Sympatho-excitatory response to pulmonary chemosensitive spinal afferent activation in anesthetized, vagotomized rats

Abstract

The sensory innervation of the lung is well known to be innervated by nerve fibers of both vagal and sympathetic origin. Although the vagal afferent innervation of the lung has been well characterized, less is known about physiological effects mediated by spinal sympathetic afferent fibers. We hypothesized that activation of sympathetic spinal afferent nerve fibers of the lung would result in an excitatory pressor reflex, similar to that previously characterized in the heart. In this study, we evaluated changes in renal sympathetic nerve activity (RSNA) and hemodynamics in response to activation of TRPV1‐sensitive pulmonary spinal sensory fibers by agonist application to the visceral pleura of the lung and by administration into the primary bronchus in anesthetized, bilaterally vagotomized, adult Sprague‐Dawley rats. Application of bradykinin (BK) to the visceral pleura of the lung produced an increase in mean arterial pressure (MAP), heart rate (HR), and RSNA. This response was significantly greater when BK was applied to the ventral surface of the left lung compared to the dorsal surface. Conversely, topical application of capsaicin (Cap) onto the visceral pleura of the lung, produced a biphasic reflex change in MAP, coupled with increases in HR and RSNA which was very similar to the hemodynamic response to epicardial application of Cap. This reflex was also evoked in animals with intact pulmonary vagal innervation and when BK was applied to the distal airways of the lung via the left primary bronchus. In order to further confirm the origin of this reflex, epidural application of a selective afferent neurotoxin (resiniferatoxin, RTX) was used to chronically ablate thoracic TRPV1‐expressing afferent soma at the level of T1–T4 dorsal root ganglia pleura. This treatment abolished all sympatho‐excitatory responses to both cardiac and pulmonary application of BK and Cap in vagotomized rats 9–10 weeks post‐RTX. These data suggest the presence of an excitatory pulmonary chemosensitive sympathetic afferent reflex. This finding may have important clinical implications in pulmonary conditions inducing sensory nerve activation such as pulmonary inflammation and inhalation of chemical stimuli.

Mechanisms underlying the stimulatory effect of inhaled sulfur dioxide on vagal bronchopulmonary C‐fibres

“…recently demonstrated a sympathetic pressor reflex response that was elicited by application of capsaicin to the visceral pleura surface of the lungs or into the primary bronchus in vagotomized rats, clearly pointing to an involvement of stimulation of TRPV1 receptors expressed in the sympathetic spinal pulmonary afferents (Shanks et al . ). Whether and to what extent this reflex mechanism plays a part in the SO 2 ‐induced increase in ABP observed in this study remains to be determined.…”

Resiniferatoxin (RTX) ameliorates acute respiratory distress syndrome (ARDS) in a rodent model of lung injury

“…In a pilot experiment, the upper thoracic spinal afferents were ablated by epidural application of RTX as previously described. 11 Briefly, rats were anesthetized using 2%-3% isoflurane:oxygen mixture. Rats were placed in the prone position and a small midline incision was made in the region of the T13-L1 thoracic vertebrae.…”

“…8,9 On the other hand, activation of spinal afferents tends to be sympathoexcitatory and pro-inflammatory. [10][11][12][13][14][15] It is well known that small diameter spinal Transient Receptor Vanilloid 1 (TRPV1)-positive afferent c-fibers contain neuropeptides such as substance P (SP) and calcitonin gene related peptide (CGRP). 16 These peptides tend to dilate adjacent vasculature and increase microvascular permeability.…”

Sympathoexcitation in response to cardiac and pulmonary afferent stimulation of TRPA1 channels is attenuated in rats with chronic heart failure

“…Using an experimental design similar to CSAR activation, we recently demonstrated that topical application of bradykinin and capsaicin directly to the lung visceral pleura results in a sympathetic reflex in anesthetized, vagotomized, open-chested rats (33). This reflex, to the best of our knowledge previously undescribed, includes increases in MAP, HR, and RSNA (33). We named this reflex the pulmonary spinal afferent reflex (PSAR).…”

“…We named this reflex the pulmonary spinal afferent reflex (PSAR). We know that both the PSAR and CSAR originate at the level of T1ϪT4 DRG, which provide sensory afferent innervation to the heart and lung, because chemical denervation of T1ϪT4 DRG sensory afferents with the potent neurotoxin resiniferatoxin abolishes both reflexes (33,49). However, whether pulmonary spinal sensory afferents are also sensitive to TRPA1 receptor agonists remains unknown.…”