Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension
| Autor: | Gergely Albu, Fabienne Fontao, Ferenc Peták, Maurice Beghetti, Britta S. von Ungern-Sternberg, Tibor Z. Jánosi, Walid Habre |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Endothelin Receptor Antagonists
Male Time Factors Pyridines Bronchoconstriction/drug effects Vasodilator Agents Vasoactive intestinal peptide Airway Resistance/drug effects Phosphodiesterase 5 Inhibitors/pharmacology Administration Oral Tetrazoles Blood Pressure Piperazines Endothelins Rats Sprague-Dawley Receptors Endothelin/antagonists & inhibitors/metabolism Signal Transduction/drug effects Hypertension Pulmonary/complications/drug therapy/metabolism/physiopathology Infusions Parenteral Vasoactive Intestinal Peptide/pharmacology Sulfones Piperazines/pharmacology Lung Pyridines/pharmacology ddc:618 ddc:617 Receptors Endothelin Infusion Pumps Implantable respiratory system Iloprost/pharmacology medicine.anatomical_structure Bronchial hyperresponsiveness Cardiology Lung/blood supply/drug effects/metabolism/physiopathology Bronchial Hyperreactivity Lung Volume Measurements Purines/pharmacology medicine.drug Signal Transduction Vasoactive Intestinal Peptide medicine.hormone Pulmonary and Respiratory Medicine medicine.medical_specialty Bronchoconstriction Hypertension Pulmonary Bronchial Hyperreactivity/etiology/metabolism/physiopathology/therapy Nitric Oxide Blood Pressure/drug effects Bronchial Provocation Tests Sildenafil Citrate Internal medicine medicine Animals Prostaglandins I Antihypertensive Agents/administration & dosage/pharmacology Iloprost Vasodilator Agents/administration & dosage/pharmacology Antihypertensive Agents lcsh:RC705-779 Analysis of Variance business.industry Research Airway Resistance lcsh:Diseases of the respiratory system Phosphodiesterase 5 Inhibitors medicine.disease Endothelins/metabolism Angiotensin II Pulmonary hypertension Sulfones/pharmacology Tetrazoles/pharmacology Rats Prostaglandins I/metabolism Disease Models Animal Endocrinology Purines Nitric Oxide/metabolism Methacholine business |
| Zdroj: | Respiratory Research Respiratory Research, Vol. 12 (2011) P. 58 Respiratory Research, Vol 12, Iss 1, p 58 (2011) |
| ISSN: | 1465-993X |
| DOI: | 10.1186/1465-9921-12-58 |
| Popis: | Background: 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. Methods: 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). Results: 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. Conclusions: 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. Background There has recently been substantial progress in the development of new therapeutic strategies for the management of patients with pulmonary hypertension (PHT) [1-5]. The improvements are based on a better understanding of the mechanisms involved in the development of PHT. These treatment strategies are based on the recognition that a key role is played in the modulation of the tone of the smooth muscle cells in the pulmonary vasculature by an imbalance between the vasoactive constrictor and proliferative mediators (endothelin-1 (ET-1), substance P and angiotensin II) and the vasorelaxing and antiproliferative mediators (adrenomedullin, vasoactive intestinal peptide (VIP), prostacyclins (PCs) and nitric oxide (NO)) [6]. The bronchoactive potential of these peptides has been recognized as the major cause of the lung function deterioration [1,2,7-10]. We earlier reported a lung function impairment in a reproducible model of precapillary PHT following the creation of a shunt between the abdominal aorta and the vena cava in rats [11]. We also demonstrated that precapillary PHT leads to the development of bronchial hyperresponsiveness (BHR) to methacholine subsequent to the altered mechanical interdependence between the pulmonary vasculature and the respiratory tract. Although novel strategies are available for the treatment of pulmonary vascular diseases, no studies have yet characterized how the adverse pulmonary consequences of these clinically important pulmonary vascular abnormalities can be prevented. Accordingly, in the present study we set out to |
| Databáze: | OpenAIRE |
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