title: Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension.
abstract: 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.
authors.affiliation: Pediatric Anesthesia Unit, Geneva Children's Hospital, University Hospitals of Geneva, 6, Rue Willy Donze, CH-1205, Geneva, Switzerland.
authors.forename: Walid
authors.initials: W
authors.lastname: Habre
authors.forename: Gergely
authors.initials: G
authors.lastname: Albu
authors.forename: Tibor Z
authors.initials: TZ
authors.lastname: Janosi
authors.forename: Fabienne
authors.initials: F
authors.lastname: Fontao
authors.forename: Britta S
authors.initials: BS
authors.lastname: von Ungern-Sternberg
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
authors.forename: Ferenc
authors.initials: F
authors.lastname: Petak
mesh_terms: D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016285:Iloprost / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D007263:Infusions, Parenteral; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008176:Lung Volume Measurements; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D044062:Prostaglandins I / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D044062:Prostaglandins I; D011687:Purines; D011725:Pyridines; D017466:Receptors, Endothelin; D013450:Sulfones; D013777:Tetrazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; C120582:tezosentan; D000068677:Sildenafil Citrate; D016285:Iloprost