Cromolyn Sodium Decreases the Pulmonary Vascular Response to Alveolar Hypoxia in Lambs

Abstract

ABSTRACT. We investigated the effect of cromolyn sodium, a mast cell stabilizing agent, on the pulmonary vascular response to alveolar hypoxia in six chronically instrumented lambs aged 9 to 11 days. Each lamb was instrumented on day 6 or 7 for measurements of systemic arterial, pulmonary arterial and left atrial pressures, and pulmonary blood flow. The animals were allowed to recover from surgery at least 3 days before they were studied. Each animal was studied twice, once with a cromolyn sodium infusion and once with a normal saline infusion (placebo). These paired experiments were separated by 24 h. Physiologic measurements were made during a 1-min predose control period, after an 8-min drug or placebo infusion, and after a 15-min period of alveolar hypoxia. Cromolyn sodium infusion alone did not affect baseline cardiovascular variables. Alveolar hypoxia following placebo infusion produced an increase in pulmonary arterial pressure and pulmonary vascular resistance; these responses were blocked in the animals given cromolyn sodium prior to induction of hypoxia. These results show that cromolyn sodium blocks the pulmonary vascular response to hypoxia and provide indirect evidence that mast cell degranulation, with subsequent release of vasoactive agents, mediates the pulmonary vascular response to hypoxia in newborn lambs. (Pediatr Res 20: 834-837,1986) It is known that alveolar hypoxia produces pulmonary vasoconstriction (1, 2), but the exact mechanism underlying this physiologic response remains unknown. Perivascular tissue is needed to produce hypoxic pulmonary vasoconstriction in isolated pulmonary arteries, suggesting an indirect effect of hypoxia on parenchymal tissue rather than a direct effect on vascular smooth muscle (3). Mast cells are present in large numbers in pulmonary perivascular tissue (4), placing them in an ideal location to influence vascular tone.Mast cell degranulation has been demonstrated following acute alveolar hypoxia in rats (4) and sheep (5). If alveolar hypoxia causes release of mast cell mediators which promote vasoconstriction, pharmacologic inhibition of degranulation should prevent hypoxic pulmonary vasoconstriction. Indeed, Ahmed et al. tion is accentuated in newborns (7,8) and may involve additional mechanisms not present in adults, we chose to investigate the effect of cromolyn sodium on the pulmonary vascular response to hypoxia in newborn lambs. METHODOLOGYSix lambs (5.1 f 0.9 kg) were studied between 9-1 1 days of age. The animals were housed in separate plexiglass cages with continuous access to an artificial lamb's milk diet (Lamb Milk Replacer, Land 07Lakes, Inc. Fort Dodge, IA). All animals were healthy, eating well, and gaining weight at the time of study. Lambs of both sexes were used for study. SURGICAL PREPARATIONEach lamb underwent one sterile operation at 6-7 days of age. Following an overnight fast, the animals were given atropine sulfate (0.2 mg/kg subcutaneously) and ketamine HCl (10 mg/ kg intramuscularly). Each animal's trachea was intubated with a cuffed...

The role of reactive oxygen species and nitric oxide in mast cell‐dependent inflammatory processes

“…Further evidence for mast cell involvement in hypoxia has come from studies using drugs that stabilize or activate mast cells. Use of the mast cell stabilizer cromolyn was associated with a reduction in hypoxia‐induced leukocyte adhesion (105, 106) and pulmonary arterial pressure and vascular resistance (107). Activation of mast cells in the normoxic situation by compound 48/80 mirrored the effect of hypoxia on leukocyte adhesion, and this effect was similarly blocked by mast cell stabilizers (105).…”

Pulmonary Vascular Response to Aerosolized Cromolyn Sodium and Repeated Epochs of Isocapneic Alveolar Hypoxia in Lambs

“…Results from this study and our previous work (12), as well as studies in adult sheep (4,13), dogs (10, 1 I), and rats (3) suggest that CS alters the sequence of events that leads to HPV. Additionally, the efficacy of lower doses of aerosolized CS in attenuating the physiologic response to HPV support a local site of action for the drug similar to that postulated for its local action in the treatment of asthma (2 1).…”

“…We previously showed that CS administered as an intravenous infusion blocked the pulmonary vascular response to hypoxia in lambs, noting a 3% decrease in pulmonary vascular resistance during hypoxia compared to a 57% increase with placebo (12). The animals in our previous study received an intravenous loading dose of 24 mg/kg of CS before the onset of hypoxia followed by an additional 45 mg/kg during hypoxia.…”

“…CS is a known inhibitor of mast cell degranulation and when administered intravenously, has been shown to inhibit or modify HPV in adult sheep (4), dogs (10, 1 I), and newborn lambs (12). Administration of CS by aerosolization directly into the airways would provide an alternative route of delivery and might offer a more efficient means of locally depositing the drug.…”