Journal of Applied Physiology
Vol. 81, No. 6, pp. 2347-2348, December 1996

Invited Editorial on "Pulmonary chemoreflex elicited by intravenous injection of lactic acid in anesthetized rats"

Giuseppe Sant'Ambrogio

Department of Physiology and Biophysics, University of Texas Medical Branch, Galveston, Texas 77555-0641

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THE PAPER IN THIS ISSUE by Lu-Yuan Lee et al. (11) investigates the reflex changes that occur after intravenous administration of lactic acid. Intravenous injection of a great number of chemical compounds has been tried since the original experiments of von Bezold and Hint in 1867 (see Ref. 5); these authors found that intravenous veratrine elicited a remarkable drop in heart rate and blood pressure, with a sudden and brief respiratory arrest. This triad of responses (bradycardia, hypotension, and apnea) is at present described as the "pulmonary chemoreflex." An emerging consensus attributes a preponderant role to vagal afferents innervating respiratory viscera. Indeed, a pulmonary chemoreflex can also be elicited by administering the triggering agent via aerosolization or intraluminal airway instillation (13). Both procedures exclude an immediate and direct access of the active chemical to cardiovascular structures, thereby justifying the definition of pulmonary chemoreflex.

There are several substances that, administered intravenously, are capable of inducing bradycardia, hypotension, and apnea. A few of them are normal body constituents, but the majority are not. The classic triad of bradycardia, hypotension, and apnea does not include additional and important phenomena such as bronchoconstriction, mucus secretion, and laryngospasm, yet these responses are frequently seen. The variety of compounds capable of evoking the pulmonary chemoreflex with their diverse nature (e.g., potato starch, serotonin, nicotine, air embolism, hypertonic solutions, veratridine, phenylbiguanide, capsaicin) does not suggest any special structural or functional requirements. Perhaps the one common characteristic is their potential for causing harmful effects. One must also realize that intravenous injection cannot be described a "natural" route of administration! In the end, we are left with a powerful reflex leading to dramatic changes without a clear purpose. In fact, whereas apnea, bronchoconstriction, and mucus secretion could be viewed as protective and/or defensive reactions, bradycardia and hypotension are more difficult to justify as parts of a coordinated and purposeful response. Comroe (4) suggested that bradycardia and hypotension provided a "protective collapse mechanism in response to visceral injury." In any event, chemical compounds such as capsaicin and phenylbiguanide are, at present, widely used experimentally for their capability of activating C-fiber endings and for triggering the corresponding reflex responses. Actually, injection of these substances is the standard procedure to identify these endings and to characterize their reflex responses. Major objections about this methodology are the dependency on an extraneous compounds and related reflex responses, the specificity of which is still controversial (8).

Beyond the anaerobic threshold. In the study by Lee and associates (11), lactic acid has been used as the agent to induce the pulmonary chemoreflex. Lactic acid is a normal body constituent having an effectiveness as a stimulant of sensory endings in different organs such as the heart, abdominal viscera, and limb muscles that is well established. For this reason, the choice of this compound, already used in previous studies (6, 16), is of a potentially appealing physiological and/or pathophysiological interest. As a first step, the authors intended to characterize the cardiorespiratory responses evoked by intravenous bolus injection of lactic acid to see whether a pulmonary chemoreflex was evoked. This would suggest the involvement of C-fiber endings in the reflex response. The authors also demonstrated that perineural application of capsaicin on the vagus nerves, a procedure capable of selectively blocking conduction in C fibers without impairing myelinated A fibers, could definitely abolish the pulmonary chemoreflex. These results should identify the pulmonary and bronchial C-fiber endings as the sole sensors activating the pulmonary chemoreflex. Lee and co-workers were also able to record C-fiber endings activity in response to intravenous injection of lactic acid, giving further and more direct support to their conclusion.

Which C fiber? Two populations of C-fiber endings have been described in the respiratory tract: "bronchial" and "pulmonary" (2). The primary criterion for their identification as bronchial or pulmonary is based on their preferential circulatory accessibility through the systemic or the pulmonary circulation, respectively. Other differences include a greater mechanosensitivity of pulmonary C-fiber endings (2, 10) and a greater responsiveness of bronchial C-fiber endings to bradykinin (9). However, even if the more accepted view limits the access of the pulmonary blood to the more peripheral pulmonary structures (bronchioles, gas-exchanging areas), this notion has not been left without challenges. In fact, it has been shown that pulmonary blood perfuses a significant portion of large intrapulmonary bronchi and even extrapulmonary bronchi (1). Moreover, some of the vagal receptors located in large intrapulmonary airways have been found to have a preferential accessibility through the pulmonary circulation (14). Therefore, it would seem reasonable to suggest that the definition of pulmonary or bronchial C-fiber receptors should not be based solely on anatomic grounds.

Concerning the reflexogenic individuality of bronchial and pulmonary C-fiber receptors, we may consider the experimental results that show that cardiorespiratory responses, qualitatively similar to those of the pulmonary chemoreflex, can be evoked even when tracheobronchial receptors are stimulated, either preferentially, as with aerosol and intrathoracic tracheal instillation, or even exclusively, as with extrathoracic tracheal instillation (13). Moreover, experiments in which bradykinin, a selective stimulant of bronchial C-fiber endings, was directly injected into a bronchial artery or administered as an aerosol into the lower airway also show that "tracheobronchial C-fiber endings" have cardiorespiratory effects generally similar to those of pulmonary C-fiber receptors (3). These studies suggest that capsaicin-sensitive endings, irrespective of their location within the lower respiratory tract, evoke similar reflex responses. Furthermore, Hamilton et al. (7) have shown that the pulmonary chemoreflex, elicited by intravenous capsaicin in dogs, can be blocked more effectively by large-particle aerosols of topical anesthetics compared with small-particle aerosols. Because large-particle aerosols are deposited predominantly in larger airways (7), this observation suggests a greater role for C-fiber endings located in larger airways. The fact that C-fiber endings have a predominant location in the more proximal branches of the tracheobronchial tree could also be implied by the results of McDonald (12). He found that the antidromic stimulation of the cervical vagus nerve of rats could induce a neurogenic inflammatory process limited to the trachea and the first four generations of bronchi, indicating the local release of vasoactive neuropeptides by C-fiber endings. Again, these results suggest a predominant location of C-fiber afferents in the larger conducting airways. Also the results by Shimosegawa and Said (15), who studied the incidence and distribution of epithelial calcitonin gene-related peptide immunoreactivity in the respiratory tract of normal and capsaicin-pretreated rat, are consistent with the above-proposed view. Although a separation between bronchial and pulmonary C-fiber endings might still be justified, it should not be construed as indicating a precise anatomic location. Particularly dubious is an alveolocapillary location ("pulmonary") of nerve endings in a region, the lung parenchyma, found to contain very few nerve fibers (17).

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