Dietary sodium chloride as a moderator of the severity of exercise-induced asthma

Abstract

The potential influence of diet on asthma and other forms of obstructive lung disease have received relatively little attention. Epidemiological evidence indicates an association between mortality from asthma and high dietary sodium chloride intake. Subsequent experiments have shown that bronchial reactivity is increased on high sodium chloride diets. Since 40 to 90% of asthmatics exhibit airway obstruction upon an exercise challenge, it has been suggested that subjects with exercise-induced asthma (EIA) will also be affected by alterations in dietary salt (NaCl). The working hypotheses were that: 1) a low salt diet (LSD) would improve and a high salt diet (HSD) would worsen post-exercise pulmonary function in subjects with EIA, and that changes in post-exercise pulmonary function maybe mediated by the sodium and/or chloride constituent of NaCl; 2) guinea pigs fed a HSD would exhibit increased airway obstruction compared to a NSD following a dry gas hyperpnea challenge, and that the airway response to hyperpnea is mediated by NaCl-induced leukotriene release. Two sets of eight subjects with clinically diagnosed EIA and two sets of eight Control subjects volunteered for the first and second study. For the first study, subjects entered on their normal salt diet (NSD) and then were placed on either a LSD or a HSD for two weeks. A one-week washout period occurred between diets before the subjects crossed over to the alternative diet for another two weeks. Twenty-four hour urine collections were obtained at the end of each treatment period. Subjects underwent treadmill testing to peak exercise, and pre- and post-exercise pulmonary function tests were performed. Changing dietary NaCl intake had no effect on pre-exercise pulmonary function in EIA and Control subjects, and had no effect on post-exercise pulmonary function in Control subjects. However, the LSD improved and the HSD worsened postexercise pulmonary function in EIA subjects. At 15 minutes of recovery, forced expiratory volume in one-second (FEV1) decreased 14 ± 6% on the LSD, 20 ± 7% on the NSD, and 24 ± 6% on the HSD in EIA subjects. In EIA subjects, tidal volume (VT) and breathing frequency (fB) selection varied during exercise with the NaCl diets, with higher VT and lower fB on the HSD, and the opposite on the LSD. This suggests greater airway obstruction on the HSD during exercise. The Control subjects demonstrated no changes in VT or fB selection on the different NaCl diets. Urinary sodium excretion was significantly higher on the HSD compared to the NSD and LSD in a graded fashion. The subjects in the second study followed an identical testing protocol as the first study, except they followed either a LSD for two weeks (low sodium, low chloride) or a sodium bicarbonate (NaHCO3; high sodium, low chloride) diet for two weeks, and then switched over to the alternative diet after a one-week washout period. Altering sodium or chloride had no effect on pre-exercise pulmonary function values in either group or post-exercise pulmonary function values in Control subjects. However, both the LSD and NaHCO3 diet improved post-exercise pulmonary function in EIA subjects, compared to the NSD (which had a significantly higher chloride content compared to the other diets). In EIA subjects, comparing pre- to post-exercise, FEV1 decreased 7 ± 4% on the LSD, 14 ± 4% on the NaHCO3 diet, and 19 ± 2% on the NSD. While the LSD diet did not normalize pulmonary function (compared to the Control subjects) it did improve it. Likewise, the NaHCO3 diet also improved post-exercise pulmonary function in EIA subjects, but not to the extent of the LSD. This suggests that chloride may be a major contributor to this response. However, it appears that the presence of high sodium in the diet (NaHCO3) prevents the total improvement seen with the LSD (low sodium, low chloride). Urinary excretion of sodium was significantly higher on the NaHCO3 diet compared to the NSD and LSD in a graded fashion. In addition, urinary excretion of chloride was not significantly different between the NaHCO3 diet and LSD, but was significantly higher for the NSD compared to the NaHCO3 and LSD. The third study involved using an animal model of EIA. Airway responses to dry gas hyperpnea ventilation challenge mimic EIA and have been used to model this condition in animals. The mechanisms of the airway response to hyperventilation have been extensively explored using guinea pigs. Thirty-two guinea pigs were used in this study. The animals were split into two groups. One group (n=16) followed a high salt (HS) diet (2% NaCl) for two weeks and the other group (n=16) followed a normal salt (NS) diet (0.75% NaCl) for two weeks. At the end of each treatment period the animals were cannulated for drug administration, tracheotomized and mechanically ventilated with a small animal ventilator. Airway responses to hyperpnea were measured as changes in airway pressures. The HS diet elicited significantly higher airway pressures compared to the NS diet following the first hyperpnea challenge, indicating greater airway obstruction on the HS diet. Prior to a second hyperpnea challenge, the animals were either infused with Nordihydroguaiaretic acid (NDGA) which is a non-selective Ieukotriene (LT) biosynthesis and lipoxygenase (LO) inhibitor (BLO group), or saline (CON group). The LT-LO inhibitor resulted in significant blunting of the bronchoconstrictor response to the second hyperpnea challenge in the BLO groups, compared to the CON groups on both diets. However, the HS-BLO diet still elicited higher airway pressures than the NS-BLO diet during this post-hyperpnea period. One interpretation is that NaCl may mediate the release of LTs from effector cells in the airways in a dose dependent manner. Another interpretation is that NaCl loading enhances airway osmolarity. This increase in osmolarity provides an ideal environment for the release epithelial and mast-cell derived mediators and neuropeptides from sensory nerves. In addition, it is possible that NaCl loading exacerbates HIAO by increasing vascular volume in the bronchial circulation and hence microvascular pressure, leading to mucosal edema and narrowing of the airway lumen. This effect may work independent or in conjunction with the release of LTs in the development of HIAO. In conclusion, this is the first study to demonstrate that the chloride constituent of NaCl may play a major role, along with sodium, in the severity of EIA, and that dietary NaCl loading may enhance the release of inflammatory mediators from cells in the airways of guinea pigs following dry gas hyperpnea.