Quantification of nasal involvement in a guinea pig plethysmograph.

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.

Terfenadine modifies airway narrowing induced by the inhalation of nonisotonic aerosols in subjects with asthma.

A change in osmolarity of the respiratory tract is a potent stimulus for provoking an attack of asthma. The mechanism for this is thought to be the release of histamine and other mediators from airway mast cells. We studied the effect of a potent and selective H1 receptor antagonist on the airway response to nonisotonic aerosols (NIA) in 12 asthmatic subjects 19 to 57 yr of age. Terfenadine (T) (180 mg) or its placebo (P) was given 150 min before challenge with NIA. The FEV1 was measured before and after the inhalation of aerosols of isotonic (0.9%), hypertonic (1.8, 3.6, 4.5, and 5.4%), and hypotonic NaCl (0.6, 0.3, and 0%) aerosols. Each concentration of aerosol was inhaled for 3 min, and each day the concentration was increased or decreased until a 20% fall in FEV1 was recorded. Terfenadine caused a significant reduction in airway narrowing as assessed by (1) the percent fall in FEV1 (hypertonic mean +/- 1 SD P, 26.1 +/- 9.5 versus T, 15.6 +/- 14, p = 0.025; hypotonic P, 29.8 +/- 13.1 versus T, 16.6 +/- 13.1, p less than 0.02); (2) the lowest FEV1 percent predicted (%FEV1) (hypertonic P, 61 +/- 13 versus T, 76 +/- 16, p less than 0.005; hypotonic P, 56 +/- 10 versus T, 78 +/- 14, p less than 0.001) documented at the dose common to both placebo and terfenadine test days; (3) the difference in %FEV1 before and after challenge (hypertonic, p less than 0.034; hypotonic, p less than 0.035).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of non-isotonic solutions on human isolated airway smooth muscle.

In patients with asthma, bronchoconstriction can be provoked by the inhalation of aerosols of non-isotonic solutions. In order to determine if this bronchoconstriction results from a direct effect on airway smooth muscle we decided to examine the effects of non-isotonic solutions on the resting tone of human isolated bronchi and on responses to carbachol, histamine and field stimulation. Human bronchi were obtained from thoracotomy and dose-response relationships for each agonist were obtained for bronchial rings suspended in isotonic Krebs-Henseleit solution (290 mOsm). A second curve was then obtained with half the rings immersed in a solution made hypotonic (145 mOsm) or hypertonic (440 mOsm) by the addition of NaCl or salts and glucose. The other half remained in isotonic solutions as controls. In a separate series of experiments, field stimulation responses to a submaximal frequency (15 Hz) were measured before and after a change from isotonic to non-isotonic bathing solution. The resting tone of the preparations was transiently reduced by hypertonic solutions and increased by hypotonic solutions. Contractile responses to agonists were significantly diminished by non-isotonic solutions. Agonist potency was unaffected by hypertonic solutions but the potency of carbachol was reduced by hypotonic solutions. Responses to field stimulation were unaffected by the hypertonic solution but reduced by the hypotonic solution. We conclude that the bronchoconstrictor actions of non-isotonic solutions and their effects on airway reactivity are unlikely to be due to direct effects on airway smooth muscle.

Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation.

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 microM). Adenosine (1-100 microM) produced only very weak contractions, whereas carbachol (EC50 = 0.40 microM), histamine (EC50 = 0.63 microM), prostaglandin D2 (EC50 = 0.50 microM), substance P (EC50 = 4.6 microM) and ATP (1-100 microM) produced much greater ones. 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. Terbutaline, theophylline and enprofylline relaxed carbachol (2.0 microM = EC70)-contracted preparations. Terbutaline (3-3000 nM) relaxed 4 out of 11 bronchioles. Theophylline (10-4000 microM) and enprofylline (1-400 microM) consistently relaxed the bronchiolar preparations including those exhibiting little responsiveness to the beta 2-adrenoceptor agonist. 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. 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.

Substance P antagonists and the role of tachykinins in non-cholinergic bronchoconstriction.

Electrical field stimulation of guinea-pig isolated hilus bronchi induced tetrodotoxin-sensitive contractions of which only a minor part could be inhibited by atropine. The remaining non-cholinergic bronchoconstriction was antagonized by a heptapeptide and an undecapeptide substance P (SP) analogue (Arg5, D-Trp7,9) SP5-11, IC50 = 24.0 microM and (D-Pro2, D-Trp 7,9) SP, IC50 = 10.0 microM. Of the exogenously added tachykinins, both eledoisin (8 times) and physalaemin (3 times) were more potent bronchoconstrictors than SP. Pretreatment with the SP-analogues shifted concentration-response curves to the tachykinins to the right, eledoisin being most readily antagonized. (Arg5, D-Trp 7,9) SP 5-11 also antagonized the neural response more readily than that of SP. In addition, in the frog isolated sciatic nerve preparation the two SP-analogues were found to possess potent lidocaine-like neurodepressant actions which further complicated the interpretation of the neural inhibitory effects of these compounds. It is concluded that if a tachykinin contributes to non-cholinergic bronchoconstriction, an eledoisin-like peptide is a more likely candidate than SP itself. Since SP-antagonists may have local anaesthetic properties their value as tools in neurophysiology seems limited. Inferentially, the non-cholinergic bronchoconstrictive neurotransmitter remains to be identified.

Cholinergic responses in the human lung parenchymal strip: a structure-function correlation.

We have examined the contractile response of the human lung parenchymal strip to carbachol. Responses were highly variable both within and between subjects. In only 50 of the 72 strips studied could a measurable cumulative concentration-response relationship to carbachol be elicited (geometric mean EC50 3.1 x 10(-7) mol/l, 95% confidence limits 2.2, 4.2 x 10(-7) mol/l). In 22 strips, no such response could be elicited. Fifteen lung strips, including some which contracted to carbachol and others which did not, were subjected to morphometric analysis, using a point-counting procedure, to estimate volume proportions of tissue components of the lung strips. There was a significant correlation (r = 0.71, P less than 0.01) between maximal contraction of a strip to carbachol and its volume proportion of airways. These results suggest that the contractile response to carbachol in the human lung parenchymal strip originates from airway smooth muscle.