title: Spasmolytic effects of colforsin daropate on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs.
abstract: BACKGROUND
  We have previously found that agents increasing intracellular cAMP levels of smooth muscles, such as PDE3 inhibitors, aminophylline and prostaglandin E1, produce both bronchodilation and pulmonary vasodilation in serotonin-induced pulmonary hypertension and bronchoconstriction models. In the present study we have simultaneously evaluated the spasmolytic effects of colforsin daropate, a novel forskolin derivative, on serotonin-induced pulmonary hypertension and bronchoconstriction.
  
  
  METHODS
  Ten mongrel dogs were anesthetized with pentobarbital. The pulmonary hypertension and bronchoconstriction were elicited with serotonin (10 microg/kg + 1 mg x kg(-1) x h(-1)) and assessed as percentage changes in pulmonary vascular resistance (PVR) and bronchial cross-sectional area (BCA) (basal = 100%). Initially, the relaxant effects of colforsin daropate (0-300 microg/kg) were determined. The PVR and BCA were assessed before and 30 min after serotonin infusion began and 5 min after each dose of colforsin daropate. To determine whether colforsin daropate-induced relaxation is independent of plasma catecholamine, propranolol 0.4 mg/kg was given following colforsin daropate 300 microg/kg i.v.
  
  
  RESULTS
  Colforsin daropate reversed both pulmonary hypertension and bronchoconstriction dose-dependently: -logED50 (95% confidence intervals, mean ED50) for pulmonary hypertension and bronchoconstriction 5.44 (5.08-5.80, 3.6 microg/kg) and 4.90 (4.06-5.20, 12.5 microg/kg), respectively. However, colforsin daropate (>or= 30 microg/kg) produced a more pronounced systemic than pulmonary vasodilation. Although colforsin daropate (>or= 30 microg/kg) significantly increased plasma catecholamines, propranolol did not reverse the relaxant effects.
  
  
  CONCLUSIONS
  Colforsin daropate may attenuate bronchoconstriction and pulmonary hypertension. In addition, as beta-blockade did not change the attenuation, the relaxant effects may be independent of plasma catecholamines.
authors.affiliation: Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan. masuika@cc.hirosaki-u.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Hirota
authors.forename: H
authors.initials: H
authors.lastname: Yoshioka
authors.forename: S
authors.initials: S
authors.lastname: Kabara
authors.forename: Y
authors.initials: Y
authors.lastname: Koizumi
authors.forename: H
authors.initials: H
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: A
authors.initials: A
authors.lastname: Matsuki
mesh_terms: D000818:Animals; D001986:Bronchial Spasm / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects*; D002395:Catecholamines / Q000097:blood; D005576:Colforsin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D010276:Parasympatholytics / Q000494:pharmacology*; D011652:Pulmonary Circulation; D012701:Serotonin; D012702:Serotonin Antagonists / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002395:Catecholamines; D010276:Parasympatholytics; D012702:Serotonin Antagonists; D014665:Vasodilator Agents; C122001:colforsin daropate; D005576:Colforsin; D012701:Serotonin