Involvement of the fastigial nuclei in vagally mediated respiratory responses

Xu, Fadi, and Donald T. Frazier. Involvement of thefastigial nuclei in vagally mediated respiratory responses.J. Appl. Physiol. 82(6):1853-1861, 1997.Previous studies have demonstrated that thecerebellum, especially the fastigial nucleus (FN), is capable ofmodulating respiratory responses to chemical and mechanical stimuli.Because there is evidence to show projections from vagal afferents tothe FN, the goal of this study was to determine the role of the FN inthe respiratory reflexes elicited by activation of vagal afferents.Experiments were performed in anesthetized (chloralose), paralyzed, andartificially ventilated cats with an occipital exposure of thecerebellum. Administration of capsaicin (Cap; 5-10 µg/kg) viathe right external jugular vein at the end of inspiration andapplication of lung inflation (LI; 10 cmH₂O) during inspiration werecarried out to stimulate nonmyelinated and myelinated vagal afferents,respectively. The phrenic neurogram was recorded as anindex of the respiratory motor output. Control cardiorespiratoryvariables [expiratory duration(TE), arterial bloodpressure] and their immediate responses to stimuli were comparedbefore and after bilateral lesions of the FN. The results showed thefollowing. 1) Capinjection and LI resulted in a dramatic increase inTE (apnea).2) FN lesions did not significantlyalter the control TE; however,the apneic duration induced by Cap injection was prolonged.3) Neither FN lesions norcerebellectomy affected the apneic duration that resulted fromapplication of LI. 4) Cold blockadeof the vagi (6-8°C) eliminated the respiratory responses elicited by LI but not Cap injection; vagotomy abolished the responses to both stimuli. 5) FN lesions didnot change the control ABP or its responses to either LI or Capinjection. It is concluded that the FN is involved in vagally mediatedrespiratory reflexes elicited by activation of nonmyelinated (C-fiber)vagal afferents.

     

Stimulation of vagal pulmonary C fibers by inhaled wood smoke in rats

Lai, C. J., and Y. R. Kou. Stimulation of vagalpulmonary C fibers by inhaled wood smoke in rats. J. Appl. Physiol. 84(1): 30-36, 1998.This studyinvestigated the stimulation of vagal pulmonary C fibers (PCs) by woodsmoke. We recorded impulses from PCs in 58 anesthetized, open-chest,and artificially ventilated rats and delivered 6 ml of wood smoke intothe lungs. Within 1 or 2 s after the smoke delivery, an intense andnonphasic burst of discharge [ = +7.4 ± 0.7 (SE)impulses/s, n = 68] was evoked in 60 of the 68 PCs studied and lasted for 4-8 s. This immediate stimulation was usually followed by a delayed and more sustained increase in C-fiber activity ( = +2.0 ± 0.4 impulses/s). The overall stimulation was not influenced by removal of smoke particulates (n = 15) or by pretreatment withvehicle (n = 8) for dimethylthiourea (DMTU; a hydroxyl radical scavenger) or indomethacin (Indo; a cyclooxygenase inhibitor). The immediate-phase stimulation was notaffected by pretreatment with Indo (n = 8) but was largely attenuated by pretreatment with DMTU(n = 12) or by a combined treatmentwith DMTU and Indo (DMTU+Indo; n = 8).Conversely, the delayed-phase stimulation was partially suppressedeither by DMTU or by Indo but was totally abolished by DMTU+Indo. Theseresults suggest that 1) thestimulation of PCs is linked to the gas phase of wood smoke and2) hydroxyl radical, but notcyclooxygenase products, is involved in the immediate-phasestimulation, whereas both metabolites are responsible for evoking thedelayed-phase stimulation.

     

Ozone enhances excitabilities of pulmonary C fibers to chemical and mechanical stimuli in anesthetized rats

Acute exposureto ozone (O₃) enhances pulmonarychemoreflex response to capsaicin, and an increased sensitivity ofbronchopulmonary C-fiber afferent endings may be involved. The presentstudy was aimed at determining the effect ofO₃ on the responses of pulmonary Cfibers to chemical and mechanical stimuli. A total of 31 C fibers werestudied in anesthetized, open-chest, and vagotomized rats. Duringcontrol, right atrial injection of a low dose of capsaicin abruptlyevoked a short and mild burst of discharge [0.77 ± 0.28 impulses (imp)/s, 2-s average]. After acute exposure toO₃ (3 parts/million for 30 min),there was no significant change in arterial blood pressure, trachealpressure, or baseline activity of C fibers. However, the stimulatoryeffect of the same dose of capsaicin on these fibers was markedlyenhanced (6.05 ± 0.88 impulses/s;P < 0.01) and prolonged immediatelyafter O₃ exposure, and returnedtoward control in 54 ± 6 min. Similarly, the pulmonary C-fiberresponse to injection of a low dose of lactic acid was also elevatedafter O₃ exposure. Furthermore,O₃ exposure significantly potentiated the C-fiber response to constant-pressure (tracheal pressure = 30 cmH₂O) lunginflation (control: 0.19 ± 0.07 imp/s; afterO₃: 1.12 ± 0.26 imp/s;P < 0.01). In summary, these results show that the excitabilities of pulmonary C-fiber afferents to lunginflation and injections of chemical stimulants are markedly potentiated after acute exposure toO₃, suggesting a possible involvement of these afferents in theO₃-induced changes in breathing pattern and chest discomfort in humans.

     

Role of vagal fibers in the hypoxia-induced increases in end-expiratory lung volume and diaphragmatic activity

Bonora, M., and M. Vizek. Role of vagalfibers in the hypoxia-induced increases in end-expiratory lung volumeand diaphragmatic activity. J. Appl.Physiol. 83(3): 700-706, 1997.The possible role of pulmonary C fibers in thehypoxia-induced concomitant increases in end-expiratory lung volume(EELV) and in the activity of the diaphragm at the end of expiration(DE) were evaluated bymeasuring the effects of hypoxia (10%O₂) on ventilation, EELV, andDE in eight chloralose-urethananesthetized rats. Recordings were made before and after blocking vagalC fibers and after bilateral vagotomy. C-fiber conduction was blockedby applying capsaicin perineurally to the cervical vagi. The efficiencyof C-fiber blockade was tested with intravenous capsaicin and itsselectivity by the Hering-Breuer reflex. Perineural capsaicin abolishedthe reflex apnea induced by intravenous capsaicin and transientlyreduced Hering-Breuer reflex. Perineural capsaicin affected neitherventilation, DE, and EELV in airnor the hypoxia-induced increases in these parameters. Vagotomy causedthe typical changes of breathing pattern in air, but the ventilatoryresponse to hypoxia was unchanged. Vagotomy performed during hypoxiaresulted in large decreases inDE and EELV. Hypoxia increasedDE and EELV in vagotomized rats but less than in intact rats. We conclude that the hypoxia-induced increases in EELV and diaphragmatic activity are probably not mediatedby vagal C fibers and that vagal afferents are involved but not fullyresponsible for this phenomenon.

     

Stimulation of vagal pulmonary C-fibers by a single breath of cigarette smoke in dogs

Inhalation of cigarette smoke into the lower airway via a tracheostomy evokes immediate apnea, bradycardia, and systemic hypotension in dogs. These responses can still be evoked when conduction in myelinated vagal fibers is blocked preferentially by cooling but are abolished by vagotomy, suggesting that they are mediated by afferent vagal C-fibers. To examine this possibility, we recorded impulses in pulmonary C-fibers in anesthetized, open-chest dogs and delivered 120 ml cigarette smoke to the lungs in a single ventilatory cycle. Pulmonary C-fibers were stimulated within 1 or 2 s of the delivery of smoke generated by high-nicotine cigarettes, activity increasing from 0.3 +/- 0.1 to a peak of 12.6 +/- 1.3 (SE) impulses/s, (n = 60); the evoked discharge usually lasted 3-5 s. Smoke generated by low-nicotine cigarettes evoked a milder stimulation in 33% of pulmonary C-fibers but did not significantly affect the overall firing frequency (peak activity = 2.2 +/- 1.1 impulses/s, n = 36). Hexamethonium (0.7-1.2 mg/kg iv) prevented C-fiber stimulation by high-nicotine cigarette smoke (n = 12) but not stimulation by right atrial injection of capsaicin. We conclude that pulmonary C-fibers are stimulated by a single breath of cigarette smoke and that nicotine is the constituent responsible.     

Carotid sinus nerve is involved in cardiorespiratory responses to intracarotid injection of capsaicin in the rat.

The carotid sinus nerve (CSN), important in cardiorespiratory modulation, mainly contains C fibers (CSCFs). Previous studies have demonstrated that selective stimulation of bronchopulmonary C fibers (PCFs) via right atrial injection of capsaicin (Cap; approximately 0.25 microg) results in an apnea (approximately 3 s) associated with hypotension and bradycardia. The present study was undertaken to determine the effects of activating CSCFs on cardiorespiratory activities. Intracarotid injection of Cap was performed before and after bilateral transection of the CSN in anesthetized and spontaneously breathing rats. Our results showed that 1) low doses of Cap (up to 2 ng) produced an increase in minute ventilation by elevating both tidal volume and respiratory frequency with the threshold dosage at 1.0 ng (P < 0.05); 2) high doses (4-64 ng) generated an apnea (prolongation of expiratory duration by approximately 8-fold) and hypertension (P < 0.05); 3) bilateral transection of the CSN reduced excitatory and inhibitory respiratory responses by 30 and 81%, respectively, and increased the hypertension by 88% (P < 0.05); and 4) the same doses of Cap delivered into the right atrium to stimulate PCFs failed to evoke detectable cardiorespiratory responses. Our results suggest that compared with PCFs, CSCFs are more sensitive to Cap stimulation and that activation of these fibers significantly modulates cardiorespiratory activity in anesthetized rats.     

Acute effects of acrolein on breathing: role of vagal bronchopulmonary afferents.

Spontaneous inhalation of acrolein vapor (350 ppm, 1 ml/100 g body wt) elicited an immediate and transient inhibitory effect on breathing in anesthetized rats, characterized by a prolongation of expiratory duration and accompanied by a bradycardia; ventilation was reduced by 47 +/- 6%, which returned to baseline after three to seven breaths. When both vagi were cooled to 6.6 +/- 0.1 degrees C, the reflex apneic response to lung inflation was completely abolished but the bradypneic response to acrolein was not affected. After perineural capsaicin treatment of both cervical vagi to selectively block the capsaicin-sensitive C-fiber afferents, acrolein no longer evoked an inhibitory effect on breathing; conversely, an augmented inspiration was consistently elicited with the first breath of acrolein inhalation, which was subsequently abolished by cooling both vagi to 6.5 degrees C. The inhibitory effect of inhaling acrolein at a lower concentration (200 ppm) was not detectable, whereas that of a higher concentration (600 ppm) was more intense and prolonged. All these responses were completely eliminated by bilateral vagotomy. These results suggest that inhaled acrolein activated both vagal C-fiber endings and rapidly adapting irritant receptors in the airways, but the acrolein-induced inhibitory effect on breathing was elicited primarily by the C-fiber afferent stimulation.     

Mechanisms of stimulation of vagal pulmonary C fibers by pulmonary air embolism in dogs

Chen, H. F., B. P. Lee, and Y. R. Kou. Mechanisms ofstimulation of vagal pulmonary C fibers by pulmonary air embolism indogs. J. Appl. Physiol. 82(3):765-771, 1997.We investigated the involvement of thecyclooxygenase metabolites and hydroxyl radical (^· OH) in thestimulation of vagal pulmonary C fibers (PCs) by pulmonary air embolism(PAE). Impulses were recorded from PCs in 51 anesthetized, open-chest,and artificially ventilated dogs. Fifty of 59 PCs were stimulated byinfusion of air into the right atrium (0.2 ml ^· kg^{1 ·} min¹for 10 min). As a group (n = 59), PCactivity increased from a baseline of 0.4 ± 0.1 to a peak of 1.7 ± 0.2 impulses/s during the period from 1 min before to 2 min afterthe termination of PAE induction. In PCs initially stimulated by PAEinduction, PAE was repeated after the intervening treatment (iv) withsaline (n = 9), ibuprofen (acyclooxygenase inhibitor; n = 11), ordimethylthiourea (a ^· OH scavenger;n = 12). The responses of PCs to PAEwere not altered by saline vehicle but were abolished by ibuprofen and significantly attenuated by dimethylthiourea. Although hyperinflation of the lungs reversed the PAE-induced bronchomotor responses, it didnot reverse the stimulation of PCs (n = 8). These results suggest that 1)cyclooxygenase products are necessary for the stimulation of PCs byPAE, whereas changes in lung mechanics are not, and2) the functional importance ofcyclooxygenase products may be mediated in part through the formationof ^· OH.

     

Reflex apneic response evoked by laryngeal exposure to wood smoke in rats: neural and chemical mechanisms

Lin, Y. S., and Y. R. Kou. Reflex apneic responseevoked by laryngeal exposure to wood smoke in rats: neural and chemical mechanisms. J. Appl. Physiol. 83(3):723-730, 1997.We investigated the neural and chemical mechanismscontributing to the immediate ventilatory responses to laryngealexposure to wood smoke in anesthetized Sprague-Dawley rats. Fivemilliliters of wood smoke were delivered into a functionally isolatedlarynx at a constant flow rate of 1.4 ml/s while the animals breathedspontaneously. Within 1 s after exposure, laryngeal wood smokeconsistently triggered an apnea in each of the 42 rats tested. Theapneic duration reached 1,636.4 ± 105.4 (SE) % (n = 42) of the baseline expiratoryduration. This apneic response was not affected by denervation ofrecurrent laryngeal nerves (n = 6) orby removal of smoke particulates (n = 14), but it was totally eliminated by topical application of ananesthetic (n = 8; lidocainehydrochloride, 8%) to the laryngeal mucosa or by sectioning of thesuperior laryngeal nerves (n = 42).Furthermore, laryngeal application of a hydroxyl radical scavenger(dimethylthiourea; 500 mg/ml; n = 8)greatly diminished or abolished the smoke-induced apneic response, butit did not affect the apneic response evoked by laryngeal exposure toair saturated with 6% ammonia. These results suggest that theimmediate apneic response to laryngeal wood smoke is a reflex resulting from the stimulation of the superior laryngeal afferents by the gasphase of wood smoke and that the stimulation is mediated through ahydroxyl radical mechanism.

     

Protoveratrines A and B increase sleep apnea index in Sprague-Dawley rats

Trbovic, Sinisa M., Miodrag Radulovacki, and David W. Carley. Protoveratrines A and B increase sleep apneaindex in Sprague-Dawley rats. J. Appl.Physiol. 83(5): 1602-1606, 1997.The action ofprotovertarines A and B, which stimulate carotid sinus baroreceptorsand vagal sensory endings in the heart as well as pulmonary bed, wereassessed on spontaneous and postsigh central sleep apneas in freelymoving Sprague-Dawley rats. During the 6-h recording period, animalswere simultaneously monitored for sleep by using electroencephalogramand electromyogram recordings, for respiration by single-chamberplethysmography, and for blood pressure and heart period by usingradiotelemetry. After administration of 0.2, 0.5, or 1 mg/kg sc ofprotoveratrines, cardiopulmonary changes lasting at least 6 h wereobserved in all three behavioral states [heart period increasedup to 23% in wakefulness, 21% in non-rapid-eye-movement (non-REM)sleep, and 20% in REM sleep; P < 0.005 for each]. At the same time, there was a substantial increase in the number of spontaneous (375% increase;P = 0.04) and postsigh (268%increase, P = 0.0002) apneas. Minuteventilation decreased by up to 24% in wakefulness, 25% in non-REM,and 35% in REM sleep (P < 0.05 foreach). We conclude that pharmacological stimulation of baroreflexespromotes apnea expression in the sleeping rat.

     

Respiratory-related neurons of the fastigial nucleus in response to chemical and mechanical challenges

Xu, Fadi, and Donald T. Frazier. Respiratory-relatedneurons of the fastigial nucleus in response to chemical and mechanical challenges. J. Appl. Physiol. 82(4):1177-1184, 1997.Responses of cerebellar respiratory-relatedneurons (CRRNs) within the rostral fastigial nucleus and the phrenicneurogram to activation of respiratory mechano- and chemoreceptors wererecorded in anesthetized, paralyzed, and ventilated cats. Respiratorychallenges included the following: 1) cessation of the ventilator for asingle breath at the end of inspiration (lung inflation) or atfunctional residual capacity, 2)cessation of the ventilator for multiple breaths, and3) exposure to hypercapnia. NineteenCRRNs having spontaneous activity during control conditions werecharacterized as either independent (basic, n = 14) or dependent (pump,n = 5) on the ventilator movement. Thirteen recruited CRRNs showed no respiratory-related activity untilbreathing was stressed. Burst durations of expiratory CRRNs wereprolonged by sustained lung inflation but were inhibited when thevolume was sustained at functional residual capacity; it was vice versafor inspiratory CRRNs. Multiple-breath cessation of the ventilator andhypercapnia significantly increased the firing rate and/orburst duration concomitant with changes noted in the phrenic neurogram.We conclude that CRRNs respond to respiratory inputs fromCO₂ chemo- and pulmonarymechanoreceptors in the absence of skeletal muscle contraction.

     

Prolongation in expiration evoked from ventrolateral pons of adult rats

Jodkowski, Józef S., Sharon K. Coles, and Thomas E. Dick. Prolongation in expiration evoked from ventrolateral pons ofadult rats. J. Appl. Physiol. 82(2):377-381, 1997.Activation of neurons in the ventrolateral (vl)pons was hypothesized to alter the breathing pattern becauseprevious studies demonstrated apneusis after inhibitingneuronal activity with bilateral muscimol (10 mM) microinjectionsinto the vl pons (17). The excitatory amino acid L-glutamate (10 mM) was microinjected(10-100 nl) into the vl pons in anesthetized, vagotomized,paralyzed, and ventilated adult rats(n = 8). In four of these animals, thetarget site was approached from the ventral surface of the pons toavoid penetrating the dorsolateral (dl) pons. The expiratory phase wasprolonged transiently and concurrently with the microinjection. Thelocation of the injection sites included the A5 area, was independentof the approach, and was distinct from the dl pons. These results complement our previous data and indicate that neurons located in thevl pons influence respiration specifically by prolonging expirationwhen activated and by delaying the inspiratory-to-expiratory phasetransition when inhibited.

     

Stimulation of breathing by activation of pulmonary peripheral afferents in rabbits

Respiratoryresponse to selective activation of vagal afferents in the peripheralairways was investigated in anesthetized, open-chest, and artificiallyventilated rabbits. Phrenic activity was used as an index of centralrespiratory drive before and after injection of hypertonic saline(8.1%, 0.1 ml) into the periphery of the lung to stimulate theafferents. The amplitude of "integrated" phrenic activity andphrenic burst rate increased by 19 ± 3.4 and 53.7 ± 12.7%(n = 23;P < 0.001),respectively. The response peaked at 5.5 ± 1.6 s andreturned to the baseline at 7 min (median) after the injection. Themagnitude of the response was positively related to the concentrationof injected NaCl. The response could not be elicited by injection ofnormal saline and was abolished by vagotomy. Because artificialventilation caused phrenic activity to be entrained with theventilator, respiratory drive was further assessed after the ventilatorwas stopped. Again, neural hyperpnea and tachypnea were observed.Because activation of a small fraction of the pulmonary peripheralafferents resulted in vigorous stimulation of respiratory drive, wespeculate that initiation of this reflex may contribute to hyperpneaand tachypnea under both physiological and pathophysiologicalconditions.

     

Breathing of awake goats during prolonged dysfunction of caudal M ventrolateral medullary neurons

Forster, H. V., L. G. Pan, T. F. Lowry, T. Feroah, W. M. Gershan, A. A. Whaley, M. M. Forster, and B. Sprtel. Breathing ofawake goats during prolonged dysfunction of caudal M ventrolateral medullary neurons. J. Appl. Physiol.84(1): 129-140, 1998.Cooling the caudal M ventrolateralmedullary (VLM) surface for 30 s results in a sustained apnea inanesthetized goats but only a 30% decrease in breathing in awakegoats. The purpose of the present study was to determine, in the awakestate, the effect of prolonged (minutes, hours) caudal M neuronaldysfunction on eupneic breathing andCO₂ sensitivity. Dysfunction wascreated by ejecting excitatory amino acid receptor antagonists or aneurotoxin on the VLM surface through guide tubes chronically implantedbilaterally on a 10- to 12-mm²portion of the caudal M VLM surface of 12 goats. Unilateral and bilateral ejections (1 µl) of selective antagonists forN-methyl-D-aspartic acid ornon-N-methyl-D-asparticacid receptors had no significant effect on eupneic breathing orCO₂ sensitivity. Unilateralejection of a nonselective excitatory amino acid receptor antagonistgenerally had no effect on eupneic breathing orCO₂ sensitivity. However, bilateral ejection of this antagonist resulted in a significant 2-Torrhypoventilation during eupnea and a significant reduction inCO₂ sensitivity to 60 ± 9% ofcontrol. Unilateral ejection of the neurotoxin kainic acid initiallystimulated breathing; however, breathing then returned to near controlwith no incidence of apnea. After the kainic acid ejection,CO₂ sensitivity was reducedsignificantly to 60 ± 7% of control. We conclude that in the awakestate a prolonged dysfunction of caudal M VLM neurons results incompensation by other mechanisms (e.g., carotid chemoreceptors, wakefulness) to maintain near-normal eupneic breathing, butcompensation is more limited for maintainingCO₂ sensitivity.

     

Role of bronchopulmonary C-fiber afferents in the apneic response to cigarette smoke

The role of vagal bronchopulmonary C-fiber afferents in eliciting the immediate changes in breathing pattern after acute inhalation of cigarette smoke was assessed with a selective blockade of myelinated vagal afferents (innervating both stretch and irritant receptors) utilizing the method of differential cooling. In 15 of 17 chloralose-anesthetized dogs tested, spontaneous inhalation of cigarette smoke (19.7% avg conc, 500-700 ml vol) reproducibly caused the following immediate responses: apnea, bradycardia, and hypotension. These responses occurred within 1 to 2 breaths of smoke inhalation and were followed by a delayed hyperpnea. The apneic duration reached 326 +/- 33% (SE) (n = 15) of the mean base-line expiratory duration. Differential cold block of both vagi (coolant temperature 8.4 +/- 0.3 degrees C) abolished the reflex apnea induced by a positive-pressure (7-10 cmH2O) lung inflation but did not affect the apneic response to smoke inhalation (345 +/- 35%). The smoke-induced apnea was completely abolished by lowering the coolant temperature to -1.3 +/- 0.2 degrees C (n = 10) or by bilateral vagotomy (n = 5) and returned to the control level after both vagi were rewarmed. Based on these results, we suggest that the immediate apneic response to inhaled cigarette smoke is elicited by a stimulation of vagal C-fiber afferents in the lungs and airways.     

Sleep apnea in obese miniature pigs

Lonergan, Robert P., III, J. Catsby Ware, Richard L. Atkinson, W. Christopher Winter, and Paul M. Suratt. Sleep apnea in obese miniature pigs. J. Appl.Physiol. 84(2): 531-536, 1998.We postulated thatthree extremely obese Yucatan miniature pigs would have more sleepapnea than three nonobese Yucatan miniature pigs. Pigs were studiedwith the use of electroencephalograms, inductance plethysmography,oximetry, expired nasal CO₂, orthermistors. All of the obese pigs, but none of the nonobese pigs, hadboth sleep apnea (8.5, 10.3, and 97.0 in obese pigs vs. 0 apnea + hypopnea/h in all nonobese pigs; P < 0.05) and oxyhemoglobin desaturation episodes during sleep [9.4 ± 3.0 vs. 0 + 0.53 (SD) mean desaturation episodes/h in obese pigsvs. nonobese pigs, respectively; P < 0.05]. Two of the extremely obese pigs had obstructive sleepapnea, whereas the third obese pig had central sleep apnea. We conclude that sleep apnea occurs in extremely obese Yucatan minipigs and suggestthat this animal can be used as a model for sleep apnea in obesity.

     

Central chemoreception in the region of the ventral respiratory group in the rat

Nattie, Eugene E., and Aihua Li. Centralchemoreception in the region of the ventral respiratory group in therat. J. Appl. Physiol. 81(5):1987-1995, 1996.We injected acetazolamide (AZ; 5 × 10⁶ M, 1 nl) into theregion of the ventral respiratory group (VRG) of anesthetized paralyzedventilated rats. Control injections (mock cerebrospinal fluid,n = 6, or the inactive AZ analogue 2-acetylamino-1,3,4-thiadiazole-5-sulfon-t-butylamide,n = 6) did not increase the integratedphrenic neurogram [phrenic nerve amplitude (PNA)]. The AZinjections produced a focal region of tissue acidosis with a radius < 300-400 µm and are used as a probe for sites of centralchemosensitivity. Injection location is determined by anatomicanalysis. Of 22 VRG injections of AZ, 14 increased the amplitude of thePNA over 15-90 min; 8 had no effect. In 17 cases, we measuredmedullary tissue pH at the injection center and/or at a distantsite and reaffirmed the size of the acidotic region produced by suchsmall AZ injections. Of injections with pH electrodes within300-400 µm of the injection center, all responders showed anacid pH; three nonresponders showed an acid pH, and one an alkaline pH.In a subgroup of five rats, at VRG sites with known respiratory effectsidentified by prior glutamate injection (10 nl, 100 mM), all subsequentAZ injections produced a PNA response. Simultaneous measurement of PNAand tissue pH responses at the injection center of eight rats did notshow a uniform correlation in time; initially, both changed with asimilar time course, but PNA recovered more quickly. We conclude that1) the region of the VRG containssites of ventilatory chemoreception,2) ineffective AZ injections doproduce a tissue acidosis but at sites with minimal impact onbreathing, and 3) tissuepH does not uniquely represent the chemoreceptor stimulus.

     

Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea

Cala, S. J., P. Sliwinski, M. G. Cosio, and R. J. Kimoff.Effect of topical upper airway anesthesia on apnea duration through the night in obstructive sleep apnea. J. Appl.Physiol. 81(6): 2618-2626, 1996.It haspreviously been reported that the duration of obstructive apneasincreases from the beginning to the end of the night (M. Charbonneau,J. M. Marin, A. Olha, R. J. Kimoff, R. D. Levy, and M. Cosio.Chest 106: 1695-1701, 1994). The purpose of this study wasto test the hypothesis that stimulation of upper airway (UA) sensoryreceptors during obstructed inspiratory efforts contributes to arousaland apnea termination and that a progressive attenuation of thismechanism through the night contributes to apnea lengthening. Westudied seven patients (six men, one woman) with severe obstructivesleep apnea (apnea-hypopnea index = 93 ± 26 events/h) during twoconsecutive nights of polysomnographic monitoring. On one night (randomorder), we performed topical UA anesthesia with 0.2% tetracaine and onthe control night, sham anesthesia. We measured apnea duration,esophageal pressure (Pes) during apneas, and apneicO₂ desaturation. Consistent withprevious findings, apnea duration, number of efforts per apnea, andpeak Pes at end apnea increased from the beginning to the end of the control nights. UA anesthesia produced a significant increase in apneaduration at the beginning of the night but no change in apnea length atthe end of the night. Peak Pes and the rate of increase in Pes duringthe anesthesia nights were greater than during control nights, but therate of increase in Pes was similar for the beginning and end of thecontrol and anesthesia nights. These findings suggest that UA sensoryreceptors play a role in mediating apnea termination at the beginningof the night but that the contribution of these receptors diminishes asthe night progresses such that greater inspiratory efforts arerequired to trigger arousal, leading to apnea prolongation.

     

Reflex regulation of the circulation after stimulation of cardiac receptors by prostaglandins

Prostaglandins (PGs) are potent vasoactive substances that may participate in the control of coronary blood flow, platelet aggregation, and inflammation. An important action of PGs may be the stimulation of c fibers in general and vagal cardiac c fibers in particular. The Bezold-Jarisch reflex after intracoronary injection of Veratrum alkaloids is very similar to the vagal bradycardia elicited by stimulation of cardiac PG synthesis or injection of prostacyclin (PGI2). The characteristic features of this reflex are 1) stimulation of c fibers, 2) inferoposterior wall location of receptors, 3) vagal afferents, 4) vagal efferents to the heart, 5) sympathetic efferents to peripheral blood vessels, and 6) interaction with other reflexes. Vagal cardiac c fibers are activated by intracoronary injections of PGI2 or arachidonic acid, resulting in a vagal reflex bradycardia and hypotension due to withdrawal of peripheral alpha-adrenergic tone to resistance vessels. The cardiac receptors are located predominantly in the inferoposterior wall of the left ventricle. When stimulated by PGs, cardiac receptors may also modify the regulation of arterial pressure by the baroreflexes, altering the inverse relationship between systemic arterial pressure and heart rate. Thus, there is a striking parallelism between the veratridine-induced Bezold-Jarisch reflex and PG-induced cardiac reflexes, although the physiological and clinical significance of these reflexes remains to be determined.     

The possibility of peripheral cholinolytic action of psychostimulants

The cholinolytic effect of sydnophen discovered in earlier anesthetized cats was confirmed on unanesthetized fish and frogs: the vagal bradycardia induced by electric stimulation of peripheral vagal end was decreased or even abolished by intravenous injection of sydnophen (0.2-20 mg/kg). The amphetamine (0.2-30 mg/kg) also blocked the vagal bradycardia in anesthetized cats and unanesthetized frogs. The maximum vagolytic action of amphetamine appeared later (in 4-8 min after injection) in compared with sydnophen (1-3 min). The small dose of amphetamine (0.2-0.3 mg/kg) in contrast to sydnophen didn't decrease the vagal bradycardia but even increased it. It was suggested that the cholinolytic effect of sydnophen and amphetamine is due to different mechanisms.