Soluble guanylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

Rodent models of pulmonary hypertension: harmonisation with the world health organisation's categorisation of human PH.

The WHO classification of pulmonary hypertension (PH) recognises five distinct groups, all sharing a mean, resting, pulmonary artery pressure (PAP) > 25 mmHg. The aetiology of PH varies by group (1-pulmonary vascular disease, 2-high left heart filling pressures, 3-hypoxia, 4-unresolved pulmonary embolism and 5-miscellaneous). Inclusion in a group reflects shared histological, haemodynamic and pathophysiological features and has therapeutic implications. Advantages of using rodent models to understand the pathophysiology of human PH and to test experimental therapies include the economy, safety and mechanistic certainty they provide. As rodent models are meant to reflect human PH, they should be categorised by a parallel PH classification and limitations in achieving this ideal recognised. Challenges with rodent models include: accurate phenotypic characterisation (haemodynamics, histology and imaging), species and strain variations in the natural history of PH, and poor fidelity to the relevant human PH group. Rat models of group 1 PH include: monocrotaline (± pneumonectomy), chronic hypoxia + SU-5416 (a VEGF receptor inhibitor) and the fawn-hooded rat (FHR). Mouse models of group 1 PH include: transgenic mice overexpressing the serotonin transporter or dominant-negative mutants of bone morphogenetic protein receptor-2. Group 1 PH is also created by infecting S100A4/Mts1 mice with γ-herpesvirus. The histological features of group 1 PH, but not PH itself, are induced by exposure to Schistosoma mansoni or Stachybotrys chartarum. Group 3 PH is modelled by exposure of rats or mice to chronic hypoxia. Rodent models of groups 2, 4 and 5 PH are needed. Comprehensive haemodynamic, histological and molecular phenotyping, coupled with categorisation into WHO PH groups, enhances the utility of rodent models.

A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) and cancer share elements of pathophysiology. This provides an opportunity for the cross-development of anticancer agents that can be used in improving PAH care. The adaptation of new drugs across these disease populations warrants a structured approach. This study was a 16-week, phase Ib, single-center, open-label trial of the multikinase/angiogenesis inhibitor sorafenib. In order to assess the safety of sorafenib in PAH, patients with advanced but stable disease on parenteral prostanoids (with or without oral sildenafil) were initiated on treatment at the lowest active dosage administered to cancer patients: 200 mg daily. Patients underwent weekly clinical evaluations and monthly functional testing and dose escalations to a final dosage of 400 mg twice daily. Among 12 patients (10 of them women), sorafenib was well tolerated at 200 mg twice daily. The most common adverse events were moderate skin reactions on the hands and feet and alopecia. Our conclusion was therefore that this is a tolerable dosing regimen for testing the therapeutic activity of sorafenib in PAH patients.

Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation.

The aim of the present study was to determine contemporary survival in pulmonary arterial hypertension (PAH), and to investigate whether or not the National Institutes of Health (NIH) equation remains an accurate predictor of survival. In 576 patients with PAH referred during 1991-2007, observed survival was described using the Kaplan-Meier method. In patients with idiopathic, familial and anorexigen-associated PAH (n = 247), observed versus NIH equation predicted survival was compared. A new survival prediction equation was developed using exponential regression analysis. The observed 1-, 3- and 5-yr survival in the total cohort were 86, 69 and 61%, respectively. In patients with idiopathic, familial and anorexigen-associated PAH, the observed 1-, 3- and 5-yr survival (92, 75 and 66%, respectively) were significantly higher than the predicted survival (65, 43 and 32%, respectively). The new equation (P(t) = e(-A(x,y,z)t), where P(t) is probability of survival, t the time interval in years, A(x,y,z) = e((-1.270-0.0148x+0.0402y-0.361z)), x the mean pulmonary artery pressure, y the mean right atrial pressure and z the cardiac index) performed well when applied to published contemporary studies of survival in PAH. Contemporary survival in the PAH cohort was better than that predicted by the NIH registry equation. The NIH equation underestimated survival in idiopathic, familial and anorexigen-associated PAH. Once prospectively validated, the new equation may be used to determine prognosis.

Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment.

The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 x 10(10) particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks < or =0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.

Differences in food habits and cardiovascular disease risk factors among Native Americans with and without diabetes: the Inter-Tribal Heart Project.

OBJECTIVE: To examine differences in food habits among Native Americans with and without diabetes. DESIGN: A cross-sectional epidemiological study in which participants underwent a physical examination and answered an extensive interviewer-administered questionnaire to assess differences in food servings, preparation and eating habits. SETTING/PARTICIPANTS: Participants aged >/=25 years were randomly selected from three reservations in Minnesota and Wisconsin. There were 990 persons without diabetes, 294 with a prior diagnosis of diabetes, and 80 with fasting glucose >125 mg dl(-1) but no prior diabetes diagnosis. RESULTS: Persons with prior diabetes diagnosis were less likely than those without diabetes to report eating fast-food meals two or more times per week, eat visible fat on meat or the skin on poultry, eat fried chicken or fried fish, to add fat to cooked vegetables and drink whole milk. Persons with previously undiagnosed diabetes were more likely than previously diagnosed persons to report eating fast-food meals two or more times per week, eat visible fat on meat and the skin on poultry, drink whole milk and eat fried fish, but were less likely to drink low-fat milk. Previously undiagnosed persons were more likely than either diagnosed persons or persons without diabetes to consume lard from cooked foods and use it when cooking. CONCLUSION: Persons with diagnosed diabetes showed healthier eating patterns than those without diabetes, while undiagnosed persons showed some less favourable patterns. Because virtually all persons with diabetes in these communities receive nutrition education, the results suggest that nutrition education programmes for diabetics may be associated with healthier eating patterns.

Association of education with dietary intake among young adults in the bi-ethnic Coronary Artery Risk Development in Young Adults (CARDIA) cohort.

OBJECTIVE: To examine associations of changes in dietary intake with education in young black and white men and women. DESIGN: The Coronary Artery Risk Development in Young Adults (CARDIA) study, a multi-centre population-based prospective study. Dietary intake data at baseline and year 7 were obtained from an extensive nutritionist-administered diet history questionnaire with 700 items developed for CARDIA. SETTING: Participants were recruited in 1985-1986 from four sites: Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and Oakland, California. SUBJECTS: Participants were from a general community sample of 703 black men (BM), 1006 black women (BW), 963 white men (WM) and 1054 white women (WW) who were aged 18-30 years at baseline. Analyses here include data for baseline (1985-1986) and year 7 (1992-1993). RESULTS: Most changes in dietary intake were observed among those with high education (>or=12 years) at both examinations. There was a significant decrease in intake of energy from saturated fat and cholesterol and a significant increase in energy from starch for each race-gender group (P<0.001). Regardless of education, taste was considered an important influence on food choice. CONCLUSION: The inverse relationship of education with changes in saturated fat and cholesterol intakes suggests that national public health campaigns may have a greater impact among those with more education.

Triple-bonded unsaturated fatty acids are redox active compounds.

Unsaturated fatty acids with triple bonds are used as inhibitors of unsaturated fatty acid metabolism or cytochrome P450 reactions because they are believed to be chemically inert. In this paper we use in vitro cytochrome C reduction to show that two commonly used triple-bonded unsaturated fatty acids are in fact potent electron transfer agents and could affect the multiple cellular systems that are redox-modulated.

Alterations in a redox oxygen sensing mechanism in chronic hypoxia.

The mechanism of acute hypoxic pulmonary vasoconstriction (HPV) may involve the inhibition of several voltage-gated K+ channels in pulmonary artery smooth muscle cells. Changes in PO2 can either be sensed directly by the channel(s) or be transmitted to the channel via a redox-based effector mechanism. In control lungs, hypoxia and rotenone acutely decrease production of activated oxygen species, inhibit K+ channels, and cause constriction. Two-day and 3-wk chronic hypoxia (CH) resulted in a decrease in basal activated oxygen species levels, an increase in reduced glutathione, and loss of HPV and rotenone-induced constriction. In contrast, 4-aminopyridine- and KCl-mediated constrictions were preserved. After 3-wk CH, pulmonary arterial smooth muscle cell membrane potential was depolarized, K+ channel density was reduced, and acute hypoxic inhibition of whole cell K+ current was lost. In addition, Kv1.5 and Kv2.1 channel protein was decreased. These data suggest that chronic reduction of the cytosol occurs before changes in K+ channel expression. HPV may be attenuated in CH because of an impaired redox sensor.

Potassium channels regulate tone in rat pulmonary veins.

Intrapulmonary veins (PVs) contribute to pulmonary vascular resistance, but the mechanisms controlling PV tone are poorly understood. Although smooth muscle cell (SMC) K(+) channels regulate tone in most vascular beds, their role in PV tone is unknown. We show that voltage-gated (K(V)) and inward rectifier (K(ir)) K(+) channels control resting PV tone in the rat. PVs have a coaxial structure, with layers of cardiomyocytes (CMs) arrayed externally around a subendothelial layer of typical SMCs, thus forming spinchterlike structures. PVCMs have both an inward current, inhibited by low-dose Ba(2+), and an outward current, inhibited by 4-aminopyridine. In contrast, PVSMCs lack inward currents, and their outward current is inhibited by tetraethylammonium (5 mM) and 4-aminopyridine. Several K(V), K(ir), and large-conductance Ca(2+)-sensitive K(+) channels are present in PVs. Immunohistochemistry showed that K(ir) channels are present in PVCMs and PV endothelial cells but not in PVSMCs. We conclude that K(+) channels are present and functionally important in rat PVs. PVCMs form sphincters rich in K(ir) channels, which may modulate venous return both physiologically and in disease states including pulmonary edema.

Gene transfer and metabolic modulators as new therapies for pulmonary hypertension. Increasing expression and activity of potassium channels in rat and human models.

UNLABELLED: Chronic Hypoxic Pulmonary Hypertension (CH-PHT) is characterized by pulmonary artery (PA) vasoconstriction and cell proliferation/hypertrophy. PA smooth muscle cell (PASMC) contractility and proliferation are controlled by cytosolic Ca++ levels, which are largely determined by membrane potential (E(M)). E(M) is depolarized in CH-PHT due to decreased expression and functional inhibition of several redox-regulated, 4-aminopyridine (4-AP) sensitive, voltage-gated K+ channels (Kv1.5 and Kv2.1). Humans with Pulmonary Arterial Hypertension (PAH) also have decreased PASMC expression of Kv1.5 and Kv2.1. We speculate this "K+-channelopathy" contributes to PASMC depolarization and Ca++ overload thus promoting vasoconstriction and PASMC proliferation. We hypothesized that restoration of Kv channel expression in PHT and might eventually be beneficial. METHODS: Two strategies were used to increase Kv channel expression in PASMCs: oral administration of a metabolic modulator drug (Dichloroacetate, DCA) and direct Kv gene transfer using an adenovirus (Ad5-Kv2.1). DCA a pyruvate dehydrogenase kinase inhibitor, promotes a more oxidized redox state mimicking normoxia and previously has been noted to increase K+ current in myocytes. Rats were given DCA in the drinking water after the development of CH-PHT and hemodynamics were measured approximately 5 days later. We also tested the ability of Ad5-Kv2.1 to increase Kv2.1 channel expression and function in human PAs ex vivo. RESULTS: The DCA-treated rats had decreased PVR, RVH and PA remodeling compared to the control CH-PHT rats (n=5/group, p<0.05). DCA restored Kv2.1 expression and PASMC Kv current density to near normoxic levels. Adenoviral gene transfer increased expression of Kv2.1 channels and enhanced 4-AP constriction in human PAs. CONCLUSION: Increasing Kv channel function in PAs is feasible and might be beneficial.

Coronary nitric oxide production in response to exercise and endothelium-dependent agonists.

BACKGROUND: Endothelium-derived nitric oxide (NO) contributes to epicardial coronary artery vasodilation during exercise. However, blockade of NO production does not impair the increase in coronary blood flow (CBF) during exercise, suggesting that NO is not obligatory for exercise-induced coronary resistance vessel dilation. In contrast, the increases in CBF produced by endothelium-dependent agonists are decreased after NO blockade. Consequently, this study was performed to determine whether the increase in coronary NO production in response to agonists is greater than that which occurs during exercise. METHODS AND RESULTS: We measured the oxidation products of NO (nitrate+nitrite=NO(x)) in aortic and coronary sinus plasma using chemiluminescence to assess NO(x) production across the coronary circulation in chronically instrumented dogs during a 3-stage treadmill exercise protocol and in response to intracoronary administration of the endothelium-dependent agonists acetylcholine (37.5 microg/min) and bradykinin (3.0 microg/min). No coronary NO(x) production could be detected at rest or during the first 2 stages of exercise; only at the highest level of exercise was a small increase in coronary NO(x) production measured. In contrast, coronary production of NO(x) was significantly increased in response to endothelium-dependent agonists. CONCLUSIONS: Coronary NO production in response to endothelium-dependent agonists is greater than in response to the increase in shear stress associated with exercise. These findings support previous studies suggesting that NO is not required for the coronary vasodilation that occurs in the normal heart during exercise.

Molecular identification of O2 sensors and O2-sensitive potassium channels in the pulmonary circulation.

Small, muscular pulmonary arteries (PAs) constrict within seconds of the onset of alveolar hypoxia, diverting blood flow to better-ventilated lobes, thereby matching ventilation to perfusion and optimizing systemic PO2. This hypoxic pulmonary vasoconstriction (HPV) is enhanced by endothelial derived vasoconstrictors, such as endothelin, and inhibited by endothelial derived nitric oxide. However, the essence of the response is intrinsic to PA smooth muscle cells in resistance arteries (PASMCs). HPV is initiated by inhibition of the Kv channels in PASMCs which set the membrane potential (EM). It is currently uncertain whether this reflects an initial inhibitory effect of hypoxia on the K+ channels or an initial release of intracellular Ca2+, which then inhibits K+ channels. In either scenario, the resulting depolarization activates L-type, voltage gated Ca2+ channels, which raises cytosolic calcium levels [Ca2+]i and causes vasoconstriction. Nine families of Kv channels are recognized from cloning studies (Kv1-Kv9), each with subtypes (i.e. Kv1.1-1.6). The contribution of an individual Kv channel to the whole-cell current (IK) is difficult to determine pharmacologically because Kv channel inhibitors are nonspecific. Furthermore, the PASMC's IK is an ensemble, reflecting activity of several channels. The K+ channels which set EM, and inhibition of which initiates HPV, conduct an outward current which is slowly inactivating, and which is blocked by the Kv inhibitor 4-aminopyridine (4-AP) but not by inhibitors of Ca(2+)- or ATP-sensitive K+ channels. Using anti-Kv antibodies to immunolocalize and inhibit Kv channels, we showed that the PASMC contains numerous types of Kv channels from the Kv1 and Kv2 families., Furthermore Kv1.5 and Kv2.1 may be important in determining the EM and play a role as effectors of HPV in PASMCs. While the Kv channels in PASMCs are the "effectors" of HPV, it is uncertain whether they are intrinsically O2-sensitive or are under the control of an "O2 sensor". Certain Kv channels are rich in cysteine, and respond to the local redox environment, tending to open when oxidized and close when reduced. Candidate sensors vary the PASMC redox potential in proportion to O2. These include Nicotinamide Adenine Dinucleotide Phosphate Oxidase, (NADPH oxidase) and the cytosolic ratio of reduced/oxidized redox couples (i.e. glutathione GSH/GSSG), as controlled by electron flux in the mitochondrial electron transport chain (ETC). Using a mouse that lacks the gp91phox component of NADPH oxidase, we have recently shown that loss of the gp91phox-containing NADPH oxidase as a source of activated oxygen species does not impair HPV. However, inhibition of complex 1 of the mitochondrial electron transport chain mimics hypoxia in that it inhibits IK, reduces the production of activated O2 species and causes vasoconstriction. We hypothesize that a redox O2 sensor, perhaps in the mitochondrion, senses O2 through changes in the accumulation of freely diffusible electron donors. Changes in the ratio of reduced/oxidized redox couples, such as NADH/NAD+ and glutathione (GSH/GSSG) can reduce or oxidize the K+ channels, resulting in alterations of PA tone.

Dexfenfluramine elevates systemic blood pressure by inhibiting potassium currents in vascular smooth muscle cells.

Appetite suppressants, such as dexfenfluramine (dex), are associated with primary pulmonary hypertension, valvular heart disease, and systemic vascular complications, such as coronary, cerebral, or mesenteric ischemia. These drugs suppress appetite by enhancing release and inhibiting reuptake of serotonin in the central nervous system. The effects of dex on the systemic circulation have not been studied. K(+) channels regulate vascular tone in most vascular beds. We hypothesized that dex is a systemic vasoconstrictor acting primarily by inhibiting K(+) channels, independent of effects on serotonin. The effects of clinically relevant concentrations of dex (10(-6) to 10(-4) M) on outward K(+) current and membrane potential were studied with whole-cell patch clamping in freshly isolated smooth muscle cells from rat renal, carotid, and basilar arteries. Tone was measured in tissue baths. Blood pressure, cardiac output, and left ventricular end diastolic pressure were assessed in open- and closed-chest anesthetized rats. At 10(-4) M, dex inhibits outward K(+) current (50%) and increases membrane potential (by >35 mV), an effect comparable with 4-aminopyridine (5 mM). Furthermore, dex constricts rings and acutely elevates systemic pressure (+17 +/- 3 mm Hg) and systemic vascular resistance in the presence of ketanserin. Dex vasoconstriction is dose-dependent (threshold dose 10(-6) M; 156 microg/ml) and enhanced in L-NAME-fed rats. We conclude that dex causes acute systemic vasoconstriction, at least in part by inhibition of voltage-gated K(+) channels, independent of effects on serotonin. To our knowledge, this is the first time that a commonly prescribed drug with voltage-gated K(+) channel-blocking properties is shown to have significant hemodynamic effects in vivo.

Aerosol delivery of diethylenetriamine/nitric oxide, a nitric oxide adduct, causes selective pulmonary vasodilation in perinatal lambs.

Postnatal adaptation of the pulmonary circulation is mediated partly by endothelium-derived nitric oxide (NO). Recent studies have demonstrated that inhaled NO causes selective and sustained vasodilation in infants with persistent pulmonary hypertension of the newborn. Because the short half-life of NO limits its clinical application, we hypothesized that aerosol delivery of an NO-adduct, diethylenetriamine (DETANO), can cause sustained and selective pulmonary vasodilation. To test the acute effects of DETANO, we studied the pulmonary vascular response of late-gestation fetal lambs (n = 8; age = 138 days; term = 147) to aerosolized DETANO in the presence of an endothelium-derived NO inhibitor, nitro-L-arginine. To determine whether DETANO has a sustained effect, fetal lambs were ventilated with FiO2 0.10 before and 15 minutes after they were treated with aerosolized DETANO. Fetal lambs were acutely prepared. Nitro-L-arginine (1 mg/min x 30 minutes) was infused into the left pulmonary artery before ventilation with FiO2 1.00 for 30 minutes, followed by continued ventilation with FiO2 0.10 for 10 minutes. This represented the control period. Ventilation was continued with FiO2 1.00, and aerosolized DETANO was given in doses of 0.1, 0.4, and 1.0 mg. Fifteen minutes after the last dose of DETANO was administered, animals were ventilated with FiO2 0.10. In the control period, during ventilation with FiO2 0.10, left pulmonary artery flow was 122+/-33 mL/min and decreased to 104+/-22 mL/min. Aerosol delivery of DETANO increased left pulmonary artery flow to 176+/-26 mL/min (P<.05) and had no effect on aortic pressure or heart rate. After DETANO was administered, ventilation with FiO2 0.10 did not cause any change in left pulmonary artery flow. We conclude that DETANO can cause selective fetal pulmonary vasodilation. Aerosol delivery of DETANO may increase the clinical applications of NO.

Dexfenfluramine increases pulmonary artery smooth muscle intracellular Ca2+, independent of membrane potential.

The anorexic agent dexfenfluramine causes the development of primary pulmonary hypertension in susceptible patients by an unknown mechanism that may include changes in K+-channel activity and intracellular Ca2+ concentration ([Ca2+]i). We investigated the dose-dependent effects of dexfenfluramine on [Ca2+]i, K+ current, and membrane potential in freshly dispersed rat pulmonary artery smooth muscle cells. Dexfenfluramine caused a dose-dependent (1-1,000 microM) increase in [Ca2+]i, even at concentrations lower than those necessary to inhibit K+ currents (10 microM) and cause membrane depolarization (100 microM). The [Ca2+]i response to 1 and 10 microM dexfenfluramine was completely abolished by pretreatment of the cells with 0.1 microM thapsigargin, whereas the response to 100 microM dexfenfluramine was reduced. CoCl2 (1 mM), removal of extracellular Ca2+, and pretreatment with caffeine (1 mM) reduced but did not abolish the response to 100 microM dexfenfluramine. We conclude that dexfenfluramine increases [Ca2+]i in rat pulmonary artery smooth muscle cells by both release of Ca2+ from the sarcoplasmic reticulum and influx of extracellular Ca2+.

GTP (gammaS) and GDP (betaS) as electron donors: new wine in old bottles.

G proteins are membrane-bound regulatory proteins which modulate the activity of ion channels and other effector systems. The GTP and GDP analogs GTP (gammaS) and GDP (betaS) have been used to study the role of G proteins in numerous physiologic systems. The prolonged effects of these analogs have been thought to be due to the fact that they are nonhydrolyzable. However, in this paper we show that the GTP (gammaS) and GDP (betaS) analogs are potent reducing agents at physiologic pH. This observation suggests that previous data obtained using these compounds may need to be reinterpreted.

Vitamin A decreases the incidence and severity of nitrofen-induced congenital diaphragmatic hernia in rats.

Congenital diaphragmatic hernia (CDH) is a major cause of refractory respiratory failure in the newborn. Pulmonary hypoplasia often limits survival. Vitamin A (Vit A) is an important signal for lung growth. We hypothesized that antenatal treatment with Vit A would stimulate lung growth and decrease mortality in experimental CDH induced in rats by ingestion of the herbicide nitrofen (2, 4-dichlorophenyl-p-nitrophenyl ether). Nitrofen was administered to pregnant rats on day 12 of gestation (term 22 days). Rats were assigned to five groups: three groups received one dose of oral antenatal Vit A (15,000 IU) before (day 10), concomitant with (day 12), or after (day 14) nitrofen administration; one group received only nitrofen; and a control group received vehicle (olive oil). The incidence of CDH was markedly lower in all groups receiving Vit A (day 10, 44%; day 12, 20%; and day 14, 40%) compared with the nitrofen-treated group (84%; P < 0.05). The 72-h survival was higher in all 3 Vit A-treated groups (day 10, 40%; day 12, 58%; and day 14, 70%) compared with the nitrofen-treated group (16%; P < 0.05). Lung-to-body weight ratio and radial saccular count were significantly increased by Vit A. Antenatal treatment with Vit A lowers the incidence and severity of experimental CDH and increases lung growth and maturation.