montelukast and Hypoxia

Previous research has demonstrated that blood and urine concentrations of various leukotrienes are elevated with acute hypoxic exposure. Some of these studies have suggested that leukotrienes may be mediators in the pathogenesis of acute mountain sickness (AMS). We conducted a randomized, double-blind study to determine if AMS symptoms correlated with the increase in leukotriene synthesis and if prophylactic leukotriene receptor blockade would prevent the development of AMS in a simulated high altitude exposure. Three male and five female subjects completed two normobaric hypoxia chamber exposures (average F(IO2) 12.4 +/- 0.09%), receiving montelukast 10 mg daily for 4 days prior to one session and placebo for 4 days prior to the other session. There were no differences in Lake Louise AMS scores, time spent in the chamber, average oxygen saturation, and average heart rate during the montelukast and placebo sessions. Headache scores were higher during treatment with montelukast than during treatment with placebo. Compared to preexposure values, urinary leukotriene E4 concentrations were unchanged during the hypoxic chamber exposure following treatment with placebo or montelukast. Urinary leukotriene E4 excretion during the hypoxic exposure did not differ between the two sessions. A 4-day course of leukotriene receptor blockade does not prevent symptoms of AMS. These results suggest that leukotrienes do not play a causal role in the pathophysiology of AMS.

Topics: Acclimatization; Acetates; Administration, Oral; Adult; Altitude Sickness; Atmosphere Exposure Chambers; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Humans; Hypoxia; Leukotriene Antagonists; Leukotriene E4; Male; Premedication; Quinolines; Severity of Illness Index; Statistics, Nonparametric; Sulfides

Bronchoprovocation with cysteinyl-leukotrienes (LTs) induces airflow obstruction and gas exchange abnormalities, namely ventilation-perfusion ratio (V'(A)/Q') imbalance. However, it is unknown which of the two different receptors for cysteinyl-LTs mediate these V'(A)/Q' disturbances. In a double-blinded, crossover design, 10 patients with mild asthma were randomised to receive an oral single dose of the selective cysteinyl-LT1 receptor antagonist montelukast (40 mg) or placebo before leukotriene (LT)D4 inhalation challenge. Gas exchange, including V'(A)/Q' descriptors were measured at baseline, 3 h after montelukast/placebo pretreatment and 5, 15 and 45 min after the LTD4 challenge. Compared with montelukast, inhalation of LTD(4) induced a marked fall in forced expiratory volume in one second (mean+/-se 33+/-2%) and profound V'(A)/Q' mismatching, reflected by a decreased arterial oxygen tension (from 100+/-4 to 75+/-3 mmHg) and an increased overall index of V'(A)/Q' heterogeneity dispersion of retention minus excretion inert gases corrected for dead space (from 4.9+/-1.2 to 8.4+/-1.1; normal< or =3.0; dimensionless), 5 min after placebo. Following montelukast, LTD4 produced no significant changes in any of the variables. In conclusion, these findings point to the view that leukotriene D4)-induced gas exchange disturbances and bronchoconstriction are both mediated by the cysteinyl-leukotriene1 receptor.

Topics: Acetates; Adult; Asthma; Bronchial Provocation Tests; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Humans; Hypoxia; Leukotriene Antagonists; Leukotriene D4; Male; Membrane Proteins; Quinolines; Receptors, Leukotriene; Severity of Illness Index; Sulfides; Ventilation-Perfusion Ratio

To evaluate the preventive effects of montelukast on the collagen expression of pulmonary arterioles in chronic hypoxic rats.. Thirty male Wistar rats were randomly divided into three groups: control group, hypoxic group and montelukast preventive group. The animal model of pulmonary hypertension was established by exposing the rats to normabaric hypoxic conditions 8 hours q.d. for 3 weeks. The expression levels of collagen I and III in arterioles were observed by immunohistochemistry.. The positive degree of collagen I in pulmonary arterioles of hypoxic group was higher than that of control group (1.51+/-0.09 vs 1.15+/-0.05, P<0.01), and the positive degree of collagen I in pulmonary arterioles of preventive group (1.19+/-0.06) was lower than that of hypoxic group (P<0.01). The differences of positive degree of collagen III in pulmonary arterioles were not significant among the three groups (P>0.05).. Montelukast can reduce the hypoxia-induced deposition of collagen I in the pulmonary arterioles wall.

Topics: Acetates; Animals; Arterioles; Collagen Type I; Cyclopropanes; Hypertension, Pulmonary; Hypoxia; Leukotriene Antagonists; Male; Pulmonary Artery; Quinolines; Random Allocation; Rats; Rats, Wistar; Sulfides

To evaluate the role of cysteinyl leukotriene(CysLT) in the pathogenesis of hypoxic pulmonary hypertension and the preventive effects of montelukast, a CysLT receptor antagonist, on hypoxic pulmonary hypertension.. Thirty male Wistar rats were randomly divided into three groups: control group, hypoxic group and montelukast preventive group. The animal model of pulmonary hypertension was established by exposing the rats to normabaric hypoxic conditions for 3 weeks. The thickness of pulmonary arterioles was measured by a computerized image analyzer. The level of LTC4 in plasma was measured by EIA.. In the hypoxic group, the index of right ventricular hypertrophy[RV/(LV + S)] and the index of wall thickness of pulmonary arteriole (WT% and WA%) increased significantly when compared against those in the control group [RV/(LV + S): 30.85% +/- 1.44% vs 20.75% +/- 1.97%; WT%: 23.54% +/- 4.43% vs 13.17% +/- 3.67%; WA%: 72.76% +/- 9.28% vs 50.41% +/- 6.37%, P < 0.01, respectively]. Meanwhile, the plasma level of LTC4 in hypoxic rats was higher than that in control rats [(2395.40 +/- 193.86) pg/ml vs (1006.50 +/- 193.17) pg/ml, P < 0.01]. In the preventive group, the RV/(LV + S) (24.09% +/- 1.09%), WT% (15.44% +/- 4.72%) and WA% (51.98% +/- 12.18%) decreased remarkably as compared with those of the hypoxic group(P < 0.01). The plasma level of LTC4 in the preventive group (2706.25 +/- 350.49 pg/ml) was not significantly different from that in the hypoxic group(P > 0.05).. Chronic hypoxia stimulates synthesis and release of LTC4. CysLT may play an important role in the pathogenesis of hypoxic pulmonary hypertension and montelukast can prevent hypoxi pulmonary hypertension.

Topics: Acetates; Animals; Cyclopropanes; Hypertension, Pulmonary; Hypoxia; Leukotriene Antagonists; Leukotriene C4; Male; Membrane Proteins; Quinolines; Random Allocation; Rats; Rats, Wistar; Receptors, Leukotriene; Sulfides