Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats.

Exposure to hypoxia and subsequent development of pulmonary hypertension is associated with an impairment of the nitric oxide (NO) mediated response to endothelium-dependent vasodilators. Inhaled NO may reach resistive pulmonary vessels through an abluminal route. The aim of this study was to investigate if continuous inhalation of NO would attenuate the development of pulmonary hypertension in rats exposed to chronic hypoxia. In conscious rats previously exposed to 10% O2 for 3 wk, short-term inhalation of NO caused a dose-dependent decrease in pulmonary artery pressure (PAP) from 44 +/- 1 to 32 +/- 1 mmHg at 40 ppm with no changes in systemic arterial pressure, cardiac output, or heart rate. In normoxic rats, acute NO inhalation did not cause changes in PAP. In rats simultaneously exposed to 10% O2 and 10 ppm NO during 2 wk, right ventricular hypertrophy was less severe (P < 0.01), and the degree of muscularization of pulmonary vessels at both alveolar duct and alveolar wall levels was lower (P < 0.01) than in rats exposed to hypoxia alone. Tolerance to the pulmonary vasodilator effect of NO did not develop after prolonged inhalation. Brief discontinuation of NO after 2 wk of hypoxia plus NO caused a rapid increase in PAP. These data demonstrate that prolonged inhalation of low concentrations of NO induces sustained pulmonary vasodilation and reduces pulmonary vascular remodeling in response to chronic hypoxia.

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats.

Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O(2) for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 10(8) plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [(3)H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.

Adenovirus-mediated atrial natriuretic protein expression in the lung protects rats from hypoxia-induced pulmonary hypertension.

Endogenous as well as exogenous atrial natriuretic peptide (ANP) attenuates the development of chronic hypoxic pulmonary hypertension (CHPH) in rats. We built a recombinant adenovirus type 5 containing ANP cDNA under the control of the Rous sarcoma virus long terminal repeat (Ad.ANP). The efficiency of this vector in delivering the ANP gene was first examined in rat primary cultures of pulmonary vessel smooth muscle cells (SMCs) in comparison with Ad.beta GAL. Conditioned medium collected from Ad.ANP-infected cells (1000 TCID(50)/cell) contained 5 x 10(9) M immunoreactive ANP and elicited relaxation of isolated rat pulmonary arteries preconstricted with phenylepinephrine. To examine the effects of adenovirus-mediated ANP expression in the CHPH rat lung, Ad.ANP or Ad.beta GAL was administered via the tracheal route. Immunoreactive ANP was detected in bronchoalveolar fluid as early as 4 days and until 10-17 days after Ad.ANP administration (5 x 10(8) TCID(50)). Lung ANP immunostaining was mainly localized in bronchial and alveolar epithelial cells. As compared with Ad.beta GAL-treated controls, rats given Ad.ANP (5 x 10(8) TCID(50)) on the day before a 2-week exposure to hypoxia (10% O(2)) had lower values for pulmonary artery pressure (32.1 +/- 1.93 vs. 35.5 +/- 2 mmHg, p < 0.01) and Fulton's index (0.52 +/- 0.089 vs. 0.67 +/- 0.12, p < 0.001) and less severe right ventricular hypertrophy and distal vessel muscularization. These results suggest that induction of ANP expression in the lung may hold promise in the treatment of pulmonary hypertension.

Glucocorticoids inhibit sulfur mustard-induced airway muscle hyperresponsiveness to substance P.

To explore the mechanisms of airway hyperreactivity to aerosolized substance P observed in guinea pigs 14 days after intratracheal injection of sulfur mustard (SM), we studied the effects of epithelium removal and inhibition of neutral endopeptidase (NEP) activity on airway muscle responsiveness. Tracheal rings from SM-intoxicated guinea pigs expressed a greater contractile response to substance P than rings from nonintoxicated guinea pigs. After epithelium removal or incubation with the NEP inhibitor phosphoramidon, the contractile responses of tracheal rings to substance P did not differ in guinea pigs injected with SM or ethanol (SM solvent). Treatment of the guinea pigs with betamethasone for 7 days before measurement abolished the airway muscle hyperresponsiveness observed in untreated SM-intoxicated guinea pigs and partially restored tracheal epithelium NEP activity. In addition, the tracheal epithelium height and cell density of SM-intoxicated guinea pigs treated with betamethasone were significantly greater than in those without betamethasone. These results demonstrate that SM intoxication induces airway muscle hyperresponsiveness to substance P by reducing tracheal epithelial NEP activity and that glucocorticoids might inhibit this hyperresponsiveness by increasing this activity.

Acute and chronic respiratory effects of sulfur mustard intoxication in guinea pig.

Sulfur mustard (SM) has been used as a vesicant chemical warfare agent. To investigate the respiratory damages it causes, we studied the effects on guinea pigs of an intratracheal injection of 0.3 mg/kg of SM 5 h and 14 days after injection. Five hours after SM intoxication, respiratory system resistance and microvascular permeability were increased. These alterations were not prevented by pretreatment with 50 mg/kg sc of capsaicin 2 wk before SM intoxication. Histological studies showed columnar cell shedding all along the tracheal epithelium, bronchoconstriction, and peribronchial edema. Fourteen days after SM intoxication, guinea pigs demonstrated airway hyperreactivity to aerosolized substance P and histamine. Pretreatment with phosphoramidon caused a further increase in airway responsiveness to substance P. Neutral endopeptidase activity in the tracheal epithelium was decreased by twofold in SM-intoxicated guinea pigs. At this stage, the tracheal epithelium was disorganized and atrophic. These results demonstrate that in guinea pigs SM intoxication induces severe lesions to the tracheal epithelium, which might account for the airway hyperresponsiveness observed 14 days after intoxication.

Experimental radiation pneumonitis studied with indium-111-pentetreotide.

OBJECTIVES: To understand the evolution of lung uptake of 111-In-Pentetreotide in a rat model of pulmonary radiation pneumonitis. METHODS: A 15 Gy 60-Co thoracic irradiation (1.4 Gy/min) was delivered to Wistar rats. Irradiated and control animals were studied during 8 weeks after irradiation. 24 hours after an injection of 111-In-pentetreotide (12-18 MBq), the uptake in the lung tissue (ULT), in the alveolar cells (UpC) and in different organs, was determined. Histological examinations were performed. RESULTS: ULT and UpC after irradiation increased significantly peaking at 4 weeks (ULT: 32.8 +/- 13.0 in 10(-5) of the injected dose versus 10.8 +/- 2.0 for control; and, UpC was 19.3 +/- 7.2 versus 7.3 +/- 4.1) and decreased afterwards. Pre-injection of cold octreotide decreased the lung uptake. This evolution parallels the histological changes: alveolitis with granulomas in the interstitium at 4 weeks followed by development of sites of interstitial fibrosis. These observations suggest that the uptake is due to activated cells, mainly macrophages within the granulomas and in the alveoli, expressing somatostatin receptors. CONCLUSION: 1) The uptake of 111-In-pentetreotide in injured lungs after irradiation, already described in man, was confirmed in a rat model; 2) our results suggest that it is possible to follow the evolution of radiation lung injury by using In-111-pentetreotide.

Rat diaphragm during postnatal development. I. Changes in distribution of muscle fibre type and in oxidative potential.

The changes occurring in the histochemical characteristics of the rat diaphragm during the postnatal period were examined. Fibre-type distribution, fibre oxidative capacity, i.e. succinate-dehydrogenase (SDH) activity, and cross-sectional area were compared in the costal (COS) and crural (CRU) regions, and across their abdominal and thoracic surfaces. The proportions of type I and IIb fibres in both COS and CRU increased with age, while the proportion of type IIa fibres progressively decreased. For COS, fibre distribution was homogeneous over the entire muscle and did not change after 4 weeks. For CRU, it was heterogeneous with a higher proportion of type I fibres on the thoracic surface as from the first week. All fibre types significantly increased in cross-sectional area between 1 and 8 weeks, with no significant differences in COS and CRU. Mean SDH activity did not differ between COS and CRU or across the muscles. Mean SDH activities-were low and identical in all fibre types at birth, and then increased, peaking at the 6th week in type I and IIa fibres. When total muscle fibre oxidative capacity was calculated from an index including fibre-type proportion, cross-sectional area and mean SDH activity, it was significantly higher at 1 than at 8 weeks after birth; this might have functional implications for the newborn.

Rat diaphragm during postnatal development. II. Resistance to low- and high-frequency fatigue.

The effects on the rat diaphragm of fatigue induced by low- and high-frequency stimulation (at 5 Hz for 1.5 min and 75 Hz for 1 min) were examined during postnatal development. Experiments were performed on isolated costal diaphragm strips. Before stimulation, twitch contraction time and half relaxation time were longest in the neonate and decreased significantly between weeks 1 and 6. Correspondingly, the specific twitch tension (corrected for cross-sectional area) increased progressively with age. After either low- or high-frequency fatigue, the force recovery was complete in 1- and 2-week-old rats, whereas the force production progressively decreased in older rats. In addition, the neonate diaphragm further enhanced its force selectively after high-frequency fatigue. It is concluded that the rat diaphragm is comparably resistant to fatigue during the early postnatal period, whether fatigue is induced by low- or by high-frequency stimulation. This suggests that postnatal changes in diaphragm contractile and fatigue properties may be related to changes in the process of force production. The possibility is discussed that a higher total muscle oxidative potential and the mechanisms leading to force potentiation in the neonate might explain the fatigue resistance.

Airway epithelial damage induced by sulfur mustard in guinea pigs, effects of glucocorticoids.

Sulfur mustard (SM) represents a potential chemical warfare agent. In order to characterize SM-induced airway epithelial damage, we studied the effects of an intratracheal injection of 0.3 mg/kg of SM in guinea pigs, 5 h, 24 h, 14 days and 35 days after exposure. During the acute period, lesions prevailed in tracheal epithelium exhibiting intra-epithelial blisters, inflammatory cell infiltration and columnar cell shedding with exposure of basal cells. Fourteen days after intoxication, tracheal epithelium appeared disorganized and showed a significant decrease in height and cell density. Tracheal epithelium recovery was still not complete even 35 days after SM-intoxication. At day 14, in SM-intoxicated guinea pigs treated with betamethasone from day 7 to day 14, epithelium height, cell density and cell proliferation (evaluated by immunohistochemistry) were significantly increased compared to untreated guinea pigs. In conclusion, the lesions observed in SM-intoxicated guinea pigs seem to be in accordance with clinical human observations and are relevant to the study of airway epithelial damage induced by SM. This animal model could be used to illustrate tracheal epithelium regeneration mainly derived from basal cells and to show glucocorticoid effects on airway epithelial recovery after chemical aggression.

[A macrotome for the sampling of frozen or fixated tissues]. / Un macrotome pour l'échantillonnage des tissus congelés ou fixés.

The tool presented here is a cutter for systematized random sampling. The cutting by the means of parallel blades provides 2,3 mm thick sections, which are dropped automatically, avoiding any further handling for gathering them. In addition to its use in stereology, this cutter yields specimens suitable for incubation in histochemical studies.

[Herovici's picropolychromium. Application to the identification of type I and III collagens]. / Le picropolychrome de Herovici. Application à l'identification des collagènes de types I et III.

A staining technique differentiating two colorimetric types of connective fibers had been proposed by Herovici previously to the identification of collagen types. This technique has been applied to skin, lung and liver specimens and the results have been compared with immunotyping and literature data on collagen types I, III and IV. The conclusions are focused on the ability of the technique to identify at a first approach collagen types I and III, which are known to be of crucial importance in mechanical tissular properties.

[Possible difference in elastin content between the right and left lung in rats]. / Note sur une éventuelle différence de teneur en élastine entre poumons droit et gauche du rat.

Elastin and collagen were measured on separate right and left lungs of rats, within two age-groups : 3 months and 8-15 months. The elastin content was significantly higher in the left series. An explanation based upon the bronchovascular density was tested and the results suggest a difference in regard to the development of the parenchyma surrounding the left bronchovascular tree. The knowledge of such peculiarities, if they are confirmed, may help understanding the structural basis of function, by the means of separate tests of mechanical properties.

Mechanisms of endothelin-mediated bronchoconstriction in the guinea pig.

Intravenous injection of anesthetized ventilated guinea pigs with doses of endothelin ranging from 0.25 to 2.50 micrograms/kg caused dose-dependent decreases in respiratory system conductance and compliance. These effects were maximal 1 min after injection and had disappeared 15 min thereafter. When guinea pigs were pretreated with 3 mg/kg of propranolol or 5 mg/kg of hexamethonium, endothelin-induced bronchoconstriction rose significantly, but when they were pretreated with 3 mg/kg of propranolol plus 3 mg/kg of atropine it remained unchanged. The bronchoconstrictor effects of endothelin were suppressed in guinea pigs pretreated with 0.5 or 2 mg/kg of meclofenamate but remained unchanged in those pretreated with 30 micrograms/kg of nicardipine. Endothelin did not increase either lung permeability, as assessed by 99m technetium diethylenetriamine pentaacetic acid clearance, or airway responsiveness to histamine or 5-hydroxy-tryptamine. Histological studies showed that endothelin induced reversible contraction of airway and pulmonary artery smooth muscles but no inflammatory reactions. These results demonstrate that, in guinea pigs, endothelin 1) induces airway smooth muscle contraction mediated by cyclooxygenase metabolites and modulated by the autonomic nervous system and 2) does not induce airway hyperreactivity or inflammation.

Acute response of the arterial wall to pulsed laser irradiation.

This study was designed to examine the acute response of normal arterial wall to pulsed laser irradiation. Irradiation with an Excimer or a Holmium YAG laser was performed in 15 normal iliac sites of 8 male New Zealand white rabbits. The excimer laser was operated at 308 nm, 25 Hz, 50 mJ/mm2/pulse, and 135 nsec/pulse and the Ho:YAG laser was operated at 2.1 microns, 3.5 Hz, 400 mJ/pulse, 250 microseconds/pulse. The excimer and Ho:YAG laser were coupled into a multifiber wire-guided catheter of 1.4 and 1.5 mm diameter, respectively. The mean luminal diameter increased similarly from 2.01 +/- 0.29 to 2.46 +/- 0.27 mm (P < 0.0005) and from 2.09 +/- 0.53 to 2.45 +/- 0.30 mm (P < 0.005) after excimer and Ho:YAG laser irradiation, respectively. Perforation occurred in 3 of 15 Ho:YAG irradiated sites and 0 of 15 excimer laser irradiated sites. The sites irradiated with excimer or Ho:YAG laser had similar histologic features, consisting of shedding of the endothelium, disorganization of internal elastic lamina, localized necrosis of vascular smooth muscle cells, and fissures in the medial layer. However, the sites irradiated with excimer laser had lower grading scores than those irradiated with the Ho:YAG laser (P < 0.05). Irradiation with excimer or Ho:YAG laser of normal arteries results in: (1) vasodilation of the irradiated artery; (2) localized mechanical vascular injury, and (3) Ho:YAG laser induces more severe damage to the arterial wall than excimer.

Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats.

The aim of this study was to investigate the potential role of endothelin (ET) in the development of chronic hypoxic pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of bosentan, a new nonpeptide mixed antagonist of ETA and ETB receptors. The effect of chronic treatment with bosentan was then examined in rats that were exposed to chronic hypoxia and developed pulmonary hypertension. In lungs from normoxic rats, bosentan (10(-5) M) abolished the vasodilator responses to ET-1 (10(-10) M) or to the ETB-selective agonist IRL-1620 (10(-10) M) and attenuated the vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the pressor response to 3 x 10(-10) M ET-1 was abolished by bosentan and partially reduced by the selective ETA antagonist BQ-123. In conscious rats previously exposed to hypoxia for 15 days, pretreatment with bosentan (100 mg.kg-1.day-1 by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to hypoxia for 15 days and simultaneously treated with bosentan, pulmonary arterial pressure was lower (P < 0.05) and right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of tachykinins in pentamidine-induced airway constriction and microvascular leakage in the guinea pig.

We investigated the effects of aerosolized pentamidine isethionate on airway constriction and microvascular leakage in the guinea pig, and the role of tachykinins in these abnormalities. The bronchoconstrictor response to pentamidine was determined in anesthetized, tracheotomized and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized pentamidine (5 to 30 mg/ml; 60 breaths). Respiratory system resistance was measured by the occlusion method. Airway microvascular permeability was evaluated by measuring the Evans blue dye concentration in the trachea and main bronchi. Aerosolized pentamidine caused a concentration-related increase in respiratory system resistance that was prevented by pretreatment with 50 mg/kg capsaicin given subcutaneously 2 wk before pentamidine and was significantly reduced by pretreatment with 1 mg/kg morphine given intravenously. Pretreatment with 10(-4) M aerosolized phosphoramidon (90 breaths) significantly enhanced the bronchoconstrictor response to pentamidine. Aerosolized pentamidine (50 mg/ml; 90 breaths) increased airway microvascular permeability, as the Evans blue dye concentration was 72.6 +/- 3.7 ng/mg tissue in guinea pigs aerosolized with pentamidine versus 34.2 +/- 3.5 ng/mg tissue in the controls. Capsaicin pretreatment inhibited the increase in microvascular leakage induced by pentamidine. Pretreatment with 5 mg/ml aerosolized albuterol (90 breaths) prevented the bronchoconstrictor response to pentamidine but failed to prevent the pentamidine-induced increase in microvascular permeability. Atropine did not modify the bronchoconstrictor response to pentamidine. These results indicate that in the guinea pig, pentamidine isethionate induces bronchoconstriction and airway microvascular leakage, which are mediated by tachykinins released from sensory nerves. Albuterol, which is used in humans to prevent bronchoconstriction, does not seem able to prevent airway edema.

Dexfenfluramine-associated changes in 5-hydroxytryptamine transporter expression and development of hypoxic pulmonary hypertension in rats.

The appetite suppressant dexfenfluramine, which inhibits neuronal 5-HT uptake and elevates plasma 5-HT levels, has been associated with an increase in the relative risk of developing primary pulmonary hypertension. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PA-SMCs), an effect that depends upon activity of the 5-HT transporter (5-HTT). To investigate the relationship between dexfenfluramine and pulmonary hypertension, we examined 1) the effect of dexfenfluramine on 5-HT uptake by PA-SMCs and the mitogenic response of these cells to 5-HT, and 2) 5-HTT mRNA in lung tissue from normoxic and chronically hypoxic rats during and at discontinuation of a 4-week dexfenfluramine treatment (2 mg/kg/day). In cultured PA-SMCs, dexfenfluramine (10(-6) M) markedly reduced [3H]5-HT uptake and [3H]thymidine incorporation in response to 5-HT (10(-6) M). In lungs from rats exposed to 4-week hypoxia (10% O(2)), 5-HTT mRNA levels were higher than in normoxic rats (233.5 +/- 22.5 versus 121.8 +/- 4.8 amol/mg of RNA, P < 0.05), but were not affected by concomitant treatment with dexfenfluramine. One week after discontinuation of dexfenfluramine, 5-HTT mRNA levels increased substantially, this effect being additive with that of hypoxia (364.0 +/- 13.1 in hypoxic versus 164.2 +/- 10 amol/mg of RNA in normoxic rats). When exposure to 2 weeks of hypoxia followed discontinuation of a 4-week treatment, right ventricular hypertrophy was more severe and muscularization of distal pulmonary arteries more marked (P < 0.01) than in rats pretreated with the vehicle. These data show that, in rats, the increased 5-HTT expression that follows dexfenfluramine discontinuation promotes the development of hypoxic pulmonary hypertension.

Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertension.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is upregulated during exposure to hypoxia. In this study, we analyzed heart and lung VEGF mRNA expression and examined pulmonary vascular remodeling as well as myocardial capillary density in two rat models of pulmonary hypertension involving exposure to chronic hypoxia (CH) and treatment with monocrotaline (MCT), respectively. The rats were studied after 0.5, 1, 3, 15, and 30 days of exposure to 10% O2 or 1, 6, and 30 days after a subcutaneous MCT injection (60 mg/kg). Both CH and MCT induced pulmonary hypertension and hypertrophy of the right ventricle (RV) with increased RV weight and atrial natriuretic peptide mRNA expression. VEGF mRNA expression as assessed by Northern blot analysis was potently induced after 12 h of hypoxia in both the right and left ventricles. After prolonged exposure to hypoxia, VEGF mRNA returned to baseline in the left ventricle (LV) but remained increased in the RV, where it peaked after 30 days. In MCT rats, VEGF mRNA was unchanged in the LV but decreased by 50% in the RV and by 90% in the lungs after 30 days. VEGF mRNA remained unchanged in the lungs from CH rats. Pulmonary vascular remodeling was more pronounced in MCT than in CH rats. The number of capillaries per RV myocyte was increased in rats exposed to 30 days of hypoxia, whereas it remained unchanged in MCT rats despite a similar degree of RV hypertrophy. Our results suggest that the sustained increase in VEGF expression in the hypertrophied RV during CH may account for the increased number of capillaries per myocyte. In contrast, reduced VEGF expression in the lungs and RV of MCT rats may aggravate pulmonary vascular remodeling and compromise RV myocardial perfusion.

Effects of neuraminidase on airway reactivity in the guinea pig.

We investigated the effects of neuraminidase, a viral enzyme that cleaves alpha ketosidic cell-bound sialic acids, to see if it accounts for parainfluenza and influenza virus-induced airway hyperreactivity. Accordingly, Vibrio cholerae neuraminidase was administered intratracheally in guinea pigs, and airway reactivity was assessed 3 h later. Removal of sialic acid residues was evaluated by histologic studies. Airway responsiveness was determined in anesthetized, tracheotomized, and mechanically ventilated guinea pigs by exposing them to increasing concentrations of aerosolized bronchoconstrictor agents. Respiratory system conductance was measured by the occlusion method. Neuraminidase injected intratracheally did not change airway reactivity to 10(-4) to 10(-2) M acetylcholine or 10(-4) to 2.5 x 10(-3) M histamine; nor did it prevent aerosolized albuterol from inhibiting histamine-induced bronchoconstriction. Substance P (10(-6) to 5 x 10(-5) M) had no significant bronchoconstrictor effect on guinea pigs pretreated with saline or neuraminidase. In guinea pigs pretreated with aerosols of the neutral endopeptidase inhibitor phosphoramidon (10(-4) M) before the concentration curve to aerosolized substance P was recorded, neuraminidase significantly reduced substance P-induced bronchoconstriction. When bronchoconstriction was induced by the 4-11 fragment of substance P (10(-5) to 10(-2) M), which is devoid of positive charges, it did not differ significantly in guinea pigs pretreated with saline and those pretreated with neuraminidase. These results indicate that in the guinea pig, neuraminidase injected intratracheally does not induce non-specific airway hyperreactivity and may alter the binding of substance P to its receptors.

Synthesis and secretion of atrial natriuretic factor during chronic hypoxia: a study in the conscious instrumented rat.

1. To investigate the mechanisms leading to enhanced synthesis and release of atrial natriuretic factor during chronic hypoxia, we measured immunoreactive plasma atrial natriuretic factor, blood gases, packed cell volume, pulmonary artery pressure and systemic artery pressure in male Sprague-Dawley rats exposed to 1, 2 or 3 weeks of normobaric hypoxia. Rats were implanted with pulmonary and carotid artery catheters and studied conscious, 23 h after return to hypoxia. 2. The concentration of atrial natriuretic factor messenger RNA was measured in the right and left ventricular free walls of rats exposed to 3 weeks of hypoxia and in normoxic control rats. 3. There was a trend for plasma atrial natriuretic factor to increase with the duration of exposure to hypoxia but only the 3-week hypoxic rats had a significantly higher level (1080 +/- 193 pg/ml) than the normoxic control rats (318 +/- 46 pg/ml, P less than 0.05, mean +/- SEM). When all the data from normoxic and hypoxic rats were considered together, plasma atrial natriuretic factor was positively correlated with packed cell volume (r = 0.66, P less than 0.001), pulmonary artery pressure (r = 0.68, P less than 0.002), and the index of right ventricular hypertrophy (r = 0.54, P less than 0.01), but after analysis of partial correlation, packed cell volume was the only independent contributing factor to the variance in the level of plasma atrial natriuretic factor (r2 = 0.24).(ABSTRACT TRUNCATED AT 250 WORDS)