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It has been recently reported that pulmonary reflex responses to injection or inhalation challenge of capsaicin are enhanced by exogenous Prostaglandin E(2) (PGE(2)). The present study was carried out to determine whether PGE(2) enhances the stimulatory effects of chemical stimulants and lung inflation on vagal pulmonary C fibers, and if so, whether the excitabilities of other types of lung afferents are also augmented by PGE(2). In anesthetized, open-chest rats, administration of PGE(2) (1.5 microgram/kg/min for 2 min) did not significantly change the baseline activity of vagal pulmonary C fibers, but it markedly enhanced the stimulatory effects of both low (0.25 microgram/kg) and high doses (0.5 microgram/kg) of capsaicin on these fibers. Similarly, potentiating effects of PGE(2) were found on the pulmonary C-fiber responses to injections of lactic acid and adenosine, although considerable variability existed in the degrees of potentiation between the different stimulants. Furthermore, PGE(2) infusion also significantly enhanced the C-fiber response to constant-pressure lung inflation (tracheal pressure [Pt] = 30 cm H(2)O). In contrast, PGE(2) did not alter the responses of either slowly adapting pulmonary receptors or rapidly adapting pulmonary receptors to lung inflation. In summary, these results show that the sensitivity of pulmonary C-fiber afferents to both mechanical and chemical stimuli is enhanced by PGE(2), suggesting that endogenous release of this autocoid may play a part in the airway irritation and dyspneic sensation associated with airway inflammation.

1. Intravenous administration of adenosine (Ado) to patients can cause dyspnoea, chest discomfort and bronchoconstriction. To assess the role of vagal pulmonary C fibres in evoking these adverse reactions, the effect of Ado on single pulmonary C fibres was studied in anaesthetized and artificially ventilated rats. 2. Right-atrial injection of Ado (320 microg kg-1) activated 68 % (73/107) of pulmonary C fibres; the total number of action potentials during a period of 15 s increased from a baseline of 0.2 +/- 0.1 impulses to a peak of 16.4 +/- 2.6 impulses (P < 0.01, n = 107) after Ado. Inosine, the metabolite of Ado, did not activate any of eleven C fibres tested in six rats. Furthermore, C fibres were activated only by right-atrial and not by left-ventricular injection of the same dose of Ado. 3. Unlike the immediate and transient stimulation of C fibres by capsaicin, the C fibre stimulation by Ado had a latency of 6.5 +/- 0.3 s (range, 3-18 s) and lasted longer. 4. The stimulation of C fibres by Ado was significantly attenuated by pretreatment with aminophylline, a non-selective Ado receptor antagonist, was completely prevented by 1,3-dipropyl-8-cyclopentylxanthine, an Ado A1 receptor antagonist, but was unaffected by 3,7-dimethy-1-propargylxanthine, an A2 receptor antagonist. None of these Ado receptor antagonists prevented capsaicin-induced C fibre stimulation. 5. In conclusion, Ado stimulates pulmonary C fibre terminals through an activation of A1 receptors. The stimulation of pulmonary C fibres may play an important role in Ado-induced adverse respiratory effects.

The clinical use of adenosine is commonly associated with pulmonary side effects, namely dyspnea, that suggest the possible involvement of bronchopulmonary sensory afferents. Our objective in this study was to characterize the effects of adenosine on breathing and to determine whether the vagal pulmonary afferents play a role in mediating these effects. We measured respiratory and cardiovascular changes in anesthetized, spontaneously breathing rats after bolus injections of adenosine at therapeutic doses. Right atrial injection of adenosine (0.04-0.6 mg/kg) elicits, in a dose-dependent manner, a pulmonary chemoreflex-like response consisting of a delayed apnea, bradycardia, and hypotension. In contrast, the classic capsaicin-elicited pulmonary chemoreflex occurs immediately after injection. Perineural capsaicin treatment of the cervical vagi blocked the adenosine-induced respiratory inhibition. Left ventricular administration of adenosine failed to elicit an apneic response. Pretreatment with the adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine attenuated the adenosine-induced apnea. These results indicate that adenosine elicits a respiratory inhibition via stimulation of pulmonary C fibers and that activation of the A1-receptor is probably involved. It is unclear, however, what accounts for the exceedingly long latency in this response.

1. The contributions of H+ and lactate ions to the stimulation of single pulmonary C fibres by lactic acid were examined in anaesthetized and artificially ventilated rats. 2. Lactic acid injected into the right atrium caused a transient decrease in arterial blood pH (pHa) and a short but intense burst of afferent activities in pulmonary C fibres, whereas sodium lactate had no effect. The fibre activity usually reached a peak within 1-1.5 s, with an onset latency of < 1 s, and returned to the baseline in 5 s. 3. The injection of hydrochloric acid at the same pH as that of lactic acid did not significantly decrease pHa, nor did it stimulate any C fibres studied. 4. Formic acid has a pKa value (the negative logarithm of the dissociation constant) almost identical to that of lactic acid; thus, its injection decreased pHa to the same degree as did the injection of lactic acid. However, the response of C fibres to lactic acid was 134% stronger than that to formic acid. 5. We conclude that H+ is primarily responsible for the activation of pulmonary C fibres by lactic acid, probably through a direct effect of H+ on these afferent endings. The lactate ion, by itself, does not activate C fibres, but it seems to potentiate the stimulatory effect of H+ on these afferents.