Acute Hyperoxic Injury Attenuates the Relaxing Effects of “Loop” Diuretics and Salbutamol on Large Airways of Newborn Guinea Pigs

Abstract

We have previously found an age-dependent relaxing effect of furosemide in normal fetal, newborn, and adult guinea pig airways with fetal trachea exhibiting the greatest relaxation and adult tissue the least. This study was designed to expand upon this finding by determining if in vivo hyperoxic exposure would influence in vitro airway relaxation mediated by the loop diuretics, furosemide and ethacrynic acid, and the P2-adrenoceptor agonist, salbutamol. Newborn guinea pigs were raised in >95% FiO, until ill; controls in room air. Isometric relaxation to 3 X lop5 M furosemide, 3 X 10-% ethacrynic acid, or 1 0~' -1 0~" M salbutamol was recorded in 3 X lop" M histamine-constricted airway rings. Ethacrynic acid, like furosemide, relaxed newborn Recent evidence suggests that furosemide modulates airway reactivity in vivo. Inhaled furosemide attenuates exercise-(I), allergen-(2), and cold air-(3, 4) induced bronchoconstriction in asthmatic adults, and cold air-induced bronchospasm in asthmatic children (5). Furthermore, systemic furosemide decreases airway resistance in infants with bronchopulmonary dysplasia (6-10). Although the mechanisms of furosemide's pulmonary effects have yet to be fully established, most researchers conclude that these effects are unrelated to diuresis. Various mechanisms have been espoused, including inhibition of pulmonary nerves ( l l ) , increased pulmonary venous capacitance (12), increased efferent pulmonary lymph flow (13) Medical Center; University of Hawaii Leahi Trust; and National Institutes of Health Grant guinea pig airways. Hyperoxia did not alter the contractile effect of 3 X 1 0 -M histamine but did significantly decrease the relaxing effect of furosemide, ethacrynic acid, and salbutamol. Loop diuretic mediated airway relaxation was accentuated in HEPES buffer when compared with Krebs, whereas salbutamolmediated relaxation was unaffected. These results suggest that hyperoxia nonspecifically decreases airway responsiveness to the relaxing agents studied. (Pediatr Res 38: 280-285, 1995) Abbreviations ORT, optimal resting tension FiO,, fraction of inspired oxygen increased oncotic pressure leading to decreased efferent pulmonary transcapillary flow (12,14). Stevens et al. (15) found that furosemide directly relaxes normal isolated guinea pig airways, suggesting another possible mechanism.Furosemide, bumetanide, and ethacrynic acid bind to a Na+-K+-Cl-cotransporter in the thick ascending loop of Henle (16,17). This transporter is also functional in other tissues (18). The possible role of this cotransporter in vascular smooth muscle function was first hypothesized by Deth and coworkers (19) who found evidence for a functional Na+-K+-C1-cotransporter in vascular smooth muscle by demonstrating that: 1) '%b uptake (a marker for Kt transport) is inhibited by furosemide in the presence of ouabain (to inhibit Na-KATPase) and is ~a + -, K+-, and C1--(substrate) dependent; and 2) uptake of 4 5~a in rat aorta is reduced by furosemide. They further suggest that HEPES buffer increases...

Prolonged Moderate Hyperoxia Induces Hyperresponsiveness and Airway Inflammation in Newborn Rats

“…In the present study, a fixed duration of exposure to O 2 of 15 d was chosen a priori because it has practical clinical implications. Because each animal has its own individual susceptibility to inhaled toxic substances (27), this could explain the scatter observed in the inflammatory cell counts. The variability may also have been enhanced by the young age of the animals, which are still in the process of airway maturation.…”

“…The variability may also have been enhanced by the young age of the animals, which are still in the process of airway maturation. However, we had no objective signs to determine when to cease exposure to have a uniform set of subjects (27).…”