Furosemide Differentially Relaxes Airway and Vascular Smooth Muscle in Fetal, Newborn, and Adult Guinea Pigs

Abstract

Furosemide, an inhibitor of Cl-dependent Na+,K+ cotransport, is the most frequently used diuretic in newborns. Recently, furosemide was also demonstrated to decrease bronchial hyper-responsiveness in adults, although little is known about the direct effect of furosemide on smooth muscle of immature animals. This in vitro study was designed to determine the action of furosemide on airway and vascular smooth muscle during ontogeny. Extrathoracic trachea (ET), main stem bronchi, main pulmonary artery, and thoracic aorta ring segments from fetal, newborn, and adult Hartley albino guinea pigs were suspended in HEPES solution for measurement of isometric tension. Furosemide (30 or 300 microM) was administered after preconstriction with an ED35-70 concentration of histamine or acetylcholine for airway and ED40-100 concentration of norepinephrine for vessels. Furosemide (30 microM) caused significant relaxation of airway smooth muscle at all ages. After histamine-induced preconstriction, fetal airway segments exhibited greatest relaxation (183 +/- 28%), with newborn airway demonstrating 123 +/- 15% relaxation and modest relaxation seen in adults (40 +/- 4%). This pattern was similar for both ET and bronchus and appeared greater for histamine compared with ACh preconstriction. Epithelial removal slightly enhanced relaxation. Furosemide also relaxed pulmonary artery segments, but at a 10-fold higher concentration. In striking contrast to the pattern seen in airway, adult pulmonary artery relaxed more than newborn and newborn, more than fetus. Cyclooxygenase blockade and endothelium removal did not change pulmonary artery relaxation. Furosemide did not significantly relax aorta after NE preconstriction. Taken together, these results suggest that furosemide may be more effective in relaxing airway compared with vascular smooth muscle, and the ontogeny of these responses indicates a greater efficacy and selectivity in airways of immature animals.