The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEVy) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV, when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22°C to 36°C eight of 10 patients had a similar change in FEV, with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.The measurement of the airway response to the inhalation of ultrasonically nebulised solutions of hypotonic and hypertonic solutions provides a new approach for the investigation of nonimmunologically mediated bronchial reactivity.We have previously measured airway reactivity to these solutions by determining the total volume of inhaled aerosol (that is, ventilation) required to reduce the forced expiratory volume in one second (FEVy) For this reason we have determined the delivered dose required to induce a 20% reduction in FEV1 and compared the responses in FEV, to equivalent doses of water under different conditions. Furthermore, we have measured the proportion of a delivered dose which is retained by the patient. We have also studied the effects of sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride on the airway response to the same dose of inhaled solution. MethodsWe studied 55 patients aged 11-56 years (mean ± SD 28-5 + 10-8 years) with clinically recognised asthma who were taking beta-sympathomimetic aerosols regularly for control of their symptoms. All medications were withheld for at least four hours before any test. The protocol was approved by the ethics review committee and informed consent obtained. Sixteen non-asthmatic subjects volunteered as controls. The FEVI was measured

1 Human lung bronchiolar segments (about 2 mm long and with a diameter of 0.6-1.5 mm) were dissected and circular muscle tension recorded. Airways were identified by histology and in some preparations by relaxant responses to noradrenaline (0.1-10 -OM).2 Adenosine (1-100 gM) produced only very weak contractions, whereas carbachol (EC50 = 0.40 jM), histamine (EC0= 0.63 pM), prostaglandin D2 (EC50 = 0.50 gM), substance P (ECm = 4.6 pM) and ATP (1-100 pM) produced much greater ones.3 The contractions generally developed rapidly and were stable. The mean maximum increase in tension achieved with the most efficient constrictor, carbachol, was 0.5 g. ATP was the least efficient producing only about 40% of carbachol's maximum. 4 Terbutaline, theophylline and enprofylline relaxed carbachol (2.0 gM = EC70)-contracted preparations. Terbutaline (3-3000nM) relaxed 4 out of 11 bronchioles. Theophylline (10-400011M) and enprofylline (1-400 pM) consistently relaxed the bronchiolar preparations including those exhibiting little responsiveness to the P2-adrenoceptor agonist.5 Since enprofylline (which does not block adenosine receptors) was a five times more potent relaxant than theophylline and since adenosine produced only weak contractions, antagonism of adenosine receptors is probably not involved in relaxation of the small airways. 6 It is suggested that the present data, which apparently differ from those obtained with lung parenchymal strips, are of relevance for human small airways responsiveness.

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We have developed a technique for measuring lung function in conscious guinea pigs using a whole body plethysmograph. Because guinea pigs breathe through the nose, a technique was also developed to measure nasal and lower respiratory system conductance simultaneously in anesthetized animals. The upper and the lower airways could be challenged separately and studied in a manner similar to the conditions in the plethysmograph. Aerosols of histamine, carbachol, or ovalbumin delivered to the nose in sensitized animals had no effect on nasal conductance, even in doses 100 times higher than that required to reduce lower respiratory system conductance. However, intravenous histamine increased nasal conductance. Thus, although nasal resistance constitutes the majority of the total respiratory system resistance measured in the plethysmograph, nasal resistance is unaffected by the aerosol drugs studied. We therefore consider changes in resistance measured in the plethysmograph to originate at or below the larynx. The plethysmographic technique described here is a reliable, reproducible, and rapid technique that enables repeated measurement in animals and minimizes animal trauma.