sildenafil-citrate and Bronchial-Hyperreactivity

Hyperoxia exposure leads to the development of lung injury and bronchial hyperreactivity (BHR) via involvement of nitric oxide (NO) pathway. We aimed at characterizing whether the stimulation of the NO pathway by sildenafil or vasoactive intestinal peptide (VIP) is able to prevent the hyperoxia-induced development of BHR. The respective roles of the preserved lung volume and alveolar architecture, the anti-inflammatory and anti-apoptotic potentials of these treatments in the diminished lung responsiveness were also characterized.. Immature (28-day-old) rats were exposed for 72 hours to room air (Group C), hyperoxia (>95%, Group HC), or hyperoxia with the concomitant administration of vasoactive intestinal peptide (VIP, Group HV) or sildenafil (Group HS). Following exposure, the end-expiratory lung volume (EELV) was assessed plethysmographically. Airway and respiratory tissue mechanics were measured under baseline conditions and following incremental doses of methacholine to assess BHR. Inflammation was assessed by analyzing the bronchoalveolar lavage fluid (BALF), while biochemical and histological analyses were used to characterize the apoptotic and structural changes in the lungs.. The BHR, the increased EELV, the aberrant alveolarization, and the infiltration of inflammatory cells into the BALF that developed in Group HC were all suppressed significantly by VIP or sildenafil treatment. The number of apoptotic cells increased significantly in Group HC, with no evidence of statistically significant effects on this adverse change in Groups HS and HV.. These findings suggest that stimulating the NO pathway by sildenafil and VIP exert their beneficial effect against hyperoxia-induced BHR via preserving normal EELV, inhibiting airway inflammation and preserving the physiological lung structure, whereas the antiapoptotic potential of these treatments were not apparent in this process.

Topics: Animals; Bronchial Hyperreactivity; Hyperoxia; Lung; Male; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Vasoactive Intestinal Peptide

The development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.. Five groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).. BHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.. The efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Topics: Administration, Oral; Airway Resistance; Analysis of Variance; Animals; Antihypertensive Agents; Blood Pressure; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstriction; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelins; Hypertension, Pulmonary; Iloprost; Infusion Pumps, Implantable; Infusions, Parenteral; Lung; Lung Volume Measurements; Male; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins I; Purines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Endothelin; Signal Transduction; Sildenafil Citrate; Sulfones; Tetrazoles; Time Factors; Vasoactive Intestinal Peptide; Vasodilator Agents

Nitric oxide (NO) levels are elevated in the exhaled breath of asthmatic patients and NO is considered as a biomarker of airway inflammation. However, the functions of NO in the airways are not completely understood. L-arginine, as the substrate of NO synthases, is the precursor of NO which stimulates guanylate cyclase and leads to the formation of cyclic GMP (cGMP). Sildenafil, a phosphodiestérase-5 (PDE-5) inhibitor, prevents the degradation of cGMP. In this study the effects of L-arginine and sildenafil treatment, alone or in combination, were evaluated in ovalbumin-sensitized BP2 mice. These effects concerning the airway responsiveness to inhaled methacholine (MCh) were evaluated by whole-body plethysmography (WBP), the inflammatory response evaluated by bronchoalveolar lavage fluid (BALF) analyses and lung tissue biopsies (eosinophilic inflammation associated with lung remodelling), and NO metabolite measurements (by Griess reaction) in BALF. Ovalbumin sensitization induced: (a) an inflammatory reaction with eosinophil and neutrophil influx in BALF and lung; and (b) an increased bronchial responsiveness to MCh. L-arginine treatment [50 mg/kg intraperitoneally (i.p.), for 7 days] increased the relative amount of eosinophils and neutrophils in BALF, had a tendency to increase the airway responsiveness to inhaled MCh and increased the NO metabolite level in BAL. Sildenafil treatment (20 mg/kg i.p. for 7 days) did not affect the airway responsiveness to MCh and had a lower effect compared with L-arginine on inflammatory reactions. The combination of the two treatments resulted in a dramatic enhancement of the airway responsiveness to inhaled MCh. The relative amount of eosinophils was increased and lung histology showed obvious worsened tissular lesions such as epithelial shedding and hypertrophy, hyperplasia of smooth muscle cells, and fibrosis. These findings are consistent with the notion that NO production plays a role in the development of airway inflammation and hyperresponsiveness of sensitized mice and highlighted the potential risk of the L-arginine dietary complement or PDE5 treatment in asthmatic patients.

Topics: Animals; Arginine; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclic GMP; Eosinophilia; Eosinophils; Lung; Male; Methacholine Chloride; Mice; Nitric Oxide; Ovalbumin; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Plethysmography, Whole Body; Purines; Sildenafil Citrate; Sulfones

Phosphodiesterase (PDE)-5 degrades guanosine 3',5'cyclic monophosphate (cGMP) and its inhibitor sildenafil citrate (Viagra) treats erectile dysfunction by smooth muscle relaxation through elevated cGMP. Sildenafil was examined in two guinea pig models of airways disease: guinea pigs exposed to LPS or sensitized guinea pigs with atopy exposed to ovalbumen. Ovalbumen exposure caused early- and late-phase bronchoconstrictor responses, measured in conscious animals by whole-body plethysmography. Twenty-four hours after ovalbumen exposure there was airway hyperreactivity (AHR) to inhaled histamine and significantly elevated macrophages, eosinophils, and nitric oxide (NO) metabolites in bronchoalveolar lavage fluid. Sildenafil treatment (1 mg/kg, intraperitoneally) failed to affect the early and late responses but significantly reduced AHR, leukocyte influx, and elevated NO. LPS exposure (30 microg/ml) caused AHR to histamine at 1 hour and macrophage, eosinophil, and neutrophil influx at 24 hours with raised NO. Sildenafil pretreatment inhibited LPS-induced AHR, leukocyte influx, and NO generation. The effectiveness of sildenafil was not dependent on endogenous NO because inhibition of NO synthase with Nomega-nitro-L-arginine methyl ester did not prevent its action. Inhibition of PDE5 by sildenafil was confirmed by elevated S-nitroso-N-acetylpenicillamine-induced cGMP generation in isolated lungs. These antiinflammatory actions of sildenafil in guinea pig models suggest that PDE5 inhibitors may have potential in treating airways disease.

Topics: Airway Resistance; Allergens; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclic GMP; Eosinophils; Guinea Pigs; Histamine; In Vitro Techniques; Lipopolysaccharides; Lung; Macrophages; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Ovalbumin; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones