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: K Hirota, H Yoshioka, S Kabara, Y Koizumi, H Abe, T Sato, A Matsuki
• Journal: Acta anaesthesiologica Scandinavica (Acta Anaesthesiol Scand) Vol. 46 Issue 3 Pg. 297-302 (Mar 2002) ISSN: 0001-5172 [Print] England
• PMID: 11939921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Parasympatholytics
• Serotonin Antagonists
• Vasodilator Agents
• colforsin daropate
• Colforsin
• Serotonin

Topics

• Animals
• Bronchial Spasm (physiopathology)
• Bronchoconstriction (drug effects)
• Catecholamines (blood)
• Colforsin (analogs & derivatives, pharmacology)
• Dogs
• Dose-Response Relationship, Drug
• Hypertension, Pulmonary (blood, chemically induced, physiopathology)
• Parasympatholytics (pharmacology)
• Pulmonary Circulation
• Serotonin
• Serotonin Antagonists (pharmacology)
• Vascular Resistance (drug effects)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)