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

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

Thrombin impairs alveolar fluid clearance by promoting endocytosis of Na+,K+-ATPase.

Coagulation is an emerging area of interest in the pathogenesis and treatment of acute lung injury. Concentrations of the edemagenic coagulation protease thrombin are elevated in plasma and lavage fluids from afflicted patients. We explored the impact of thrombin on the formation and resolution of alveolar edema. Intravascularly applied thrombin inhibited active transepithelial 22Na transport in intact rabbit lungs, suppressing alveolar fluid clearance. Epithelial permeability was unaffected, whereas endothelial permeability was increased. In A549 human lung epithelial cells and in mouse primary alveolar type II cells, thrombin blocked ouabain-sensitive Na+,K+-ATPase-mediated 86Rb+ uptake, without altering amiloride-sensitive sodium currents. Furthermore, thrombin downregulated cell-surface expression of Na+,K+-ATPase, but not ENaC alpha and beta subunits. The endocytosis inhibitor phalloidin oleate blocked all thrombin-induced effects on sodium transport activity. Similarly, diphenyleneiodonium chloride, an inhibitor of reactive oxygen radical production, as well as a protein kinase C-zeta inhibitor, prevented these thrombin-induced effects. Thus, thrombin signaling via reactive oxygen species and protein kinase C-zeta promotes Na+,K+-ATPase endocytosis, resulting in loss of function. We propose here a dual role for thrombin in mediating disturbances to fluid balance in the lung: thrombin concomitantly provokes edema formation by increasing endothelial permeability, and inhibits alveolar edema resolution by blocking Na+,K+-ATPase function.

Oleic acid inhibits alveolar fluid reabsorption: a role in acute respiratory distress syndrome?

Levels of oleic acid (OA) are elevated in plasma and bronchoalveolar lavage fluids of patients with acute respiratory distress syndrome (ARDS). OA is also widely used to provoke edema, by unknown mechanisms, in experimental models of ARDS. We investigated the impact of intravascularly applied OA on epithelial lining fluid balance. OA (25 microM) dramatically blocked active transepithelial (22)Na(+) transport (by 92%) in an isolated, ventilated, and perfused rabbit lung model, provoking alveolar edema, assessed by increases in lung weight and epithelial lining fluid volume. OA did not alter epithelial permeability, measured by [(3)H]mannitol and fluorescently labeled albumin flux, but did increase endothelial permeability, assessed by capillary filtration coefficient. In A549 cells, OA completely blocked amiloride-sensitive sodium currents measured by patch clamp, and also largely abrogated ouabain-sensitive Na(+),K(+)-ATPase-mediated (86)Rb(+) uptake. Although OA did not alter epithelial sodium channel or Na(+),K(+)-ATPase surface expression, it covalently associated with both molecules and directly, dramatically, and dose-dependently inhibited the catalytic activity of purified Na(+),K(+)-ATPase. Therefore, OA impaired the two essential transepithelial active sodium transport mechanisms of the lung, and could thus promote alveolar edema formation and prevent edema resolution, thereby contributing to the development of ARDS.

Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial.

BACKGROUND: Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation. OBJECTIVE: To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension. DESIGN: Randomized, double-blind, placebo-controlled crossover study. SETTING: University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest. PARTICIPANTS: 14 healthy mountaineers and trekkers. MEASUREMENTS: Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp). INTERVENTION: Oral sildenafil, 50 mg, or placebo. RESULTS: At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants. LIMITATIONS: The study did not examine the effects of sildenafil on normoxic exercise tolerance. CONCLUSIONS: Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.

Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension.

Only a small percentage of patients with chronic thromboembolic pulmonary hypertension are eligible for pulmonary thrombendarterectomy. We investigated the effects of oral sildenafil on hemodynamics and exercise capacity in 12 nonoperable chronic thromboembolic pulmonary hypertension patients. All patients were in disease progression despite sufficient long-term anticoagulation and the best supportive care and suffered from severe pulmonary hypertension (pulmonary vascular resistance index 1,935 +/- 228 dyn. s. cm-5. m2, cardiac index 2.0 l. min-1. m-2, 6-minute walking distance 312 +/- 30 m). After approximately 6 months of sildenafil treatment, pulmonary hemodynamics and exercise capacity improved significantly (pulmonary vascular resistance index 1,361 +/- 177 L. min-1. m2, p = 0.004, cardiac index 2.4 +/- 0.2 L. min-1. m-2, p = 0.009, 6-minute walking distance 366 +/- 28 m, p = 0.02). Therefore, oral sildenafil may offer a new option for medical treatment of this devastating disease.