Spasmolytic effects of colforsin daropate on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs.
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.
Hirota
K
K
Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan. masuika@cc.hirosaki-u.ac.jp
Yoshioka
H
H
Kabara
S
S
Koizumi
Y
Y
Abe
H
H
Sato
T
T
Matsuki
A
A
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*
D002395:Catecholamines; D010276:Parasympatholytics; D012702:Serotonin Antagonists; D014665:Vasodilator Agents; C122001:colforsin daropate; D005576:Colforsin; D012701:Serotonin