Slowly Adapting Pulmonary Stretch Receptors Activity Research Articles

Airway Mechanosensor Behavior during Application of Positive End-Expiratory Pressure

Background: Positive end-expiratory pressure (PEEP) is commonly used in clinical settings. It is expected to affect the input from slowly adapting pulmonary stretch receptors (SARs), leading to altered cardiopulmonary functions. However, we know little about how SARs behave during PEEP application. Objectives: Our study aimed to characterize the behavior of SARs during PEEP application. Methods: We recorded single-unit activities from 18 SARs in the cervical vagus nerve and examined their response to an increase of PEEP from 3 to 10 cm H₂O for 20 min in anesthetized, open-chest and mechanically ventilated rabbits. Results: The mean activity of the units increased immediately from 35.7 to 80.5 impulses per second at the fifth breath after increasing PEEP (n = 14, p < 0.001) and then gradually returned to 56.5 impulses per second at the end of 20 min of PEEP application (p < 0.001). In the meantime, peak airway pressure increased from 9.3 to 32.7 cm H₂O, and then gradually returned to 29.4 cm H₂O (n = 18; p < 0.05) after 20 min. The remaining four units ceased firing at 34.7 s (range 10-56 s) after their initial increased activity upon 10 cm H₂O PEEP application. The unit activity resumed as the PEEP was returned to 3 cm H₂O. Conclusions: High PEEP stimulates SARs and SAR activity gradually returns towards the baseline via multiple mechanisms including receptor deactivation, neural habituation and mechanical adaptation. Understanding of the sensory inputs during PEEP application will assist in developing better strategies of mechanical ventilation.

Flecainide inhibits the stimulatory effect of veratridine on the response of airway mechanoreceptors to maintained inflations in rats

Aims The purpose of the present study was to investigate (a) whether maintained inflations result in the inhibition of slowly adapting pulmonary stretch receptor (SAR) discharge to elicit an abrupt change in receptor activity and (b) whether pretreatment with veratridine, a Na + channel opener, and/or flecainide, a Na + channel blocker, alters the responses of SAR properties to maintained inflations. Main methods We measured the properties of SAR activity during maintained inflations at different pressures in 31 anesthetized, artificially ventilated rats with unilateral vagotomy. Key findings During maintained inflations (approximately 5, 10 and 15 cmH 2O) for about 5 s, the procedures did not produce the induction of inhibition of either 16 low-threshold SARs (firing during both inflation and deflation) or 15 high-threshold SARs (firing during inflation only). In these preparations, the excitatory responses of SARs to maintained inflations at three different pressures were markedly enhanced after administration of veratridine (50 μg/kg), but under such conditions, the inhibition of SAR discharges was not observed. In the same SAR preparations, after flecainide treatment (9 mg/kg) sufficient for the blockade of veratridine (50 μg/kg)-induced SAR stimulation, maintained inflations at higher pressures (10 and 15 cmH 2O) greatly inhibited SAR discharges. Under these conditions, the inhibition of SAR discharges was not observed during maintained inflations at 5 cmH 2O. Significance These results suggest that neither low-threshold SARs nor high-threshold SARs in the rat lung are deactivated during maintained inflations at higher pressures.

Effect of ouabain on the afterhyperpolarization of slowly adapting pulmonary stretch receptors in the rat lung

In anesthetized, artificially ventilated rats with one vagus nerve section, the purposes of the present study were to investigate whether release from phasic consecutive hyperinflations (inflation volume = 3 tidal volumes) results in the afterhyperpolarization (AHP) of the slowly adapting pulmonary stretch receptor (SAR) activity and whether the effect of ouabain, a Na +–K + ATPase inhibitor, alters AHP of the SAR activity seen after release from maintained inflations. Release from 10 consecutive phasic hyperinflations did not cause any significant inhibition of SAR activity. Release from maintained inflations (for approximately 10 and 15 cmH 2O) for 5 s produced the induction of disappearance of SAR activity, corresponding with the AHP. Intravenous administration of ouabain (20 and 40 μg/kg) had no significant effects on the responses of SAR activity and SAR adaptation index (AI) to maintained inflations, but ouabain treatment with at 40 μg/kg resulted in a significant increase in the SAR activity after stopping the respirator and significantly attenuated the AHP of the SAR activity. In the immunohistochemical study, we found Na +–K + ATPase α 3-subunit-isoforms-like immunoreactivity in SAR terminals, forming leaflike extensions in the intrapulmonary bronchioles at different diameters, and those terminals were buried in the smooth muscle. In the same sections, the α 1 subunit immunoreactivity of SAR terminals was not found. These results suggest that the mechanism of generating the AHP of SARs is mainly mediated by the activation of Na +–K + ATPase α 3 subunit isoform.

The inhibitory effect of ouabain on the response of slowly adapting pulmonary stretch receptors to hyperinflation in the rabbit

The combined effects of ouabain (Na +–K + ATPase inhibitor) and hyperinflation (inflation volume = three tidal volumes) on slowly adapting pulmonary stretch receptors (SARs) were studied before and after administration of nifedipine (an L-type Ca 2+ channel blocker) and KB-R7943 (a reverse-mode Na +–Ca 2+ exchanger blocker) in anesthetized, artificially ventilated rabbits after bilateral vagotomy. Before ouabain administration, hyperinflation stimulated SAR activity. After 20 min of ouabain administration (30 μg/kg) the SARs increased discharge rates in normal inflation. Under these conditions, hyperinflation initially stimulated SAR activity but subsequently inhibited the activity at peak inflation. Additional administration of 60 μg/kg ouabain (total dose = 90 μg/kg) caused a further stimulation of SAR activity, but 20 min later both normal inflation and hyperinflation resulted in a greater inhibition of the receptor activity. The hyperinflation-induced SAR inhibition in the presence of ouabain (30 μg/kg) was not significantly altered by administration of either nifedipine (2 and 4 mg/kg) or KB-R7943 (1 and 3 mg/kg). In another series of experiments, we further examined the combined effects of ouabain and hyperinflation in veratridine (a Na + channel opener, 40 μg/kg)-treated animals. After recovery from the veratridine effect on SAR activity, which vigorously stimulated the receptor activity, ouabain treatment (30 μg/kg) that silenced the receptor activity at peak inflation greatly inhibited hyperinflation-induced SAR stimulation. These results suggest that hyperinflation-induced SAR inhibition in the presence of ouabain may be related to a Na + overload, but not to a Ca 2+ influx via activation of L-type Ca 2+ channels, in the SAR endings.

Excitatory mechanism of deflationary slowly adapting pulmonary stretch receptors in the rat lung.

The excitatory responses of deflationary slowly adapting pulmonary stretch receptor (SAR) activity to lung deflation ranging from approximately -15 to -25 cm of H(2)O for approximately 5 s were examined before and after administration of flecainide, a Na(+) channel blocker, and K(+) channel blockers, such as 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The experiments were performed in anesthetized, artificially ventilated rats after unilateral vagotomy. The deflationary SARs increased their activity during lung deflation and its effect became more pronounced by increasing the degree of negative pressure. During lung deflation the average values for the deflationary SAR adaptation index (AI) were below 40%. Intravenous administration of veratridine (50 microg/kg), an Na(+) channel opener, stimulated deflationary SAR activity: one maintained excitatory activity mainly during deflation and the other receptors showed a tonic discharge during both deflation and inflation. Despite the difference in deflationary SAR firing patterns after veratridine administration, flecainide treatment (6.0 mg/kg) blocked veratridine-induced deflationary SAR stimulation and also caused strong inhibition of the excitatory responses of deflationary SARs to lung deflation. Under these conditions, the average values for deflationary SAR AI were over 90%. The responses of deflationary SARs and deflationary SAR AI to lung deflation were not significantly altered by pretreatment with either 4-AP (0.7 and 2.0 mg/kg) or TEA (2.0 and 6.0 mg/kg). These results suggest that the excitatory effect of lung deflation on deflationary SAR activity is mediated by the activation of flecainide-sensitive Na(+) channels on the nerve terminals of deflationary SARs.

Effects of sodium and potassium channel blockers on hyperinflation-induced slowly adapting pulmonary stretch receptor stimulation in the rat

The excitatory responses of slowly adapting pulmonary stretch receptor (SAR) activity to hyperinflation (inflation volume = 3 tidal volumes) for approximately 10 respiratory cycles were examined before and after administration of flecainide, a Na + channel blocker, and 4-aminoprydine (4-AP), a K + channel blocker. The experiments were performed in anesthetized, artificially ventilated rats after unilateral vagotomy. During hyperinflation the SARs increased their activity during inflation and decreased their discharge during deflation. The magnitude of increased SAR activity during inflation became more prominent as compared to that of decreased receptor activity during deflation. Flecainide treatment (6 mg/kg) that was sufficient to block veratridine (50 μg/kg)-induced SAR stimulation did not significantly alter the excitatory response of SAR activity to hyperinflation. Subsequent administration of 3 mg/kg flecainide (a total dose, 9 mg/kg) resulted in a greater inhibition of hyperinflation-induced SAR stimulation. Although administration of 4-AP (2 mg/kg) usually stimulated SAR activity, particularly in the deflation phase, in the control ventilation, 4-AP treatment had no significant effect on hyperinflation-induced SAR stimulation. These results suggest that the excitatory effect of hyperinflation on SAR activity may not be involved in the activation of either flecainide-sensitive Na + channels or 4-AP-sensitive K + channels.

Inhibitory mechanism of slowly adapting pulmonary stretch receptors after release from hyperinflation in anesthetized rabbits

In anesthetized, artificially ventilated rabbits with vagus nerve section, release from 10 consecutive hyperinflations (inflation volume = 3 tidal volume) caused an inhibition of the slowly adapting pulmonary stretch receptor (SAR) activity for 16–22 sec. Intravenous administration of tetraethylammonium (TEA, 10 and 20 mg/kg), a K + channel blocker, did not significantly alter either basal SAR discharge or tracheal pressure (P T). Although TEA treatment at 10.0 mg/kg had no significant effect on the magnitude and duration of inhibited SAR activity seen after release from hyperinflation, the increasing dose of this K + channel blocker up to 20 mg/kg inhibited these effects of the receptor activity but this inhibition was small. The Na +-K + ATPase inhibitor ouabain (5 and 10 μg/kg) that had no significant effect on SAR activity and P T in the control abolished or attenuated the inhibitory action of SARs in a dose-dependent manner. Furthermore, the changes in dynamic lung compliance (Cdyn) and P T in response to post-hyperinflation were not significantly influenced by pretreatment with either TEA or ouabain. These results suggest that the inhibitory action of receptors seen during post-hyperinflation corresponded with the induction of slow afterhyperpolarization (sAHP), and that the mechanism of generating the sAHP of SARs is mainly mediated by the activation of Na +-K + pump activity.

Effects of ouabain and flecainide on CO 2-induced slowly adapting pulmonary stretch receptor inhibition in the rabbit

The inhibitory effect of CO 2 on slowly adapting pulmonary stretch receptors (SARs) was examined before and after administration of ouabain, a Na +7z.sbnd;K + ATPase inhibitor, and flecainide, a Na + channel blocker. The experiments were performed in anesthetized, artificially ventilated rabbits after vagus nerve section. CO 2 inhalation (maximal tracheal CO 2 concentration ranging from 9.2 % to 10.4 %) for about 60 sec decreased the receptor activity during both inflation and deflation. The magnitude of decreased SAR activity during deflation was greater than that seen during inflation. Administration of ouabain (25 μg/kg) initially stimulated SAR activities during inflation and deflation, and after 20 min, the SAR response was still kept excitatory in both inflation and deflation phases. Under these conditions, CO 2 inhalation inhibited SAR activities during inflation and deflation. Flecainide treatment (3 mg/kg) that abolished veratridine (30 μg/kg)-induced SAR excitation had no significant effect on the inhibitory responses of SAR activity to CO 2. These results suggest that the inhibitory effect of CO 2, occurs when ouabain results in intracellular Na + concentration ([Na +] i) increases in the SAR endings, and that CO 2-induced SAR inhibition may not be related to the reduction of influx of Na + through voltage-gated Na + channels.

Excitatory mechanism of veratridine on slowly adapting pulmonary stretch receptors in anesthetized rabbits

The excitatory effects of veratridine on slowly adapting pulmonary stretch receptors (SARs) were studied before and after administration of ouabain (a Na +-K + ATPase inhibitor) in anesthetized, artificially ventilated rabbits after vagus nerve section. Administration of veratridine (40 μg kg ) stimulated SAR activity but did not significantly alter tracheal pressure. Administration of ouabain (50 μg kg ) initially stimulated SAR activity during both inflation and deflation, but after 20 min, two different types of SAR responses were observed; one became silent at the peak, of inflation only, and the other maintained excitatory activity during both inflation and deflation phases. Veratridine usually inhibited SAR activity in ouabain-treated animals, irrespective of the difference of ouabain effects. These results suggest that veratridine-induced stimulation of SARs is closely related to the change in the Na + ion gradient, which is regulated by Na + pump activity.

Effects of vagal stimulation on slowly adapting pulmonary stretch receptors and lung mechanics in anesthetized rabbits.

An in vivo preparation was designed to investigate the effect of vagus nerve stimulation-induced bronchoconstriction on the relationship of slowly adapting pulmonary stretch receptor (SAR) activity and lung mechanics. SAR activities were recorded from the left vagus nerve. The responses of SARs, total lung resistance (RL), and dynamic lung compliance (Cdyn) to electrical stimulation of the peripheral end of the cut right vagus nerve (10-15 V, 5-30 Hz, 0.2 ms) were examined before atropine and 5 and 10 min after atropine (2 mg/kg) in anesthetized, artificially ventilated, bilaterally vagotomized rabbits. In the time course profile during vagal stimulation, an increase in RL and a decrease in Cdyn occurred simultaneously, and these opposite changes were frequency dependent. The average responses of SAR activity, RL, and Cdyn to vagal stimulation became more pronounced as the frequencies of the stimulation were increased. The responses obtained during vagal stimulation (5-30 Hz) were blocked or diminished greatly by the administration of atropine. Repeated vagus nerve stimulation in the presence of atropine did not show any significant change in SAR activity and lung mechanics. These results suggest that changes of SAR activity, RL, and Cdyn induced by vagal stimulation occur as a result of smooth muscle contraction in the airways, which is mediated mainly by muscarinic receptor activation and which is not involved in the release of neurotransmitters to relax airway smooth muscle.

Effects of pulmonary air embolism on discharge of slowly adapting pulmonary stretch receptors

Pulmonary air embolism (PAE) usually causes small-airway collapse. Local transpulmonary pressure (Ptr) is thought to be closely associated with the activity of slowly adapting pulmonary stretch receptors (SAPSRs). To test whether discharge of SAPSRs located distal to collapsed airways is closely related to the overall Ptr, we studied 65 SAPSRs in anesthetized paralyzed open-chest dogs that were ventilated at constant tidal volume and frequency. PAE increased both Ptr and total pulmonary resistance but decreased dynamic lung compliance. Three groups of SAPSRs were identified on the basis of their locations in intrapulmonary airways. Group I had 29 SAPSRs located in airways < 1 mm in diameter. Group II had 10 SAPSRs that were found in intrapulmonary airways between 1 and 2 mm in diameter. PAE decreased the activity of 31 of the 39 SAPSRs in these two groups. Their activity during PAE was not related to Ptr. The 26 SAPSRs in group III were in airways > 2 mm in diameter. PAE increased the peak firing rate of 18 of these receptors, and there was a close relationship between the discharge frequency of these SAPSRs and the Ptr during PAE. In groups I and II, the dissociation between Ptr and SAPSR activity during PAE may have been caused by peripheral airway collapse. Activity of central fibers was blocked at higher temperatures than activity of peripheral fibers. We suggest that the response of a SAPSR to PAE depends on the location of the receptor within the lungs, and we speculate that threshold and fiber type are also related to location.

Effects of calcium channel and H1-receptor blockers on the responses of slowly adapting pulmonary stretch receptors to histamine in vagotomized rabbits

We studied the effects of calcium channel antagonists (verapamil and nifedipine) and H1-receptor blockers (mequitazine) on changes in the slowly adapting pulmonary stretch receptors (SARs) located below the carina in response to right atrial injections of histamine (60 and 80 micrograms/kg) in anesthetized artificially ventilated rabbits with bilateral vagotomy. After histamine was injected into the right atrium, the SARs became more active during expiration but decreased their activity during inspiration. These changes were more pronounced by increasing the dosage of histamine. However, administration of histamine had no significant effect on tracheal pressure (PT). Verapamil treatment (1 mg/kg) did not alter the SAR response to histamine, whereas the responses of SARs to histamine at different dosages were significantly diminished by treatment with nifedipine (1 mg/kg). Mequitazine (1 mg/kg), a potent H1-receptor blocker, blocked completely all the responses of SAR activity to histamine. These results suggest that the effect of histamine 60-80 micrograms/kg on SAR activity is mediated by the activation of H1-receptors of the peripheral airway smooth muscle and that this activation, at least in part, involves the opening of calcium channels of the airway smooth muscle.

Cholinergic and H 1-receptor influences of histamine on slowly adapting pulmonary stretch receptor activity in the rabbit

Afferent impulses of slowly adapting pulmonary stretch receptors (SARs) were obtained by dissecting fine slips from the left vagus nerve (LVN) and by leaving the rest of the nerve intact. In the same SAR preparation, changes of the receptor activity in response to right atrial injections of histamine (10 and 60 μg/kg) were successively examined before and after atropine (1 mg/kg), partial vagal efferent ablation, and mequitazine (1 mg/kg) in 10 rabbits. Administration of histamine led to an increase in the SAR activity, and this effect became more pronounced by increasing the dose of histamine. Atropine treatment diminished the responses of SARs to histamine at different doses. Partial vagal efferent ablation produced by denervation of the rest of the intact LVN slightly reduced the response of SARs to histamine at 10 μg/kg but had no significant effect on the SAR response to 60 μg/kg histamine. In the absence of vagal afferent and efferent activities on the left side, mequitazine, a potent H 1-receptor blocker, completely blocked low- and high-dose effects of histamine on SARs. We compared the responses of the receptor activity to aerosol histamine (1 and 4%) and to topical application of histamine (0.1 ml, 0.025% and 0.1%) in six SAR preparations. The magnitude and duration of increased SAR activity became more prominent by increasing the concentration of histamine. The firing pattern and discharge rate of SARs following aerosol or intratracheal administration of histamine were similar to those after intra-atrial histamine. In addition, we also examined the excitatory responses of SAR activity to right atrial injections of histamine at 10 and 60 μg/kg before and after topical administration of atropine (0.1 ml, 1%, n − 6) or mequitazine (0.1 ml, 1%, n = 6) in 12 SAR preparations. Intratracheal atropine diminished the response of SARs to 10 μg/kg of histamine but had no significant effect on the response of SARs to histamine at 60 μg/kg. All the responses of SARs to histamine were completely blocked by topical application of mequitazine. These results suggest that the change of SAR activity produced by histamine at 10 μg/kg occurs mainly as a result of the release of acethylcholine (ACh) via the vagovagal reflex and that the activation of H 1-receptors of the airway smooth muscle contributes importantly to the response of SARs to histamine at 60 μg/kg.

II. Effect of CO 2 on afferent vagal endings in the canine lung

We have attempted to identify the afferent endings responsible for the pulmonary-CO 2 ventilatory reflex. We recorded afferent vagal impulses arising from the left lung in anesthetized dogs with separately ventilated lungs. When the left pulmonary artery was occluded, left lung P CO 2 fell to 3 mm Hg and slowly-adapting pulmonary stretch receptor activity increased 46%. Firing declined to its original intensity when left lung P CO 2 was raised in steps by administration of CO 2, firing decreasing most between 2 and 19 mm Hg, and least between 30 and 50 mm Hg. Irritant receptor activity also increased (from 2.8 to 7.4 impulses/sec) after pulmonary arterial occlusion, the effect being reversed by administration of CO 2. These procedures caused trivial changes in pulmonary and bronchial C-fiber activity. Effects on both slowly-adapting stretch receptors and irritant receptors appeared to result from a direct action of CO 2 on the endings themselves, rather than from mechanical changes in the lung. Changes in slowly-adapting stretch receptor activity provide an adequate explanation for the pulmonary CO 2 ventilatory reflex, the relationship between impulse frequency and lung P CO 2 suggesting that these afferents may have a role in limiting CO 2 loss under conditions causing hypocapnia, but be less effective in stimulating breathing during hypercapnia.