Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.
In seven normal subjects we investigated whether a nonadrenergic bronchodilator nervous system is demonstrable in humans in vivo. After inhalation of leukotriene D4 (LTD4), respiratory resistance (Rrs) increased by 115 +/- 11% (SE). Subsequent inhalation of 2 nmol of capsaicin induced coughing and a fall in Rrs of 22.1 +/- 2% (P less than 0.01). However, inhalation of the diluent of capsaicin, 10% saline-ethanol, decreased Rrs similarly. These bronchodilator responses were not altered by inhaled ipratropium bromide (120 micrograms) and oral propranolol (80 mg). After ipratropium and propranolol, voluntary coughing alone decreased Rrs by 25 +/- 3% (P less than 0.05). We next investigated whether these bronchodilator responses could be blocked by anesthesia of the airways with inhaled lidocaine. After inhalation of lidocaine and LTD4, capsaicin aerosol induced coughing and a transient increase in Rrs of 18 +/- 6% (P less than 0.05) but no bronchodilation. Inhalation of saline-ethanol (n = 4) and a deep inhalation (n = 6) decreased Rrs by 18 +/- 4% (P less than 0.05) and 34 +/- 3% (P less than 0.001), respectively. We conclude that in normal subjects a nonadrenergic, noncholinergic bronchodilator mechanism exists, which can be activated by inhalation of capsaicin and inhibited by local anesthesia.
We investigated whether stimulation of vagal afferent nerve fibers with inhaled capsaicin could induce a nonadrenergic inhibitory reflex in nine mild asthmatic subjects. Changes in total respiratory resistance (Rrs) were measured with a forced oscillation technique. First we induced a rise of 71 +/- 15% in Rrs (P less than 0.001) after leukotriene D4 aerosol. Subsequent inhalation of capsaicin (2 nmol) caused no significant change in mean Rrs of -1.1 +/- 8.2%. After the muscarinic receptor antagonist ipratropium bromide (120 micrograms) was inhaled, leukotriene D4 increased Rrs by 103 +/- 9% (P less than 0.001). Capsaicin subsequently caused bronchodilation in all subjects (Rrs = -22.3 +/- 2.7%, P less than 0.001). Ethanol-saline (diluent) alone caused a nonsignificant fall in Rrs (-9.9 +/- 4.7%) but a deep breath and coughing resulted in bronchodilation (-16.9 +/- 6.1%, P less than 0.05 and -11.6 +/- 2.9%, P less than 0.01, respectively). As observed in normal subjects, capsaicin may initiate an inhibitory reflex, presumably of nonadrenergic origin. This reflex could not be distinguished from that caused by coughing or by deep inhalation. A defect in nonadrenergic mechanisms, at least in mild asthma, seems unlikely.
In a companion paper, we have found that the alveolar epithelial basal lamina, endothelial basal lamina and both fused were significantly thicker in 6 autopsied diabetics than in 6 control subjects. The purpose of the present work was to assess whether these lesions have detrimental effects on gas exchange. We investigated 20 life-long nonsmoking subjects: 10 healthy subjects and 10 insulin-dependent diabetics. All of them had one to four diabetic complications of the following organs: kidney, retina, nerves or arteries. Their pulmonary gas exchange and their transfer factor were measured at rest and during two levels of submaximal exercise. Spirometric data, specific airway conductance, transfer factor, transfer coefficient, oxygen consumption and arterial blood gases were normal and almost identical in both groups. In conclusion, the thickening of lung basal laminae has no detrimental effect on pulmonary gas exchange in insulin-dependent diabetics with peripheral complications.
The bronchodilating effect of Duovent® (0.2 mg fenoterol + 0.8 mg ipratropium bromide) was compared with that of each of its components at the same doses. Twenty patients were included in the trial. Maximum expiratory flow-volume curves with air and helium-oxygen, intrathoracic gas volume and airway conductance were used for assessing the bronchomotor tone before and 15, 30, 60, 240 and 360 min after drug administration. All the drugs showed a significant bronchodilating effect. No differences between Duovent and fenoterol or ipratropium bromide were observed except a slight but statistically significant greater decrease of ITGV with Duovent. When expressing the data as percentage variation of the initial values, Duovent induced a better effect than the other drugs. The evaluation of density dependence was highly disappointing, and no conclusion can be drawn.
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