; decreases pulmonary arterial pressure; and attenuates right ventricular hypertrophy.     

Single lung transplantation in rats with chemically induced pulmonary hypertension.

Physiologic effects of single lung transplantation on pulmonary hypertension were studied in rats with monocrotaline-induced pulmonary hypertension. Inbred rats treated with monocrotaline (40 mg/kg) received a left lung isograft from a normal donor 2 weeks later, when pulmonary hypertension became significant (transplant group; n = 6). These rats and control rats treated with monocrotaline (mediated control group; n = 11) or vehicle alone (normal control group; n = 9) were followed up weekly by metabolic treadmill testing for exercise tolerance and oxygen consumption up to 6 weeks after monocrotaline (4 weeks after transplantation), when all rats underwent hemodynamic and histologic examinations. Whereas maximal oxygen consumption and exercise tolerance consistently deteriorated in the medicated control group of rats, indices in the transplant group stopped deteriorating 2 weeks after lung transplantation and remained at levels similar to those of normal control rats. Severe pulmonary hypertension (68 +/- 19 mm Hg) and right ventricular hypertrophy (right ventricular/left ventricular weight ratio, 0.95 +/- 0.19) were confirmed in medicated control rats in contrast to transplant animals, in which these two indices remained at normal control levels. Whereas left-to-right lung perfusion ratio was constant among rats not receiving transplants (0.69 +/- 0.16), it was significantly elevated (2.27 +/- 0.65; p less than 0.001) in those receiving transplants, suggesting preferential flow through the lung isograft. The results suggest that, in the early phase of pulmonary hypertension, single lung transplantation shifts pulmonary perfusion to the grafted lung, avoiding right ventricular pressure overload and thereby preserving exercise tolerance at a nearly normal level in rats with monocrotaline-induced pulmonary hypertension.     

Resolution of pulmonary hypertension and other features induced by chronic hypoxia in rats during complete and intermittent normoxia.

Rats subjected to 10% O2 (hypoxic rats) for various periods and recovery regimens were compared with control animals with respect to pulmonary artery pressure (Ppa), right ventricular hypertrophy (RVH), and muscularisation of small pulmonary vessels. Mean Ppa was measured in anaesthetised animals spontaneously breathing air and rose from 16 mmHg in controls to 36 mmHg in rats exposed to hypoxia for three weeks. Ppa had returned to normal after 20 weeks' recovery in air. RVH regressed a little more quickly, but muscularisation of small pulmonary vessels. Mean Ppa was measured in anaesthetised animals spontaneously breathing air and rose from 16 mmHg in controls to 36 mmHg in rats exposed to hypoxia for three weeks. Ppa had returned to normal after 20 weeks' recovery in air. RVH regressed a little more quickly, but muscularisation of small pulmonary vessels was still apparent after 20 weeks. Some hypoxic rats were subjected to an intermittent normoxic recovery regimen for either 40 or 80 hours a week in air, the remainder in 10% O2. Some reduction in RVH probably occurred after six weeks on the 80-hour regimen, but there was no reduction in Ppa or muscularisation of small pulmonary vessels. These results suggest that the pulmonary hypertension of chronic alveolar hypoxia resolves very slowly and is probably related to structural changes in the pulmonary vessels. Their relevance to human cor pulmonale and intermittent long-term oxygen treatment for these patients is discussed.     

Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents

OBJECTIVES: Overexpression of angiopoietin 1 in the lung has been associated with human pulmonary hypertension. We hypothesized that inhibiting angiopoietin 1 signaling in the lung by administration of a receptor antagonist would block the development of pulmonary hypertensive vasculopathy in rodent models. METHODS: We injected 2 and 4 x 10(10) genomic particles of adeno-associated virus containing an extracellular fragment of the TIE2 receptor (AAV-sTIE2) into the pulmonary artery of 60 rats by using adeno-associated virus-lacZ and carrier-injected rats as control animals. Pulmonary hypertension was then induced by each of the following methods: (1) monocrotaline (group 1); (2) angiopoietin 1 expression in pulmonary vascular smooth muscle by adeno-associated virus gene transfer (group 2); or (3) oxygen deprivation (group 3). Animals were sacrificed at serial time points. At each time point, pulmonary artery pressures were measured, and pulmonary angiography was performed. Lungs were harvested for pathologic-molecular analysis. RESULTS: Each rodent pulmonary hypertension model demonstrated a significant increase in pulmonary artery pressures compared with that seen in control animals (P < .01). Administration of AAV-sTIE2 prevented pulmonary hypertension in the monocrotaline and angiopoietin 1 groups (from 44.6 +/- 2.1 to 18.8 +/- 1.9 mm Hg in the monocrotaline group and from 31.2 +/- 3.7 to 18.2 +/- 1.8 mm Hg in the angiopoietin 1 group, P < .001) but did not affect pulmonary hypertension in the hypoxia group. Pathologic analysis of group 1 and 2 lungs treated with AAV-sTIE2 demonstrated absence of smooth muscle cell proliferation within arterioles. Pulmonary angiography confirmed a lack of small pulmonary vessel occlusion in group 1 and 2 animals treated with AAV-sTIE2. CONCLUSIONS: Molecular blocking of the interaction between angiopoietin 1 and its endothelial receptor, TIE2, in the lung prevents pulmonary hypertension in 2 animal models of the disease. These experiments suggest a new strategy for understanding pulmonary hypertension based on the molecular biology of the pulmonary vascular wall.     

Angiotensin converting enzyme activity and evolution of pulmonary vascular disease in rats with monocrotaline pulmonary hypertension.

We have investigated the role of angiotensin converting enzyme (ACE) in the development of pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular disease in rats given a single subcutaneous injection of the pyrrolizidine alkaloid monocrotaline. Thirty-six young female Wistar rats were divided into a test group of 27 animals and a control group of nine animals. Each test rat was given a single subcutaneous injection of monocrotaline (60 mg/kg body weight). On the first, third, fifth, seventh, tenth, twelfth, fourteenth, seventeenth, and twenty-second days after the injection of monocrotaline the mean right ventricular systolic blood pressure was measured in one control and three test rats. The animals were then killed and we measured the specific activity of ACE in serum and lung homogenate. We also evaluated muscularisation of pulmonary arterioles, medial hypertrophy of muscular pulmonary arteries, and right ventricular hypertrophy. The sequence of changes was as follows: muscularisation of pulmonary arterioles and medial hypertrophy of muscular pulmonary arteries were apparent seven days after administration of monocrotaline; pulmonary hypertension and reduced lung ACE activity occurred after 10 days; right ventricular hypertrophy was detected after 12 days. Serum ACE activity was unchanged. It is concluded that the reduction in lung ACE activity is a result rather than a cause of the pulmonary hypertension. This reduction in lung ACE activity may be a protective mechanism designed to limit the elevation of the pulmonary arterial pressure.     

盐酸戊乙奎醚对野百合碱致大鼠肺动脉高压的抑制作用

目的探讨盐酸戊乙奎醚是否能够减缓野百合碱导致的大鼠肺动脉高压及是否能够预防或缓解肺血管重构。方法 3~4周龄健康雄性SD大鼠30只,体重90~100g,随机均分为正常对照组(C组)、野百合碱肺高压组(M组)、盐酸戊乙奎醚组(P组),每组10只。M组和P组腹腔注射野百合碱60mg/kg建造大鼠肺动脉高压模型,C组腹腔注射等容量生理盐水。P组大鼠于建模前15min时腹腔注射盐酸戊乙奎醚2mg/kg,建模第2天腹腔注射盐酸戊乙奎醚1mg/kg,C组和M组在相应时点腹腔注射等容量生理盐水,连续使用3周。在建模后第21天,三组大鼠检测血流动力学(肺动脉压、右心室压);处死大鼠前采集静脉血以备血液生化检测:ELISA法检测一氧化氮(NO)含量、内皮素-1(ET-1)含量。处死大鼠后留取左肺组织行病理切片以观察肺组织病理形态学变化,取右肺组织于-80℃冻存以备后续检测。结果 M组和P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显高于C组(P0.05);P组右心室SBP、平均肺动脉压、肺动脉SBP和肺动脉DBP明显低于M组(P0.05)。M组肺小动脉明显增厚,肺小动脉管腔狭窄甚至闭塞,肺组织炎性细胞浸润非常明显。P组肺小动脉壁增厚减轻,肺组织炎性细胞浸润减轻。M组大鼠血清中NO含量明显低于,ET-1的含量明显高于C组(P0.05);P组大鼠血清中NO含量明显高于M组和C组(P0.05),ET-1含量明显高于C组,但明显低于M组(P0.05)。结论使用野百合碱成功建造了大鼠肺动脉高压模型,NO含量降低、ET-1含量增加可能与野百合碱致大鼠肺动脉高压的形成有关;盐酸戊乙奎醚减缓野百合碱致大鼠肺动脉高压模型的肺动脉压力的升高、改善肺小动脉壁增厚可能与增加NO含量、降低ET-1含量有关。     

Lung angiotensin converting enzyme activity in rats with pulmonary hypertension.

We have studied serum and lung tissue angiotensin converting enzyme (ACE) activity in female Wistar rats with pulmonary hypertension induced by two different methods. Chronic pulmonary hypertension was produced in one group of 10 rats (CH) by confinement in a hypobaric chamber (380 mmHg) for three weeks, and in another group fo 10 rats (M) by a single subcutaneous injection of monocrotaline (60 mg/kg body weight). In these two groups of tests rats and in 20 untreated controls (C), we evaluated right ventricular mean systolic blood pressure (Prvs mmHg), right ventricular hypertrophy, and serum ACE (n mol/ml/min). In lung tissue homogenate, we measured the specific activity of ACE (n mol/mg protein/min), alkaline phosphatase (AP) (IU/mg protein) and lactic dehydrogenase (LDH) (IU/mg protein). The Prvs in groups, C, CH, and M was 25 +/- 7 SD, 41 +/- 7, and 51 +/- 5, respectively. The ratio of right ot left ventricular weight (RV/(LV + S)%) in groups, C, CH, and M was 29 +/- 4, 52 +/- 5, and 56 +/- 7, respectively. The lung tissue ACE in groups C, CH, and M was 85 +/- 11, 65 +/- 20, and 22 +/- 5, respectively. In groups CH, and M the Prvs and RV/(LV + S)% were significantly elevated above control values while lung ACE was significant decreased (p less than 0.05). There was a significant inverse relationship between lung ACE on one hand, and Prvs (r = - 0.73) and RV/(LV + S)% (r = - 0.71) on the other hand. Serum ACE and lung AP were unchanged. In group M there was a slight but significant reduction in lung LDH. Chronic pulmonary hypertension, irrespective of its method of production, is associated with decreased lung ACE. The reduction in lung ACE is inversely proportional to the severity of pulmonary hypertension and right ventricular hypertrophy.     

Regional brain glucose utilization in the conscious rat exposed to prolonged hypobaric hypoxia

Because of the physiologic and metabolic changes that occur during acclimatization, we hypothesized that LCGU may be normal during prolonged hypoxia. We exposed five Sprague-Dawley rats to hypoxia (air at 380 mm Hg) for 2 weeks (hypoxic group) and six rats to 2 weeks of hypoxia followed by 2 weeks of recovery in room air (recovered group). Six control rats breathed room air (control group). Regional brain glucose utilization was measured in awake animals by using 2-[C]deoxyglucose autoradiography. Glucose utilization was comparable in the control and recovered groups and in most brain regions of hypoxic animals. Glucose utilization was decreased slightly in 10 of 12 gray matter regions examined and was 20 to 25% lower (p <0.05) in the olfactory and auditory cortices, the caudate nucleus, and the superior olive of the hypoxic group. White matter glucose utilization was unchanged. Hypoxic rats, compared to controls, had a lower PaO2 (53 +/- 3 vs. 76 +/- 3 mm Hg, mean SEM, respectively), a lower PaCO2 (22 +/- 1 vs. 36 +/- 2 mm Hg), and a higher mean pulmonary artery pressure (46 +/- 3 vs. 14 +/- 3 mm Hg) and hematocrit (61 +/- 2% vs. 48 +/- 1%; p <0.005 for all comparisons). Pulmonary hypertension and polycythemia persisted in recovered rats. Arterial pressure, pH, and plasma glucose were unaffected. Therefore, while acute hypoxia may increase glucose utilization in most brain structures, prolonged exposure does not.     

Lung mast cells in rats exposed to acute hypoxia, and chronic hypoxia with recovery.

Exposure to acute hypoxia (barometric pressure 263 mmHg) for 8 hours did not lead to increased numbers of mast cells in the lungs of rats. In contrast, in adult rats kept for 35 days at a barometric pressure of 380 mmHg there was a proliferation of mast cells around the pulmonary blood vessels and in the alveolar septa. This hyperplasia of lung mast cells in response to chronic hypoxia was reversible on removal of the hypoxic stimulus. There was a correlation between the logarithm of the perivascular lung mast cell density (defined in the paper) and the logarithm of the right ventricular weight. There was no increase in the mast cells in the carotid bodies of the hypoxic rats. Young male, old male, young female, and old female rats which had been subjected for 39 days to a barometric pressure of 380 mmHg showed a proliferation of mast cells around the pulmonary blood vessels and in the alveolar walls. This response was greatest in the adult animals and independent of their sex. In the age and sex experiment there was a correlation between the perivascular lung mast cell density and the medial thickness of the muscular pulmonary arteries. Since mast cell hyperplasia has been reported as preceding right ventricular hypertrophy, it is conceivable that mast cell proliferation in the lung may be a defence mechanism to limit the severity of hypoxic pulmonary hypertension rather than to mediate it.     

Inhaled nitric oxide versus prostacyclin in chronic shunt-induced pulmonary hypertension

OBJECTIVE: Cardiac surgery for congenital heart defects is commonly complicated by shunt-induced chronic pulmonary hypertension and associated acute hypertensive crises. To investigate the effects of vasodilators in chronic and acute pulmonary hypertension, we used the innominate artery to create a growing aortopulmonary shunt in young piglets. METHODS: Pulmonary hemodynamics and right ventricular function and their responses to hypoxia, intravenous prostacyclin, and inhaled nitric oxide were investigated after closure of the shunt by using pulmonary flow-pressure relationships, pulmonary vascular resistance partitioning, pulmonary vascular impedance, and ventriculoarterial coupling expressed as the ratio of right ventricular end-systolic elastance to effective pulmonary arterial elastance. RESULTS: Shunt-induced pulmonary hypertension was associated with medial hypertrophy of pulmonary arteries, increased resistance, increased elastance, increased wave reflection, and preserved ventriculoarterial coupling. Hypoxic pulmonary vasoconstriction was blunted in the shunt group. Compared with prostacyclin, inhaled nitric oxide was a more effective vasodilator in the shunt group and in hypoxia. Effective pulmonary arterial elastance and right ventricular end-systolic elastance increased in chronic (shunt) and acute (hypoxic) hypertension and decreased with vasodilators, preserving a normal coupling. CONCLUSIONS: A growing aortopulmonary shunt in the young pig is a reliable model of chronic pulmonary hypertension, with medial hypertrophy, increased resistance, and increased elastance. In this model inhaled nitric oxide is a better pulmonary vasodilator than intravenous prostacyclin, with neither drug having a specific inotropic effect, and normal coupling is preserved in chronic and acute pulmonary hypertension.     

Single lung transplantation in rats with fatal pulmonary hypertension.

Effects of single lung transplantation on fatal pulmonary hypertension were evaluated in rats receiving a lethal dose of monocrotaline. Inbred rats treated with monocrotaline (80 mg/kg) received a left lung isograft at 4 weeks (n = 9) and at 6 weeks (n = 6), when moderate and severe pulmonary hypertension, respectively, had developed. Medicated (n = 12) and nonmedicated rats (n = 12) served as control animals. Each rat was tested weekly with treadmill for exercise tolerance and oxygen consumption during a 10-week period after medication and after they were killed. Medicated control rats lost exercise tolerance and highest oxygen consumption per unit time consistently to the range of resting value (or 45% of nonmedicated control rats), and all died from severe pulmonary vascular occlusive disease with right ventricular hypertrophy before 10 weeks (right ventricular/left ventricular weight ratio of 1.16). All rats receiving a left lung isograft at 4 weeks survived and regained highest oxygen consumption per unit time (87% of nonmedicated control rats), with the lung transplant receiving 65% (nonmedicated control rats, 39%) of cardiac output and milder right ventricular hypertrophy (right ventricular/left ventricular weight ratio of 0.46). Except for one, all rats that received a left lung isograft at 6 weeks tolerated single lung transplantation, but they died soon after reperfusion because of pulmonary edema in the graft that received 58% of cardiac output with right ventricular/left ventricular weight ratio of 0.79. Results of single lung transplantation in rats were dependent on severity of pulmonary hypertension. In rats with moderate pulmonary hypertension, single lung transplantation was successful in reversing exercise intolerance and right ventricular hypertrophy. Single lung transplantation was unsuccessful when pulmonary hypertension was severe in the rat model because increased flow toward the lung transplant resulted in graft pulmonary edema.     

Haemodynamic effects of atrial natriuretic peptide in hypoxic chronic obstructive pulmonary disease.

BACKGROUND--Pulmonary artery pressure is elevated in patients with advanced chronic obstructive pulmonary disease (COPD). Release of atrial natriuretic peptide (ANP) is increased in pulmonary hypertension and this hormone may both selectively vasodilate pulmonary vessels and inhibit pulmonary vascular remodelling. The hypothesis that ANP has a physiological role in protection of the pulmonary circulation from pressure overload, and that it may be beneficial in patients with COPD, has been examined. METHODS--Ten patients with hypoxic COPD were infused for 30 minute periods with saline followed by ANP at 0.4, 2, and 10 pmol/kg/min respectively via a pulmonary artery catheter whilst monitoring haemodynamics and oxygenation. RESULTS--Levels of immunoreactive ANP (irANP) increased from a mean (SD) of 23 (15) pmol/l to a maximum of 94 (41) pmol/l. Neither systemic blood pressure, cardiac output nor total systemic vascular resistance showed any correlation with irANP levels. There were negative correlations between levels of ANP and mean pulmonary artery pressure which fell from 28.7 to 25.9 mm Hg, pulmonary artery wedge pressure which fell from 6.5 to 4.6 mmHg, and total pulmonary vascular resistance which fell from 489 to 428 dynes s cm-5. There was a small fall in PaCO2 from 6.2 to 5.9 kPa, whilst venous admixture and oxygen delivery both increased non-significantly. CONCLUSIONS--At these pathophysiological concentrations there was evidence that ANP selectively reduced right ventricular afterload. These data support the hypotheses that increased plasma levels of ANP may be beneficial in hypoxic COPD, and that endogenous ANP may ameliorate pulmonary hypertension in humans.     

Mesenchymal stem cells attenuate hypoxic pulmonary vasoconstriction by a paracrine mechanism

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) may be an adaptive mechanism to correct ventilation-perfusion mismatch in the face of hypoxia. In chronic hypoxia, prolonged vasoconstriction may result in pulmonary hypertension and cor pulmonale. It has been shown that during chronic hypoxia, mesenchymal stem cells (MSCs) may contribute to pulmonary vascular remodeling, anti-inflammation, and vascular stability. Also, MSCs have been shown to release growth factors when stressed by hypoxia. We hypothesized that MSCs reduce HPV by a paracrine mechanism. To test this, MSCs were stressed by hypoxia in tissue culture and the cell-free media was then used to treat the pulmonary arteries subjected to HPV. METHODS: Adult male (250-350 g) Sprague Dawley rat pulmonary arteries (n = 10/group) were isolated and suspended in physiological organ baths. Human MSCs were stressed with 60-min hypoxia and conditioned media was collected. Pulmonary artery rings were treated with vehicle or MSC-conditioned (cell-free) media prior to hypoxia. Force displacement was continuously recorded. Data (mean +/- SEM) were analyzed with two-way analysis of variance with post-hoc Bonferroni test. RESULTS: Pulmonary arteries exposed to MSC-conditioned media experienced an augmented vasodilatory phase as compared to vehicle. Maximum vasodilation was 53.58 +/- 6.42% versus 39.76 +/- 4.05% for vehicle (P < 0.001). In addition, delayed, phase II vasoconstriction was significantly attenuated as compared to vehicle. Maximum phase II vasoconstriction was 28.51 +/- 12.42 versus 86.29 +/- 15.99% for vehicle (P < 0.001). CONCLUSIONS: We conclude that acute hypoxia induces HPV and that MSC-conditioned media acutely attenuates this effect. Thus, in addition to a direct contribution to vessel remodeling in chronic hypoxia, MSCs may acutely protect and attenuate hypoxic pulmonary vasoreactivity through a paracrine mechanism.     

Molecular and functional mechanisms of right ventricular adaptation in chronic pulmonary hypertension.

BACKGROUND: Chronic pulmonary hypertension can lead to compensatory changes in the right ventricle. In this study, the adaptive mechanisms of the right ventricle in the setting of pulmonary hypertension were assessed at the molecular and functional level using a canine model of monocrotaline pyrrole-induced pulmonary hypertension. METHODS: Animals underwent pulmonary artery catheterization to measure pulmonary hemodynamics before and 8 weeks after an injection of monocrotaline pyrrole, 3 mg/kg (n = 8) or placebo (n = 8) (controls). Systolic function was assessed with load-insensitive means (preload-recruitable stroke work). Myocardial biopsy specimens were collected to analyze membrane alpha1- and beta-adrenergic receptor density and adenylate cyclase activity. RESULTS: Eight weeks after injection, significant increases in pulmonary hemodynamic indices were noted in monocrotaline-injected dogs. Significant increases in right ventricular preload-recruitable stroke work were also observed in these animals compared with controls and occurred in association with significant increases in right ventricular alpha1- and beta-adrenergic receptor density and isoproterenol hydrochloride-stimulated adenylate cyclase activity. No significant differences in basal adenylate cyclase activity in the right ventricle were noted between the two groups. CONCLUSIONS: These data suggest that alterations in right ventricular function in the setting of chronic pulmonary hypertension may partially be due to changes in myocardial adrenergic receptor signaling.     

Cyclo-oxygenase products mediate hypoxic pulmonary hypertension

High-risk infants with a fetal pattern of circulation demonstrate hyperactivity of the pulmonary vascular bed in response to stimuli including mucous plugging, atelectasis, and endotrachial tube suctioning. The resultant increase in pulmonary vascular resistance (PVR) leads to pulmonary hypertension, severe right-to-left shunting, and hypoxemia. Stimuli that trigger pulmonary hypertension cause hypoxia, suggesting the importance of hypoxic pulmonary vasoconstriction (HPV). Although many humoral mediators of HPV have been hypothesized, none have been proven. This study investigates the possible role of the cyclo-oxygenase derivatives thromboxane A2 and prostacyclin as determinants of hypoxic pulmonary hypertension. Open-chested lambs were ventilated with 13% O2 prior to and following treatment with OKY 046, a selective thromboxane inhibitor. In untreated lambs, the partial pressure of arterial oxygen fell from 80 +/- 27 (mean +/- SD) to 35 +/- 13 mm HG (P less than .01). The mean arterial pressure (MAP) remained at 50 +/- 7 mm HG, and the cardiac output (CO) was unchanged at 0.8 +/- 0.2 L/min. The mean pulmonary arterial pressure (MPAP) rose from 11 +/- 4 to 20 +/- 4 mm HG (P less than .01) whereas the PVR increased 70% (P less than .01). TxB2 rose from 147 +/- 85 to 271 +/- 154 pg/mL (P less than .05), and 6-keto-PGF1 alpha rose from 105 +/- 96 to 142 +/- 110 pg/mL. These substances are the hydrolysis products of TxA2 and prostacyclin respectively. In animals treated with OKY 046 prior to ventilation with 13% O2, values for MAP, CO, and PVR were similar to those of the nontreatment period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects on the right ventricle, pulmonary vasculature, and carotid bodies of the rat of exposure to, and recovery from, simulated high altitude

Three groups of 10 adult male Wistar albino rats were studied. The first was kept for five weeks in a hypobaric chamber exposed to a barometric pressure of 380 mmHg, equivalent to a simulated altitude of 5,500 m above sea level. The second was exposed to the same barometric pressure for five weeks and then allowed to recover in room air for a further period of five weeks. The third group acted as controls and was kept at normal barometric pressure throughout. At necropsy right ventricular weight was expressed as an inverse ratio of left ventricular weight (LV/RV ratio). The thickness of the media of the pulmonary trunk was expressed as a ratio of that of the aorta. The volumes of the carotid bodies were measured by applying Simpson's rule to histological sections. In the first group, exposed to chronic hypoxia without relief, there was hypertrophy of the right ventricle and media of the pulmonary trunk and there was an increase of carotid body volume, as compared with the values obtained in the controls. In the recovery group these three measurements had returned almost to normal. The results appear to be applicable to hypoxic cor pulmonale in man. They suggest that hypoxia rapidly produces pulmonary hypertension and its morbid anatomical associations while recovery is equally rapid once the hypoxic stimulus is removed.     

Hemodynamic unloading leads to regression of pulmonary vascular disease in rats

OBJECTIVE: Treatment options for patients with advanced pulmonary vascular disease caused by a congenital heart defect are still mainly limited to heart-lung transplantation or lung transplantation with repair of the cardiac lesion. Because we have previously shown that the structural changes associated with pulmonary hypertension can be reversed by stress unloading in an organ culture model, we now investigate whether hemodynamic unloading will lead to regression of pulmonary vascular disease in the intact animal. METHODS: Right middle and lower lobectomy and monocrotaline injection were performed in Lewis rats (n = 22) to cause pulmonary vascular disease from a combined hemodynamic and toxic injury. Twenty-eight days later the left lungs were examined (n = 10) or exposed to normal pulmonary artery pressure for an additional 14 (n = 5) or 28 (n = 7) days by transplantation into healthy recipients. Pulmonary artery pressure, ventricular weight, and pulmonary artery morphology were evaluated in each group. RESULTS: Pulmonary hypertension (50 vs 16 mm Hg; P <.001) and right ventricular hypertrophy (right ventricular/left ventricular weight 0.69 vs 0.32; P <.001) associated with pulmonary artery medial hypertrophy (28.2% vs 7.2% wall thickness; P <.001) and muscularization of small pulmonary arteries (92.3% vs 19.4%; P <.001) developed by day 28 (compared with untreated controls). However, transplantation into healthy recipients effectively unloaded the lungs (mean pulmonary artery pressure 17 and 24 mm Hg at 14 and 28 days after transplantation) and resulted in progressive normalization of medial hypertrophy (15.6% and 12.1% at 14 and 28 days) and muscularization (65.1% and 42.2% at 14 and 28 days) relative to nontransplanted controls (P <.005 in each case). CONCLUSIONS: Hemodynamic unloading of lungs with pulmonary vascular disease results in progressive normalization of pulmonary artery structure. These results are the first to provide a rationale for attempting to induce regression of pulmonary vascular disease by pressure unloading of the pulmonary circulation. Methods to mechanically unload the pulmonary circulation should be critically evaluated as a strategy for staged surgical repair of congenital heart defects despite presumed irreversible pulmonary hypertension.     

Hypoxia and lung mast cells: influence of disodium cromoglycate.

Rats kept in 10% O2 for three or more weeks developed mast cell hyperplasia in the lungs, especially round the alveoli and the small peripheral blood vessels, which became thickened during chronic hypoxia. There was a significant correlation between the degree of right ventricular hypertrophy (RVH) and the numbers of alveolar and small vessel mast cells. However, mast cell hyperplasia developed more slowly than RVH. Daily treatment with disodium cromoglycate failed to prevent RVH in hypoxic conditions but was associated with retardation of growth in both hypoxic and control rats. Neither acute nor chronic hypoxia increased the degree of degranulation in the lung mast cells.     

Effects of prostacyclin (PGI2) on the hypoxic pulmonary vasoconstriction in dogs

Effects of exogenous PGI2 on the hypoxic pulmonary vasoconstriction (HPV) were investigated by measuring %QLLL and the ratio of the left lower lobe blood flow (QLLL) to the total pulmonary blood flow (QT), in separately ventilated canine in vivo model. With PGI2 infusion, %QLLL, that had decreased from 20.7 +/- 1.9% to 4.1 +/- 1.1% by the hypoxic gas ventilation, gradually increased to 16.4 +/- 3.2% at the maximum dose (1.0 micrograms kg-1. min-1). Simultaneously both pulmonary artery pressure and PaO2 decreased significantly. Systemic blood pressure dropped markedly but cardiac output remained at the initial level. These results suggest that exogenous PGI2 improves the pulmonary circulation by reducing pulmonary hypertension induced with HPV, while PGI2 induces hypoxia by inhibiting HPV response and systemic hypotension by dilating the peripheral resistance vessels. Therefore, we have to consider these two opposite effects of PGI2 on its clinical application.     

The effects of single lung transplantation in rats with monocrotaline-induced pulmonary hypertension

Abstract Acute haemodynamic change after single lung transplantation for primary pulmonary hypertension was evaluated using a rat transplantation model. Inbred Fisher 344 rats were administered with 40 mg/kg monocrotaline in order to induce pulmonary hypertension. The rats whose mean pulmonary arterial pressure (PAP) was over 30.0 mmHg received a left lung isograft from a normal donor after right heart catheterization. In the control group, PAP increased after single lung transplantation. On the other hand, in the pulmonary hypertensive group, PAP was significantly decreased 60 min after the transplantation, but 3 and 6 h after the transplantation, the PAP significantly increased again. On the day after the operation, it again decreased significantly. Left-to-right lung blood flow ratio was significantly increased in rats with pulmonary hypertension compared to rats with normal pulmonary pressure on both the 1st and 3rd postoperative days. The oedema of the grafted lung was more severe in the pulmonary hypertensive group than in the control group in the acute phase. In conclusion, single lung transplantation for pulmonary hypertension shifted pulmonary blood perfusion to the grafted lung and this shift made pulmonary oedema of the grafts more severe in the acute phase. These oedematous changes, which were more pronounced in the grafts in the pulmonary hypertensive rats, might have contributed to the transient rise in PAP in those rats after single lung transplanation.