Furosemide-induced bronchodilation in the rat bronchus: evidence of a role for prostaglandins.
Pretreatment with inhaled fuorsemide has been shown to protect against bronchoconstrictive stimuli that indirectly activate airway smooth muscle. However, it is controversial as to whether furosemide acts directly on airway smooth muscle. To investigate this we studied the effect of furosemide on both methacholine (MCh)- and serotonin (5-HT)-induced bronchoconstriction in explanted rat airways. Lungs from 21 Sprague-Dawley rats (269 +/- 15 g) were excised, inflated with agarose solution at 37 degrees C (1% w/v, 48 ml/kg), embedded in 4% agarose, and refrigerated to gel the agarose. Lung slices (0.5-1.0 mm thick) were cultured overnight at 37 degrees C. Explants were placed on a dissecting video microscope, and airway area was measured with an image analysis system. MCh or 5-HT was administered directly to explanted airways (final concentrations 3.8 x 10(-6) M and 3.8 x 10(-5) M, respectively). Five min later furosemide (3.7 x 10(-5) M or 3.7 x 10(-4) M) was added and airway area monitored 5, 10, 15, 30, and 60 min later. Results were expressed as a percentage of the maximal response. Significant bronchodilation was seen after 30 min in airways preconstricted with MCh and after 15 min in those preconstricted with 5-HT following 3.7 x 10(-4) M furosemide (p < 0.05). 3.7 x 10(-5) M furosemide caused bronchodilation only at 60 min in airways constricted with 5-HT. The effect was blocked by a 30-min incubation of explants with 10(-6) M indomethacin. The furosemide-induced bronchodilation effect was not observed in airways strongly constricted with 3.8 x 10(-5) M MCh. These findings indicate that in the rat at least, furosemide induces a weak bronchodilator effect present only at high doses, which seems to be dependent on the production of prostaglandins. This effect may be relevant to the observed therapeutic action of furosemide in asthmatics.
Almirall
J J
JJ
Meakins-Christie Laboratories, Montreal Chest Research Institute, Royal Victoria General Hospital, McGill University, Quebec, Canada.
Dolman
C S
CS
Eidelman
D H
DH
D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005665:Furosemide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D013997:Time Factors
D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004232:Diuretics; D011453:Prostaglandins; D016210:Methacholine Chloride; D012701:Serotonin; D005665:Furosemide; D007213:Indomethacin