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Hypercapnia and hypoxia which develop during retching participate in the transition from retching to expulsion in dogs
Neuroscience Research, 17 (1993) 205-215 © 1993 Elsevier Scientific Publishers Ireland, Ltd. All rights reserved 0168-0102/93/$06.00
205
NSR 00658
Hypercapnia and hypoxia which develop during retching participate in the transition from retching to expulsion in dogs Hiroyuki Fukuda and Tomoshige Koga Department of Physiology, Kawasaki Medical School, Kurashiki, Okayama 701-01, Japan (Received 8 February 1993; revised 24 May 1993; accepted 24 May 1993)
Key words: Respiration; Retching; Vomiting; Arterial chemoreceptor; Central chemoreceptor; Blood gas tensions; Sinus nerve Summary The roles of arterial and central chemoreceptors in the transition from retching to expulsion during vomiting were studied. In spontaneously breathing decerebrate dogs, actual vomiting induced by activation of abdominal vagal afferents always consisted of retching and subsequent expulsion phases. Pulmonary ventilation almost stopped during the retching phase. Arterial blood CO 2 tension gradually increased and reached a maximum near the time of the transition from the retching phase to the expulsion phase. Similarly, when end-tidal CO 2 was maintained higher than 4.6 + 0.7% in paralyzed, artificially ventilated decerebrate dogs, stimulation of abdominal vagal afferents induced fictive retching and fictive expulsion, which were identified from the characteristic discharge patterns of the motor nerves to the costal and hiatal parts of the diaphragm, the abdominal muscles and the digastric muscle. However, only fictive retching occurred at an end-tidal CO 2 of less than 3.7 + 0.7%. Although end-tidal CO2 was at a low level, fictive retching was followed by fictive expulsion when artificial ventilation was interrupted during the fictive retching phase and when sinus nerve afferents were stimulated. Even after sino-aortic denervation, fictive retching and subsequent fictive expulsion could be induced by stimulation of either vagal afferents or the solitary tract and nucleus, but the threshold level of end-tidal CO 2 which enabled the induction of fictive expulsion increased after denervation. These results indicate that the activity of arterial and/or central chemoreceptor afferents must exceed some critical level to induce the transition from the retching phase to the expulsion phase.
Introduction Vomiting usually consists of two distinct phases in many animal species, including humans: i.e., retching and expulsion (Borison and Wang, 1953; Barnes, 1984; Miller, 1986; Andrews and Hawthorn, 1988). While both retching and expulsion primarily involve thoracic respiratory muscles and abdominal muscles, these muscles are known to be activated differently during each phase. The diaphragm and abdominal muscles concomitantly contract with each retch and the glottis closes simultaneously (Hukuhara et al., 1957; Mc-
Correspondence to: Hiroyuki Fukuda, Department of Physiology, Kawasaki Medical School, Kurashiki, Okayama 701-01, Japan. Tel.: 086-462-1111; Fax: 086-462-1199.
Carthy and Borison, 1974; Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988; Gr61ot et al., 1990). As a result, pressure in the abdominal cavity increases, while pressure in the thoracic cavity decreases with each retch (McCarthy and Borison, 1974). In contrast, the costal part of diaphragm contracts only during the early part of the expulsion phase. Moreover, the hiatal part of the diaphragm does not contract during the expulsion phase while the abdominal muscles and the adductors of the glottis maintain a powerful contraction (Hukuhara et al., 1957; Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988; Gr61ot et al., 1990). Consequently, positive pressure in the abdominal cavity may be transferred by the relaxed diaphragm to the thoracic cavity (McCarthy and Borison, 1974). The positive thoracic pressure may cause projectile expulsion. The mouth, which is closed during
206 retching, is opened widely for the expulsion phase (Borison and Wang, 1953; McCarthy and Borison, 1974). In decerebrate spontaneously breathing cats (McCarthy and Borison, 1974; Tan and Miller, 1986; Miller et al., 1988) and dogs (Hukuhara et al., 1957), application of emetic drugs or activation of abdominal vagal afferents induces vomiting which normally involves a retching phase followed by expulsion phase. Similarly, in paralyzed decerebrate cats (Bianchi and GrElot, 1989; Gr61ot et al., 1990; Nonaka and Miller, 1991; Miller and Ezure, 1992) and dogs (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992), vagal stimulation induces characteristic activities in the muscle nerves to the abdominal muscles, the hiatal and costal parts of the diaphragm (Miller et al., 1988; Fukuda and Koga, 1991) and the glottis (Fukuda and Koga, 1991). The temporal and spatial patterns of the characteristic activities of these muscle nerves in paralyzed animals are similar to those in the electromyograms recorded from these muscles during the retching and expulsion phases in nonparalyzed animals (Hukuhara et al., 1957; McCarthy and Borison, 1974; Tan and Miller, 1986; Miller et al., 1988). Consequently, the characteristic activities in these muscle nerves of paralyzed animals have been referred to as fictive retching and fictive expulsion (Bianchi and GrElot, 1989; Gr61ot et al., 1990; Koga and Fukuda, 1990, 1992; Koga, 1991; Nonaka and Miller, 1991; Fukuda and Koga, 1991, 1992; Cohen et al., 1992; Miller and Ezure, 1992). Therefore, somatic afferent activity may not participate in the transition from retching to expulsion. However, cause of this phase transition has not yet been determined. Gold and Hatcher (1926) have demonstrated that pulmonary ventilation is interrupted during the retching phase in spontaneously breathing dogs and cats. Consequently, hypercapnia and hypoxia are thought to develop during the retching phase prior to the phase transition in these nonparalyzed animals. In contrast, blood gas tension does not change during the fictive retching phase in paralyzed decerebrate animals, since constant artificial ventilation is maintained during fictive retching. When end-tidal CO 2 is maintained below 3.0% during the fictive retching phase in paralyzed dogs, fictive retching is rarely followed by fictive expulsion (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992). In contrast, fictive retching is always followed by fictive expulsion in paralyzed decerebrate cats, in which end-tidal CO 2 is routinely maintained higher than 3.5% (Bianchi and GrElot, 1989; Nonaka and Miller, 1991; Cohen et al.,
1992; Miller and Ezure, 1992). Based on these observations, we assumed that hypercapnia and/or hypoxia play a critical role in the transition from the retching phase to the expulsion phase. The present study was performed to evaluate this assumption.
Materials and methods
Eighteen dogs were used for this study, each weighing 5-10 kg. All of the dogs were anesthetized with an intramuscular injection of ketamine hydrochloride (25 mg/kg) and became quite flaccid within 5 min of the injection. During the subsequent 10 rain, 16 of the dogs were paralyzed with gallamine triethiodide (2 mg/kg, i.v.), artificially ventilated through a tracheal cannula, and precollicularly decerebrated. The dogs were then allowed to recover from the anesthesia and no further anesthesia was applied. The temperature of the abdominal cavity was maintained at 37-39°C by radiation from two 100-W tungsten lamps and a heating plate which was automatically controlled by negative feedback from the dogs' body temperatures. The pressure of the femoral artery, and the CO 2 and O 2 concentrations in tracheal air were monitored throughout the experiments. Centrifugal activities of the branch of the L1 spinal nerve to the rectus abdominis of all 16 dogs, the phrenic branch of the C5 spinal nerve of 14 dogs, the hiatal and costal branches of the phrenic nerve of 2 dogs and the trigeminal branch to the digastric muscle of 5 dogs were recorded as frequency histograms (100 ms bins) with a pen recorder. Fictive retching and expulsion were recognized from their activity patterns as described in other papers (Tan and Miller, 1986; Miller et al., 1988; Bianchi and Gr61ot, 1989; Gr61ot et al., 1990; Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992; Miller and Ezure, 1992; Nonaka and Miller, 1991). Fictive vomiting was induced by continuous stimulation of the vagal ventral trunk at the supra-diaphragmatic region in 14 dogs, and by stimulation of the solitary tract and nucleus in 4 dogs. The solitary tract and nucleus were stimulated with a monopolar cathode (lacquer-coated platinum wire 0.5 mm in diameter) placed on the surface of the vagal triangle. The bilateral sinus nerves were cut in 15 dogs, and stimulated in 9 dogs. The left and right aortic nerves were cut near the middle cervical ganglion and/or at the middle cervical portion (by a severing the vagosympathetic trunk) in 5 dogs. The remaining 2 dogs were similarly anesthetized and decerebrated, but not paralyzed. A balloon was
207 inserted into the stomach through an incision of the cervical esophagus. Actual vomiting was induced by distention of the stomach with 200-400 ml of air. The recurrent nerves were isolated from a cervical portion of the trachea. The trachea was then severed, and the severed ends were connected with two rectilinear branches of a T-cannula. Intra-tracheal pressure and CO 2 and O 2 concentrations in tracheal air (TrCO2, TrO 2) were recorded through the other rectangular branch of the cannula. Arterial blood samples of 2 - 3 ml were obtained during vomiting from the femoral artery via a cut-down tube. CO 2 and 0 2 tensions (PaCO 2, PaO 2) and the pH of the samples were measured using a blood gas analyzer.
decerebrate dogs. The threshold volume of the stomach was 2 8 3 _ 1 2 0 ml (mean_+SD, n = 9 ) . Intratracheal pressure and COz and 0 2 concentrations in tracheal air (TrCO2, TrOz; vol.%) and arterial blood (PaCO2, PaOz; Torr) were measured. Before the first vomiting episode was induced, the mean end-tidal TrCO 2 and TrO 2 and respiratory rate were 4.8%, 16.8% and 12.7 rpm, respectively. Fig. 1 shows a typical result. Each retch is represented as a negative pressure pulse (black triangle) in the intra-tracheal pressure trace, and expulsion is represented as a positive pulse indicated by a bar (E). These changes in the tracheal pressure are comparable to the changes in thoracic venous pressure observed during actual vomiting in nonparalyzed decerebrate cats by McCarthy and Borison (1974). A delay of 2.4 s caused by the tube (1.5 m in length) through which the tracheal air was sampled exists between the trace of intra-tracheal pressure and those of TrCO 2 and TrO 2. This delay is indicated by vertical and oblique lines. The respiratory rate gradually increased from 38.1 _+ 21.7 s (between vomiting, Table 1) during stomach distension to 64.6 + 24.9 rpm before retching (prodromal phase, Table 1; P in Fig. 1). As a result, end-tidal TrCO 2 and TrO 2 changed to 3.0 + 0.3% and
Results
I. Experiments in nonparalyzed spontaneously breathing decerebrate dogs Changes in C O 2 and 0 2 concentrations in tracheal air and arterial blood during vomiting Nine vomiting episodes were induced at intervals of about 25 min by stomach distention in 2 nonparalyzed
+lOOml 0".200) +100ml 0".300)
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Fig. 1. Changes in intra-tracheal pressure and COz and 02 concentrations in tracheal air and arterial blood during actual vomiting of a nonparalyzed decerebrate dog. From top to bottom, the traces represent tracheal air 02 (TrO2, vol%), arterial blood 02 tension (PaO2, Torr), arterial blood CO2 tension (PaCO2, Torr), tracheal CO2 (TrCO2, vol%) and intra-tracheal pressure. Each actual retch is represented as a negative pressure pulse in the trace of intra-tracheal pressure ( • ) and an actual expulsion corresponds to a positive pressure pulse which is indicated by a horizontal bar (E). Vomitingwas induced by stomach distention with 3 injections of 100 ml air at .~. Total volumes of injected air are indicated in parentheses as T.200 = 200 ml, T.300 = 300 ml and T.0 = 0 ml. All 300 ml of air was removed at T. Vomiting and preceding and subsequent respiratory changes were divided into the prodromal phase (P), pre-retching phase (PR), 1st retching phase (R1), 2nd retching phase (R2), expulsion phase (E) and the after-tachypnea phase (AT). Traces (12 s) were omitted during the AT phase.
208 17.2 + 1.4%, respectively (Table 1, P in Fig. 1). Next, just before retching, TrCO 2 and TrO 2 reached levels near those of fresh air, and these values were maintained for 3.8 _+2.2 s (n = 9) (pre-retching phase, Table 1; PR in Fig. 1). This pre-retching phase was observed in all 9 vomiting episodes. This result indicates that exhalation of alveolar air is suppressed during the pre-retching phase. During the pre-retching phase of fictive retching in paralyzed decerebrate dogs, discharge of the phrenic nerve increased and persisted even during expiratory phases (Figs. 2B, 4, 6B, 7). The phrenic expiratory discharge may sustain diaphragm contraction during expiration and prevent exhalation of alveolar air in nonparalyzed dogs. Therefore, the preretching phase is considered to be the period during which exhalation of alveolar air is limited and lung volume is increased. TrCO 2 and TrO 2 respectively increased and decreased at the beginning of retching, and then gradually and steadily changed for 16.3 _+ 3.5 s (n = 9) to reach their respective maximum (TrCO2, 5.0 +_0.5%) and minimum (TrO2, 12.8_+ 0.8%) values near the midpoint of the retching phase (lst phase of retching, Table 1; R1 in Fig. 1). The negative pressure pulses indicate that 14.3 _+3.1 retches occurred during the 1st phase of retching. However, these pressure pulses were not accompanied by any rapid changes in TrCO 2 and TrO 2 which were comparable to the changes caused by tracheal air flow during respiration (Fig. 1). This result indicates that tracheal air does not flow during the 1st phase, as demonstrated by Gold and Hatcher (1926). Therefore, this result is believed to be consistent with previous results which showed that the glottis was closed concomitantly with each retch (Hukuhara et al., 1957; Gr61ot et al., 1990; Fukuda and Koga, 1991; Koga and Fukuda, 1992). After the 1st phase, rapid and transient changes of various amplitudes in TrCO 2 and TrO 2 occurred between retches (2nd phase of retching, Table 1; R2 in Fig. 1). The rapid changes suggest that actual ventilations occur between retches in the 2nd phase. The 2nd phase lasted for a mean of 15.2 _+ 7.3 s and consisted of 10.0 +_4.3 retches. The 2nd phase was followed by an expulsion phase of 5.5 _+3.5 s, in which 2-4 (mean of 2.3 _+0.5) expulsion episodes occurred. However, the maximum and minimum end-tidal TrCO 2 and TrO 2 observed during the 2nd and expulsion phases were comparable with the maximum TrCO 2 and minimum TrO 2 attained during the 1st phase, respectively (Table 1). After the expulsion phase, the respiratory rate increased again to 72.9_+ 28.3 rpm and, consequently,
end-tidal TrCO 2 and TrO 2 became 2.7 +_0.5% and 17.6 _+0.8%, respectively (Table 1). During the 25 min intervals between vomiting episodes, these values did not recover to those observed before the 1st vomiting episode was induced (Table 1). PaCO 2 and PaO z of arterial blood steadily increased and decreased, respectively, during the 1st phase of retching, and reached respective maximum and minimum values during the 2nd phase. Arterial blood pH became 7.34 _+0.02 at the 2nd phase. These values of PaCO 2, PaO 2 and pH remained almost constant during the expulsion phase (Fig. 1, Table 1). These values of TrCO 2, TrO2, PaCO 2, PaO 2 and pH in the 1st and 2nd phases of retching, and in the expulsion phase significantly differed from the respective control values observed during the periods between vomiting episodes (Table 1).
I1. Experiments in paralyzed and artificially centilated decerebrate dogs Effects of an interruption of artificial uentilation on the phase transition from retching to expulsion If the sustained cessation of ventilation during the 1st phase of actual retching of nonparalyzed dogs induces the transition from the retching phase to the expulsion phase, then interrupting artificial ventilation during fictive retching of paralyzed dogs may induce a phase transition from fictive retching to fictive expulsion. Fig. 2 shows an example of the experiments which were performed in 5 paralyzed decerebrate dogs to examine this assumption. Concomitant burst firings of the phrenic and abdominal muscle nerves represent fictive retches, which are numbered in Fig. 2. A chain of 21 fictive retches was induced by stimulating vagal afferents at an endtidal TrCO 2 of 3.4%, but fictive expulsion did not occur (Fig. 2A). In contrast, when artificial ventilation was discontinued 14 s before retching began, TrCO 2 reached 7.3% at the 12th fictive retch and 2 episodes of fictive expulsion were successively induced, as indicated by horizontal bars (Fig. 2B). Fictive expulsion was recognized as the episode following retching in which the burst duration of the abdominal muscle nerve prolonged both with respect to the corresponding vomiting burst of the phrenic nerve and to the bursts of the abdominal muscle nerve during the preceding retching phase. When an interruption of artificial ventilation was initiated at a later time, fictive retching was prolonged, and, consequently, occurrence of fictive expulsion was delayed. For example, when artificial ventilation was
pH
02
CO 2
12.7 (2) 4.8 (2) 16.8 (2)
< 64.6 ± 24.9 * (9) > 3.0±0.3 * (9) < 17.2± 1.4 (9)
Prodromal phase
> 0.4±0.3 * (9) < 19.0± 1.0 * (8)
Pre-retching phase
<5.0±0.5" (9) >12.8±0.8" (9) 31.5 ± 1.7 * (6) 73.7±9.9* (6) 7.35 ± 0.03 * (6)
1st retching phase
<4.8±0.5* (8) >12.5±1.4" (8) 33.8± 3.4 * (7) 54.3±7.9* (7) 7.34 ±0.02 * (7)
2nd retching phase
<4.8±0.6" (8) >13.7±2.2" (8) 32.4 ±3.4 * (7) 68.4±5.4* (7) 7.34±0.02 * (7)
Expulsion phase
< 7Z9.±28.3 * (9) >2.7+0.5* (8) <17.6±0.8 (8) 24.7± 1.9 * (7) 95.4±8.6 (7) 7.42±0.05 (7)
After-tachypnea phase
> 38.1 ± 2 1 . 7 (7) <3.4±0.4 (7) >16.9±1.6 (7) 26.6± 1.0 (9) 87.9±8.3 (9) 7.39± 0.03 (9)
Between vomiting
Episodes of vomiting were induced at intervals of about 25 min. Vomiting and preceding and subsequent respiratory changes are divided into the prodromal, pre-retching, 1st retching, 2nd retching, expulsion and after-tachypnea phases. Values for respiratory rate and end-tidal C O 2 and 0 2 which are indicated by < and > represent the m e a n s of the maximum and m i n i m u m values attained during the phase, respectively. Since pulmonary ventilation ceased during the pre-retching phase and the 1st phase of retching, the m e a n s of the m a x i m u m CO 2 and m i n i m u m 0 2 concentrations of tracheal air which were attained during both phases are shown. N u m b e r s in p a r e n t h e s e s indicate the n u m b e r of emetic acts upon which the mean value were based. Mean values which are marked with an asterisk significantly differ from the corresponding values obtained between emetic acts (Student's t-test, P < 0.001-0.05).
Arterial blood (Torr)
Respiratory rate (rpm) End-tidal CO 2 (vol.%) Oz
Before 1st vomiting
Phases of vomiting and preceding and subsequent respiratory changes
C H A N G E S IN R E S P I R A T O R Y R A T E A N D E N D - T I D A L A N D A R T E R I A L CO 2 A N D O z C O N C E N T R A T I O N S W I T H A C T U A L V O M I T I N G
TABLE 1
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TrCO 2 at the time of the transition was 6.3 _+ 1.3f:f
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Effects of stimulating sinus nerc'e afferents on the transition form retching to expulsion If the transition from the retching phase to the expulsion phase is induced by hypercapnia a n d / o r hypoxia which develops during the retching phase, then arterial chemoreceptor afferents may contribute to the transition. To examine this possibility, sinus nerve afferents were stimulated during fictive retching in 8 paralyzed decerebrate dogs, as shown in the example in Fig. 3. End-tidal TrCO 2 was maintained at 2.6% throughout the experiment. A long chain of 29 fictive retches, without fictive expulsion, was induced by vagal stimulation (Fig. 3A). However, sinus nerve stimulation (8 V, 10 Hz) superimposed on the vagal stimulation just after the 20th retch induced a transition from fictive retching to fictive expulsion (Fig. 3B). The same sinus nerve
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Fig. 2. Effects of interrupting artificial ventilation on fictive retching which had been induced by stimulating abdominal vagal afferents. From top to bottom, the traces represent frequency histograms (100 ms bins) of the phrenic branch of the C5 spinal nerve (phrenic n.) and the rectus abdominis branch of the L1 spinal nerve (abdominal m. n.), blood pressure of the femoral artery (blood p.), CO2 concentration in tracheal air (CO2(%)), intra-tracheal pressure (intratracheal p.) and downward pulses representing stimulating pulses (10 Hz, 20V, 0.5 ms in duration) which were applied to vagal afferents. The pulses were fused by the pen recorded and appear as the thickened part of the bottom trace. Thus, the thickened part indicates the period of stimulation. Concomitant increases in discharges of the phrenic and abdominal muscle nerves represent fictive retches. Ordinal numbers of retches are indicated. Vagal afferent stimulation induced fictive retching, but not fictive expulsion at an end-tidal CO~ of 3.4% (A). Artificial ventilation was discontinued during the period indicated by the intra-tracheal pressure trace in B. TrCO 2 increased to 7.3% and 2 episodes of fictive expulsion (E) were induced. Traces of 19 and 20 s were omitted at the interrupted regions of A and B, respectively. These explanations also apply to the following figures.
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discontinued at the beginning of retching in the dog from which the traces in Fig. 1 were obtained, fictive expulsion was induced after the 19th retch, upon which TrCO 2 increased to 7.3%. A transition from the retching phase to the expulsion phase was also induced by interrupting artificial ventilation in 4 other dogs, and TrCO 2 was monitored in 2 of the 4 dogs. The mean
Fig. 3. Effects of stimulation of sinus nerve afferents on fictive retching. Fictive retching without fictive vomiting was induced by vagal afferent stimulation at an end-tidal CO 2 of 2.6% (A). Fictive expulsion was induced by stimulation (20 Hz, 15 V, 0.5 ms) of left sinus nerve afferents which was superimposed on vagal afferent stimulation (B). Pulses stimulating sinus nerve afferents are represented in the bottom trace by upward pulses, which have been fused by the pen recorder to appear as the thickest part. Traces of 7 and 15 s were omitted at the interrupted regions in A and B, respectively.
211 stimulation applied earlier (at the 15th retch) during the fictive retching phase transiently interrupted the retching, but did not induce fictive expulsion. However, an intensified sinus nerve stimulation (8 V, 40 Hz) applied at a similar time did induce fictive expulsion. Phase transitions were also induced by sinus nerve stimulation in 7 other dogs and the threshold frequency of the sinus nerve stimulation which induced the transitions similarly decreased as fictive retching progressed in all 3 of the other dogs in which this phenomenon was observed.
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Is fictive expulsion induced by interrupting artificial ventilation or stimulating sinus nerve afferents the same as actual expulsion ? To determine whether fictive expulsion in paralyzed dogs and actual expulsion in nonparalyzed dogs are identical, activities of the motor nerves to the hiatal region of the crural diaphragm and to the digastric muscle were observed during fictive vomiting in 2 and 5 paralyzed decerebrate dogs, respectively. These nerves were selected because the mouth opens with actual expulsion in nonparalyzed dogs and cats, but not with actual retching (Borison and Wang, 1953; McCarthy and Borison, 1974) and because the hiatal diaphragm contracts with each actual retch, but not with actual expulsion (Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988). In the experiment shown in Fig. 4, a hiatal branch of the phrenic nerve exhibited a characteristic activity pattern with each fictive retch: its discharge frequency reached a maximum at an early phase of each fictive retch and then promptly decreased. Discharge of the hiatal branch completely disappeared during fictive expulsion without regard to the stimuli which were used to elicit fictive expulsion, i.e, an interruption of artificial ventilation (Fig. 4A) or stimulation of sinus nerve afferents (Fig. 4B). These discharge patterns during fictive retching and fictive expulsion are quite similar to the electromyograms recorded from the hiatal diaphragm during actual vomiting in dogs (Monges et al., 1978) and cats (Tan and Miller, 1986; Miller et al., 1988). In contrast, the digastric muscle branch did not discharge with each fictive retch, but exhibited characteristic discharges with fictive expulsions which were induced by either of the stimuli: inspiratory burst discharge(s) just be-fOte'lxpulsion, a high frequency discharge which started during fictive expulsion and stopped at the beginning of the next expiratory phase, and inspiratory discharges during several subsequent breaths (Fig. 4A, B).
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Fig. 4. Discharge patterns of the phrenic costal branch> the phrenic crural branch innervating the hiatal region of the diaphragm, and the digastric muscle branch of the trigeminal nerve during fictivevomiting. Fictive retching was induced by vagal afferent stimulation and fictive expulsionwas induced by interrupting artificial ventilation (A) or by stimulating left sinus nerve afferents (B). Stimulationof the left sinus nerve (10 Hz> 8 V, 0.5 ms) was applied immediately after the vagal afferent stimulation was discontinued. Pulses of sinus nerve stimulation are represented as upward pulses on the bottom trace. Traces of 8 s were omitted at the interrupted region in B.
Similar activity patterns of the phrenic branch to the hiatal diaphragm and the digastric muscle nerve were observed during fictive retching and fictive expulsion in 1 and 4 other paralyzed decerebrate dogs, respectively.
Role of central chemoreceptors in the transition from retching to expulsion To clarify the role of central chemoreceptors in the phase transition from retching to expulsion, we performed sino-aortic denervation in 5 paralyzed decerebrate dogs and examined whether or not the phase transition could be induced by an increase in TrCO z even after denervation. When a higher level of end-tidal TrCO 2 was maintained, continuous stimulation of abdominal vagal af-
212 (%)
which only fictive r e t c h i n g was i n d u c e d was significantly (p < 0.02) i n c r e a s e d from 3.7 _+ 0.7% (n = 5) to 5.0 + 1.32% (n = 5) by the d e n e r v a t i o n ( o p e n c o l u m n in Fig. 5). Similarly, the m e a n m i n i m u m e n d - t i d a l T r C O 2 at which fictive r e t c h i n g a n d s u b s e q u e n t fictive expulsion w e r e i n d u c e d was significantly (p < 0.01) inc r e a s e d from 4.6 _+ 0.7% (n - - 5 ) to 6.2 + 1.2% (n = 5) ( h a t c h e d column). T h e role of the c e n t r a l c h e m o r e c e p t o r s was also e x a m i n e d in fictive r e t c h i n g a n d fictive expulsion which w e r e i n d u c e d by s t i m u l a t i n g t h e solitary tract a n d its nucleus (the solitary complex). U s i n g l a c q u e r - c o a t e d p l a t i n u m wire (0.5 m m in d i a m e t e r ) as a m o n o p o l a r c a t h o d e , the solitary c o m p l e x was s t i m u l a t e d from t h e surface of the vagal t r i a n g l e on the floor of the 4th ventricle in 4 p a r a l y z e d d e c e r e b r a t e dogs in which the sinus nerves h a d b e e n cut. S t i m u l a t i o n of the rostral p o r t i o n of the vagal triangle (Fig. 6C, a) elicited fictive r e t c h i n g a n d fictive expulsion, as shown in Fig. 6A. H o w e v e r , t h e s a m e s t i m u l a t i o n a p p l i e d to m o r e c a u d a l sites of the t r i a n g l e (Fig. 6C, b) i n d u c e d only fictive r e t c h i n g (Fig. 6B). Interestingly, s t i m u l a t i o n which was a p p l i e d to m o r e rostral sites c a u s e d l a r g e r i n c r e a s e s o f arterial b l o o d p r e s s u r e . Similar r e g i o n a l d i f f e r e n c e s in t h e s e effects of s t i m u l a t i o n w e r e also o b s e r v e d in 3 o t h e r dogs. However, fictive r e t c h i n g a n d fictive expulsion responses to s t i m u l a t i o n of a site in t h e vagal t r i a n g l e v a r i e d a c c o r d i n g to the levels of e n d - t i d a l T r C O 2 even
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1ram Fig. 6. Regional differences in the effects of stimulation of the solitary complex in a paralyzed decerebrate dog in which the bilateral sinus nerves had been severed. End-tidal TrCO 2 was maintained at a low level of 2.9% in A and B. Stimulation of the solitary complex at site "a" in C induced fictive retching, fictive expulsion and an increase in blood pressure (A). However, the same stimulation applied to site "b" did not elicit fictive expulsion (B). Pulses stimulating the solitary complex are represented by downward pulses on the bottom trace.
213 after sino-aortic denervation, as shown in Fig. 7. In this example, stimulation of a site in the rostral vagal triangle induced both fictive retching and fictive expulsion at an end-tidal TrCO 2 of 3.0% (Fig. 7A), but only fictive retching at 1.5% (Fig. 7B). Similar changes were observed in 6 trials in 4 paralyzed decerebrate dogs in which sino-aortic denervation had been performed. In the 6 trials, the mean maximum end-tidal TrCO z at which only fictive retching was induced was 3.7 + 1.6%, and a mean minimum TrCO 2 at which fictive expulsion followed fictive retching was 4.3 + 1.7%,
Discussion
Similarity between fictive vomiting induced by activating chemoreceptor afferents and actual vomiting Borison and Wang (1953) have described retching and vomiting (expulsion) by noting that "movements suggestive of vomiting are not equivalent to retching since retching is not ordinarily accompanied by opening of the mouth. The mouth opens immediately preceding the evacuation of the stomach whether vomiting is projectile or labored". We also frequently observed similar mouth opening during actual expulsion in awake and nonparalyzed decerebrate dogs. The activity pat-
terns of the digastric nerve, which were observed in this study during fictive expulsion (Fig. 4), are believed to correspond to the opening of the mouth. Activities of the hiatal region of the diaphragm have been observed during actual retching and actual expulsion by electromyography in dogs (Monges et al., 1978) and cats (Tan and Miller, 1986; Miller et al., 1988). These studies clearly demonstrated that the hiatal region, in contrast to the costal region, is quiescent during actual expulsion, but exhibits a characteristic activity pattern with each actual retch: i.e., its activity reaches a maximum at an early phase of each actual retch and then promptly decreases. Discharge patterns similar to the previous electromyograms were exhibited in the present study by the phrenic branch to the hiatal region during fictive retching and fictive expulsion (Fig. 4). These activity patterns of the digastric muscle nerve and the phrenic hiatal branch indicate that the fictive expulsion which was induced in this study corresponds to actual expulsion in spontaneously breathing animals.
Participation of arterial and central chemoreceptor afferents in the transition from retching to expulsion Before the first episode of actual vomiting was induced by stomach distention in nonparalyzed, spontaneously breathing decerebrate dogs in this study, the
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Fig. 7. Effects of end-tidal Tr(~,O 2 levels on fictive retching and fictive expulsion responses to stimulation of the solitary complex in a paralyzed decerebrate dog m which smo-aortlc denervatlon had been performed. The solitary complex was stimulated at a site in the rostral region of the vagal triangle in A and B. Fietqve retching and fictive expulsion were induced at an end-tidal TrCO a level of .3.0% (A), but only fictive retching was induced when the end-tidal C O : level was lowered to 1.5% by increasing the frequency of artificial ventilation (B). Traces of 8 and 15 s were omitted at the interrupted regions in A and B, respectively. .
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214 dogs exhibited respiratory rates and end-tidal TrCO 2 and TrO 2 levels which were thought to be ordinary (Table 1). These values are comparable to those which have been previously reported in dogs (Bainton and Mitchel, 1971; Berger, 1979). A long-lasting tachypnea phase followed each episode of actual vomiting, and the tachypnea did not completely recover during the 25 min interval between episodes of actual vomiting (Table 1). As a result, PaCO 2 reached an extraordinarily low value during the period between vomiting episodes (Table 1). However, during these episodes, actual vomiting always consisted of actual retching and subsequent actual expulsion. Pulmonary ventilation was completely interrupted during the 1st phase of actual retching and was depressed during the 2nd phase (Fig. 1). Consequently, PaCO 2 and PaO 2 steadily increased and decreased, respectively, during actual retching (Fig. 1, Table 1). These changes in PaCO 2 and PaO 2 suggest that activity of arterial and central chemoreceptors gradually increases as actual retching progresses (Eyzaguirre and Lewin, 1961). Stimulation of abdominal vagal afferents induced fictive retching in paralyzed decerebrate dogs, but the fictive retching was not followed by fictive expulsion when end-tidal TrCO 2 was below 3.7 + 0.7%. In contrast, fictive expulsion always followed fictive retching when end-tidal TrCO 2 was higher than 4.6 + 0.7%. Both results are consistent with previous observations: i.e., fictive retching was always followed by fictive expulsion in paralyzed decerebrate cats in which end-tidal TrCO 2 was maintained at 3.5-6.0% (Tan and Miller, 1986; Miller et al., 1988; Bianchi and Gr61ot, 1989; Gr61ot et al., 1990; Cohen et al., 1992; Miller and Ezure, 1992), while fictive retching was only occasionally followed by fictive expulsion in paralyzed decerebrate dogs in which end-tidal TrCO 2 was maintained at 2.0-3.5% (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992). Although end-tidal TrCO 2 was maintained at a low level, fictive expulsion could be induced by interrupting artificial ventilation during the fictive retching phase (Figs. 2 and 4A), and by stimulating sinus nerve afferents later during the fictive retching phase (Figs. 3 and 4B). Even after sino-aortic denervation, fictive retching and fictive expulsion could be induced by stimulating abdominal vagal afferents and the solitary complex. However, the end-tidal TrCO 2 levels at which fictive expulsion followed fictive retching increased after denervation (Figs. 5 and 7). These results indicate that the activity of arterial a n d / o r central chemoreceptors must exceed some critical level to induce the transition from the retching
phase to the expulsion phase. However, this dose not exclude the possibility that sensory cells a n d / o r neurons, which are sensitive to changes in PaCO 2 a n d / o r PaO 2, and which exist in tissue other than the carotid and aortic bodies and the ventral medulla chemosensitire areas, are participate in the phase transition. As mentioned above, stimulation of sinus nerve afferents during fictive retching induced the transition from fictive retching to fictive expulsion in paralyzed, artificially ventilated decerebrate dogs. Interestingly, the threshold intensity of the stimulation gradually decreased as retching progressed. PaCO 2 and PaO 2 may not have changed during the fictive retching phase because constant artificial ventilation was maintained. Therefore, the change in this threshold suggests that the pattern generator of the emetic act (Fukuda and Koga, 1991, 1992; Koga and Fukuda, 1992) progressively increases its responsiveness to arterial and central chemoreceptor afferents during the retching phase. Based on these results, the transition from actual retching to actual expulsion in nonparalyzed spontaneously breathing dogs is believed to occur as follows: PaCO 2 and PaO 2 gradually increase and decrease, respectively, during cessation of pulmonary ventilation in the actual retching phase, thereby activating arterial and central chemoreceptor afferents. In parallel with these changes, the pattern generator for the emetic act (Fukuda and Koga, 1991, 1992; Koga and Fukuda, 1992) progressively increases its responsiveness to the chemoreceptor afferents and the threshold activity level of the afferents which enables the transition from retching to expulsion decreases. Consequently, the retching phase is changed to the expulsion phase by the increasing afferent activity when the activity exceeds the decreasing threshold level. Fictive expulsion after fictive retching was induced by stimulation of the rostral region of the solitary complex, although end-tidal TrCO 2 was at a very low level (Figs. 6 and 7). Sinus and aortic nerve afferents distribute primarily to the lateral region of the medial subnucleus of the solitary tract (Davis and Edwards, 1973; Berger, 1979; Katz and Karten, 1979; Panneton and Loewy, 1980; Wallach and Loewy, 1980), whereas most vagal gastric afferents terminate in the medial region (Gwyn et al., 1979; Kalia and Mesulam, 1980). However, both distributions extend rostro-caudally and overlap. In the present study, when stimulation was applied to the surface of the Vagal triangle to activate the solitary complex, arterial blood pressure increased, along with fictive retching and fictive expulsion responses. Therefore, stimulation seems to activate both arterial chemoreceptor and vagal abdominal afferents,
215 and, consequently, it can induce fictive expulsion despite very low end-tidal TrCO 2 levels. Thus, the findings observed during solitary complex stimulation are not thought to contradict the conclusions mentioned above. Acknowledgment This work was supported in part by Project Research Grants from Kawasaki Medical School.
References Andrews, P.L.R. and Hawthorn, J. (1988) The neurophysiology of vomiting. Bailli6res Clin. Gastroenterol., 21: 41-168. Bainton, C.R. and Mitchel, R.A. (1971) Effect of skin cooling on exercise ventilation in the awake dog. J. Appl. Physiol., 30: 370-377. Barnes, J.H. (1984) The physiology and pharmacology of emesis. Mol. Aspects Med., 7: 397-508. Berger, A.J. (1979) Distribution of carotid sinus nerve afferent fibers to solitary tract nuclei of the cat using transganglionic transport of horseradish peroxidase. Neurosci. Lett., 14: 153-158. Berger, A.J., Krasney, J.A. and Dutton, R.E. (1973) Respiratory recovery from CO 2 breathing in intact and chemodenervated awake dogs. J. Appl. Physiol., 35: 35-41. Bianchi, A.L. and Gr61ot, L. (1989) Converse motor output to inspiratory bulbospinal premotorneurones during vomiting. Neurosci. Lett., 104: 298-302. Borison, H.L. and Wang, S.C. (1953) Physiology and pharmacology of vomiting. Pharmacol. Rev., 5: 193-230. Cohen, M.I., Miller, A.D., Barnhardt, R. and Shaw, C-F. (1992) Weakness of short-term synchronization among respiratory nerve activities during fictive vomiting. Am. J. Physiol., 263: R339-R347. Davis, R.O. and Edwards, M.W., Jr. (1973) Distribution of carotid body chemoreceptor afferents in the medulla of the cat. Brain Res., 64: 451-454. Eyzaguirre, C. and Lewin, J. (1961) Chemoreceptor activity of the carotid body of the cat. J. Physiol. (Lond.), 159: 222-237. Fukuda, H. and Koga, T. (1991) The B6tzinger complex as the pattern generator for retching and vomiting in the dog. Neurosci. Res., 12: 471-485. Fukuda, H. and Koga, T. (1992) Non-respiratory neurons in the B6tzinger complex exhibiting appropriate firing patterns to generate the emetic act in dogs. Neurosci. Res., 14: 180-194. Gold, H. and Hatcher, R.A. (1926) Studies on vomiting. J. Pharmacol. Exp. Ther., 28: 200-218. Gr61ot, L., Barillot, J.C. and Bianchi, A.L. (1990) Activity of respiratory-related oropharyngeal and laryngeal motorneurones during fictive vomiting in the decerebrate cat. Brain Res., 513: 101-105.
Gwyn, D.G., Leslie, R.A. and Hopkins, D.A. (1979) Gastric afferents to the nucleus of the solitary tract in the cat. Neurosci. Lett., 14: 13-17. Hukuhara, T., Okada, H. and Yamagami, M. (1957) On the behavior of the respiratory muscles during vomiting. Acta Med. Okayama, 11: 117-125. Kalia, M. and Mesulam, M-M. (1980) Brain stem projections of sensory and motor components of the vagus complex in the cat: II. Laryngeal, tracheobranchial, pulmonary, cardiac, and gastrointestinal branches. J. Comp. Neurol., 193: 467-508. Katz, D.M. and Karten, H.J. (1979) The discrete anatomical localization of vagal aortic afferents within a catecholamine-containing cell group in the nucleus solitarius. Brain Res., 171: 187-195. Koga, T. (1991) Discharge patterns of bulbar respiratory neurons during retching and vomiting in decerebrate dogs. Jpn. J. Physiol., 41: 233-249. Koga, T. and Fukuda, H. (1990) Characteristic behavior of the respiratory muscles, esophagus, and external anal and urethral sphincters during straining, retching, and vomiting in the decerebrate dog. Jpn. J. Physiol., 40: 789-807. Koga, T. and Fukuda, H. (1992) Neurons in the nucleus of the solitary tract mediating inputs from emetic vagal afferents and the area postrema to the pattern generator for the emetic act in dogs. Neurosci. Res., 14: 166-179. McCarthy, L.E. and Borison, H.L. (1974) Respiratory mechanics of vomiting in decerebrate cats. Am. J. Physiol., 226: 738-743. Miller, A.D. (1986) Motion-induced nausea and vomiting. In: J. Kucharczyk, D.J. Stewart and A.D. Miller (Eds), Nausea and Vomiting; Recent Research and Clinical Advances, CRC Press, Boca Raton, FL, pp. 13-41. Miller, A.D. and Ezure, K. (1992) Behavior of inhibitory and excitatory propriobulbar respiratory neurons during fictive vomiting. Brain Res., 578: 168-176. Miller, A.D., Lakos, S.F. and Tan, L.K. (1988) Central motor program for relaxation of periesophageal diaphragm during the expulsive phase of vomiting. Brain Res., 456: 367-370. Monges, H., Salducci, J. and Naudy, B. (1978) Dissociation between the electrical activity of the diaphragmatic dome and crura muscular fibers during esophageal distension, vomiting and eructation, An electromyographic study in the dog. J. Physiol. (Paris), 74: 541-554. Nonaka, S. and Miller, A.D. (1991) Behavior of upper cervical inspiratory propriospinal neurons during fictive vomiting. J. Neurophysiol., 65: 1492-1500. Panneton, W.M, and Loewy, A.D. (1980) Projections of the carotid sinus nerve to the nucleus of the solitary tract in the cat. Brain Res., 191: 239-244. Tan, L.K. and Miller, A.D. (1986) Innervation of periesophageal region of cat's diaphragm: Implication for studies of control of vomiting. Neurosci. Lett., 68: 339-344. Wallach, J.H. and Loewy, A.D. (1980) Projections of the aortic nerve to the nucleus tractus solitarius in the rabbit. Brain Res., 188: 247-251.
205
NSR 00658
Hypercapnia and hypoxia which develop during retching participate in the transition from retching to expulsion in dogs Hiroyuki Fukuda and Tomoshige Koga Department of Physiology, Kawasaki Medical School, Kurashiki, Okayama 701-01, Japan (Received 8 February 1993; revised 24 May 1993; accepted 24 May 1993)
Key words: Respiration; Retching; Vomiting; Arterial chemoreceptor; Central chemoreceptor; Blood gas tensions; Sinus nerve Summary The roles of arterial and central chemoreceptors in the transition from retching to expulsion during vomiting were studied. In spontaneously breathing decerebrate dogs, actual vomiting induced by activation of abdominal vagal afferents always consisted of retching and subsequent expulsion phases. Pulmonary ventilation almost stopped during the retching phase. Arterial blood CO 2 tension gradually increased and reached a maximum near the time of the transition from the retching phase to the expulsion phase. Similarly, when end-tidal CO 2 was maintained higher than 4.6 + 0.7% in paralyzed, artificially ventilated decerebrate dogs, stimulation of abdominal vagal afferents induced fictive retching and fictive expulsion, which were identified from the characteristic discharge patterns of the motor nerves to the costal and hiatal parts of the diaphragm, the abdominal muscles and the digastric muscle. However, only fictive retching occurred at an end-tidal CO 2 of less than 3.7 + 0.7%. Although end-tidal CO2 was at a low level, fictive retching was followed by fictive expulsion when artificial ventilation was interrupted during the fictive retching phase and when sinus nerve afferents were stimulated. Even after sino-aortic denervation, fictive retching and subsequent fictive expulsion could be induced by stimulation of either vagal afferents or the solitary tract and nucleus, but the threshold level of end-tidal CO 2 which enabled the induction of fictive expulsion increased after denervation. These results indicate that the activity of arterial and/or central chemoreceptor afferents must exceed some critical level to induce the transition from the retching phase to the expulsion phase.
Introduction Vomiting usually consists of two distinct phases in many animal species, including humans: i.e., retching and expulsion (Borison and Wang, 1953; Barnes, 1984; Miller, 1986; Andrews and Hawthorn, 1988). While both retching and expulsion primarily involve thoracic respiratory muscles and abdominal muscles, these muscles are known to be activated differently during each phase. The diaphragm and abdominal muscles concomitantly contract with each retch and the glottis closes simultaneously (Hukuhara et al., 1957; Mc-
Correspondence to: Hiroyuki Fukuda, Department of Physiology, Kawasaki Medical School, Kurashiki, Okayama 701-01, Japan. Tel.: 086-462-1111; Fax: 086-462-1199.
Carthy and Borison, 1974; Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988; Gr61ot et al., 1990). As a result, pressure in the abdominal cavity increases, while pressure in the thoracic cavity decreases with each retch (McCarthy and Borison, 1974). In contrast, the costal part of diaphragm contracts only during the early part of the expulsion phase. Moreover, the hiatal part of the diaphragm does not contract during the expulsion phase while the abdominal muscles and the adductors of the glottis maintain a powerful contraction (Hukuhara et al., 1957; Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988; Gr61ot et al., 1990). Consequently, positive pressure in the abdominal cavity may be transferred by the relaxed diaphragm to the thoracic cavity (McCarthy and Borison, 1974). The positive thoracic pressure may cause projectile expulsion. The mouth, which is closed during
206 retching, is opened widely for the expulsion phase (Borison and Wang, 1953; McCarthy and Borison, 1974). In decerebrate spontaneously breathing cats (McCarthy and Borison, 1974; Tan and Miller, 1986; Miller et al., 1988) and dogs (Hukuhara et al., 1957), application of emetic drugs or activation of abdominal vagal afferents induces vomiting which normally involves a retching phase followed by expulsion phase. Similarly, in paralyzed decerebrate cats (Bianchi and GrElot, 1989; Gr61ot et al., 1990; Nonaka and Miller, 1991; Miller and Ezure, 1992) and dogs (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992), vagal stimulation induces characteristic activities in the muscle nerves to the abdominal muscles, the hiatal and costal parts of the diaphragm (Miller et al., 1988; Fukuda and Koga, 1991) and the glottis (Fukuda and Koga, 1991). The temporal and spatial patterns of the characteristic activities of these muscle nerves in paralyzed animals are similar to those in the electromyograms recorded from these muscles during the retching and expulsion phases in nonparalyzed animals (Hukuhara et al., 1957; McCarthy and Borison, 1974; Tan and Miller, 1986; Miller et al., 1988). Consequently, the characteristic activities in these muscle nerves of paralyzed animals have been referred to as fictive retching and fictive expulsion (Bianchi and GrElot, 1989; Gr61ot et al., 1990; Koga and Fukuda, 1990, 1992; Koga, 1991; Nonaka and Miller, 1991; Fukuda and Koga, 1991, 1992; Cohen et al., 1992; Miller and Ezure, 1992). Therefore, somatic afferent activity may not participate in the transition from retching to expulsion. However, cause of this phase transition has not yet been determined. Gold and Hatcher (1926) have demonstrated that pulmonary ventilation is interrupted during the retching phase in spontaneously breathing dogs and cats. Consequently, hypercapnia and hypoxia are thought to develop during the retching phase prior to the phase transition in these nonparalyzed animals. In contrast, blood gas tension does not change during the fictive retching phase in paralyzed decerebrate animals, since constant artificial ventilation is maintained during fictive retching. When end-tidal CO 2 is maintained below 3.0% during the fictive retching phase in paralyzed dogs, fictive retching is rarely followed by fictive expulsion (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992). In contrast, fictive retching is always followed by fictive expulsion in paralyzed decerebrate cats, in which end-tidal CO 2 is routinely maintained higher than 3.5% (Bianchi and GrElot, 1989; Nonaka and Miller, 1991; Cohen et al.,
1992; Miller and Ezure, 1992). Based on these observations, we assumed that hypercapnia and/or hypoxia play a critical role in the transition from the retching phase to the expulsion phase. The present study was performed to evaluate this assumption.
Materials and methods
Eighteen dogs were used for this study, each weighing 5-10 kg. All of the dogs were anesthetized with an intramuscular injection of ketamine hydrochloride (25 mg/kg) and became quite flaccid within 5 min of the injection. During the subsequent 10 rain, 16 of the dogs were paralyzed with gallamine triethiodide (2 mg/kg, i.v.), artificially ventilated through a tracheal cannula, and precollicularly decerebrated. The dogs were then allowed to recover from the anesthesia and no further anesthesia was applied. The temperature of the abdominal cavity was maintained at 37-39°C by radiation from two 100-W tungsten lamps and a heating plate which was automatically controlled by negative feedback from the dogs' body temperatures. The pressure of the femoral artery, and the CO 2 and O 2 concentrations in tracheal air were monitored throughout the experiments. Centrifugal activities of the branch of the L1 spinal nerve to the rectus abdominis of all 16 dogs, the phrenic branch of the C5 spinal nerve of 14 dogs, the hiatal and costal branches of the phrenic nerve of 2 dogs and the trigeminal branch to the digastric muscle of 5 dogs were recorded as frequency histograms (100 ms bins) with a pen recorder. Fictive retching and expulsion were recognized from their activity patterns as described in other papers (Tan and Miller, 1986; Miller et al., 1988; Bianchi and Gr61ot, 1989; Gr61ot et al., 1990; Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992; Miller and Ezure, 1992; Nonaka and Miller, 1991). Fictive vomiting was induced by continuous stimulation of the vagal ventral trunk at the supra-diaphragmatic region in 14 dogs, and by stimulation of the solitary tract and nucleus in 4 dogs. The solitary tract and nucleus were stimulated with a monopolar cathode (lacquer-coated platinum wire 0.5 mm in diameter) placed on the surface of the vagal triangle. The bilateral sinus nerves were cut in 15 dogs, and stimulated in 9 dogs. The left and right aortic nerves were cut near the middle cervical ganglion and/or at the middle cervical portion (by a severing the vagosympathetic trunk) in 5 dogs. The remaining 2 dogs were similarly anesthetized and decerebrated, but not paralyzed. A balloon was
207 inserted into the stomach through an incision of the cervical esophagus. Actual vomiting was induced by distention of the stomach with 200-400 ml of air. The recurrent nerves were isolated from a cervical portion of the trachea. The trachea was then severed, and the severed ends were connected with two rectilinear branches of a T-cannula. Intra-tracheal pressure and CO 2 and O 2 concentrations in tracheal air (TrCO2, TrO 2) were recorded through the other rectangular branch of the cannula. Arterial blood samples of 2 - 3 ml were obtained during vomiting from the femoral artery via a cut-down tube. CO 2 and 0 2 tensions (PaCO 2, PaO 2) and the pH of the samples were measured using a blood gas analyzer.
decerebrate dogs. The threshold volume of the stomach was 2 8 3 _ 1 2 0 ml (mean_+SD, n = 9 ) . Intratracheal pressure and COz and 0 2 concentrations in tracheal air (TrCO2, TrOz; vol.%) and arterial blood (PaCO2, PaOz; Torr) were measured. Before the first vomiting episode was induced, the mean end-tidal TrCO 2 and TrO 2 and respiratory rate were 4.8%, 16.8% and 12.7 rpm, respectively. Fig. 1 shows a typical result. Each retch is represented as a negative pressure pulse (black triangle) in the intra-tracheal pressure trace, and expulsion is represented as a positive pulse indicated by a bar (E). These changes in the tracheal pressure are comparable to the changes in thoracic venous pressure observed during actual vomiting in nonparalyzed decerebrate cats by McCarthy and Borison (1974). A delay of 2.4 s caused by the tube (1.5 m in length) through which the tracheal air was sampled exists between the trace of intra-tracheal pressure and those of TrCO 2 and TrO 2. This delay is indicated by vertical and oblique lines. The respiratory rate gradually increased from 38.1 _+ 21.7 s (between vomiting, Table 1) during stomach distension to 64.6 + 24.9 rpm before retching (prodromal phase, Table 1; P in Fig. 1). As a result, end-tidal TrCO 2 and TrO 2 changed to 3.0 + 0.3% and
Results
I. Experiments in nonparalyzed spontaneously breathing decerebrate dogs Changes in C O 2 and 0 2 concentrations in tracheal air and arterial blood during vomiting Nine vomiting episodes were induced at intervals of about 25 min by stomach distention in 2 nonparalyzed
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E
Fig. 1. Changes in intra-tracheal pressure and COz and 02 concentrations in tracheal air and arterial blood during actual vomiting of a nonparalyzed decerebrate dog. From top to bottom, the traces represent tracheal air 02 (TrO2, vol%), arterial blood 02 tension (PaO2, Torr), arterial blood CO2 tension (PaCO2, Torr), tracheal CO2 (TrCO2, vol%) and intra-tracheal pressure. Each actual retch is represented as a negative pressure pulse in the trace of intra-tracheal pressure ( • ) and an actual expulsion corresponds to a positive pressure pulse which is indicated by a horizontal bar (E). Vomitingwas induced by stomach distention with 3 injections of 100 ml air at .~. Total volumes of injected air are indicated in parentheses as T.200 = 200 ml, T.300 = 300 ml and T.0 = 0 ml. All 300 ml of air was removed at T. Vomiting and preceding and subsequent respiratory changes were divided into the prodromal phase (P), pre-retching phase (PR), 1st retching phase (R1), 2nd retching phase (R2), expulsion phase (E) and the after-tachypnea phase (AT). Traces (12 s) were omitted during the AT phase.
208 17.2 + 1.4%, respectively (Table 1, P in Fig. 1). Next, just before retching, TrCO 2 and TrO 2 reached levels near those of fresh air, and these values were maintained for 3.8 _+2.2 s (n = 9) (pre-retching phase, Table 1; PR in Fig. 1). This pre-retching phase was observed in all 9 vomiting episodes. This result indicates that exhalation of alveolar air is suppressed during the pre-retching phase. During the pre-retching phase of fictive retching in paralyzed decerebrate dogs, discharge of the phrenic nerve increased and persisted even during expiratory phases (Figs. 2B, 4, 6B, 7). The phrenic expiratory discharge may sustain diaphragm contraction during expiration and prevent exhalation of alveolar air in nonparalyzed dogs. Therefore, the preretching phase is considered to be the period during which exhalation of alveolar air is limited and lung volume is increased. TrCO 2 and TrO 2 respectively increased and decreased at the beginning of retching, and then gradually and steadily changed for 16.3 _+ 3.5 s (n = 9) to reach their respective maximum (TrCO2, 5.0 +_0.5%) and minimum (TrO2, 12.8_+ 0.8%) values near the midpoint of the retching phase (lst phase of retching, Table 1; R1 in Fig. 1). The negative pressure pulses indicate that 14.3 _+3.1 retches occurred during the 1st phase of retching. However, these pressure pulses were not accompanied by any rapid changes in TrCO 2 and TrO 2 which were comparable to the changes caused by tracheal air flow during respiration (Fig. 1). This result indicates that tracheal air does not flow during the 1st phase, as demonstrated by Gold and Hatcher (1926). Therefore, this result is believed to be consistent with previous results which showed that the glottis was closed concomitantly with each retch (Hukuhara et al., 1957; Gr61ot et al., 1990; Fukuda and Koga, 1991; Koga and Fukuda, 1992). After the 1st phase, rapid and transient changes of various amplitudes in TrCO 2 and TrO 2 occurred between retches (2nd phase of retching, Table 1; R2 in Fig. 1). The rapid changes suggest that actual ventilations occur between retches in the 2nd phase. The 2nd phase lasted for a mean of 15.2 _+ 7.3 s and consisted of 10.0 +_4.3 retches. The 2nd phase was followed by an expulsion phase of 5.5 _+3.5 s, in which 2-4 (mean of 2.3 _+0.5) expulsion episodes occurred. However, the maximum and minimum end-tidal TrCO 2 and TrO 2 observed during the 2nd and expulsion phases were comparable with the maximum TrCO 2 and minimum TrO 2 attained during the 1st phase, respectively (Table 1). After the expulsion phase, the respiratory rate increased again to 72.9_+ 28.3 rpm and, consequently,
end-tidal TrCO 2 and TrO 2 became 2.7 +_0.5% and 17.6 _+0.8%, respectively (Table 1). During the 25 min intervals between vomiting episodes, these values did not recover to those observed before the 1st vomiting episode was induced (Table 1). PaCO 2 and PaO z of arterial blood steadily increased and decreased, respectively, during the 1st phase of retching, and reached respective maximum and minimum values during the 2nd phase. Arterial blood pH became 7.34 _+0.02 at the 2nd phase. These values of PaCO 2, PaO 2 and pH remained almost constant during the expulsion phase (Fig. 1, Table 1). These values of TrCO 2, TrO2, PaCO 2, PaO 2 and pH in the 1st and 2nd phases of retching, and in the expulsion phase significantly differed from the respective control values observed during the periods between vomiting episodes (Table 1).
I1. Experiments in paralyzed and artificially centilated decerebrate dogs Effects of an interruption of artificial uentilation on the phase transition from retching to expulsion If the sustained cessation of ventilation during the 1st phase of actual retching of nonparalyzed dogs induces the transition from the retching phase to the expulsion phase, then interrupting artificial ventilation during fictive retching of paralyzed dogs may induce a phase transition from fictive retching to fictive expulsion. Fig. 2 shows an example of the experiments which were performed in 5 paralyzed decerebrate dogs to examine this assumption. Concomitant burst firings of the phrenic and abdominal muscle nerves represent fictive retches, which are numbered in Fig. 2. A chain of 21 fictive retches was induced by stimulating vagal afferents at an endtidal TrCO 2 of 3.4%, but fictive expulsion did not occur (Fig. 2A). In contrast, when artificial ventilation was discontinued 14 s before retching began, TrCO 2 reached 7.3% at the 12th fictive retch and 2 episodes of fictive expulsion were successively induced, as indicated by horizontal bars (Fig. 2B). Fictive expulsion was recognized as the episode following retching in which the burst duration of the abdominal muscle nerve prolonged both with respect to the corresponding vomiting burst of the phrenic nerve and to the bursts of the abdominal muscle nerve during the preceding retching phase. When an interruption of artificial ventilation was initiated at a later time, fictive retching was prolonged, and, consequently, occurrence of fictive expulsion was delayed. For example, when artificial ventilation was
pH
02
CO 2
12.7 (2) 4.8 (2) 16.8 (2)
< 64.6 ± 24.9 * (9) > 3.0±0.3 * (9) < 17.2± 1.4 (9)
Prodromal phase
> 0.4±0.3 * (9) < 19.0± 1.0 * (8)
Pre-retching phase
<5.0±0.5" (9) >12.8±0.8" (9) 31.5 ± 1.7 * (6) 73.7±9.9* (6) 7.35 ± 0.03 * (6)
1st retching phase
<4.8±0.5* (8) >12.5±1.4" (8) 33.8± 3.4 * (7) 54.3±7.9* (7) 7.34 ±0.02 * (7)
2nd retching phase
<4.8±0.6" (8) >13.7±2.2" (8) 32.4 ±3.4 * (7) 68.4±5.4* (7) 7.34±0.02 * (7)
Expulsion phase
< 7Z9.±28.3 * (9) >2.7+0.5* (8) <17.6±0.8 (8) 24.7± 1.9 * (7) 95.4±8.6 (7) 7.42±0.05 (7)
After-tachypnea phase
> 38.1 ± 2 1 . 7 (7) <3.4±0.4 (7) >16.9±1.6 (7) 26.6± 1.0 (9) 87.9±8.3 (9) 7.39± 0.03 (9)
Between vomiting
Episodes of vomiting were induced at intervals of about 25 min. Vomiting and preceding and subsequent respiratory changes are divided into the prodromal, pre-retching, 1st retching, 2nd retching, expulsion and after-tachypnea phases. Values for respiratory rate and end-tidal C O 2 and 0 2 which are indicated by < and > represent the m e a n s of the maximum and m i n i m u m values attained during the phase, respectively. Since pulmonary ventilation ceased during the pre-retching phase and the 1st phase of retching, the m e a n s of the m a x i m u m CO 2 and m i n i m u m 0 2 concentrations of tracheal air which were attained during both phases are shown. N u m b e r s in p a r e n t h e s e s indicate the n u m b e r of emetic acts upon which the mean value were based. Mean values which are marked with an asterisk significantly differ from the corresponding values obtained between emetic acts (Student's t-test, P < 0.001-0.05).
Arterial blood (Torr)
Respiratory rate (rpm) End-tidal CO 2 (vol.%) Oz
Before 1st vomiting
Phases of vomiting and preceding and subsequent respiratory changes
C H A N G E S IN R E S P I R A T O R Y R A T E A N D E N D - T I D A L A N D A R T E R I A L CO 2 A N D O z C O N C E N T R A T I O N S W I T H A C T U A L V O M I T I N G
TABLE 1
tO
210 A
1
5
10
phrenlc n.
!t~t~T~t~,~
15
TrCO 2 at the time of the transition was 6.3 _+ 1.3f:f
20 \ ~
1s°'mp/b'r'
blood p. ,..~.i.. ................................................~,~,,,,,........................... . ~ . ~....~ . , ] ~ ] ~ 150rnmHg C0=(%)
3.4%
l.~,i~,-i.chllll p. vague
B
n, lOl,lz, 20V 1
5
10
13
~
=,,,,,,,=.._
EI t
E
,,u t!".ltHlu , . ! ,, k,,,ru' j ~,,,,,, "
. . . . . . . . . . . . . . . . . . . ...................,..............' " " = ' - - ' - - 73%
-1
~,~,_D_/" ? . _ P - - - - - . . . . . . . . . . . . . . .
(n = 5)
Effects of stimulating sinus nerc'e afferents on the transition form retching to expulsion If the transition from the retching phase to the expulsion phase is induced by hypercapnia a n d / o r hypoxia which develops during the retching phase, then arterial chemoreceptor afferents may contribute to the transition. To examine this possibility, sinus nerve afferents were stimulated during fictive retching in 8 paralyzed decerebrate dogs, as shown in the example in Fig. 3. End-tidal TrCO 2 was maintained at 2.6% throughout the experiment. A long chain of 29 fictive retches, without fictive expulsion, was induced by vagal stimulation (Fig. 3A). However, sinus nerve stimulation (8 V, 10 Hz) superimposed on the vagal stimulation just after the 20th retch induced a transition from fictive retching to fictive expulsion (Fig. 3B). The same sinus nerve
] 5@ec
Fig. 2. Effects of interrupting artificial ventilation on fictive retching which had been induced by stimulating abdominal vagal afferents. From top to bottom, the traces represent frequency histograms (100 ms bins) of the phrenic branch of the C5 spinal nerve (phrenic n.) and the rectus abdominis branch of the L1 spinal nerve (abdominal m. n.), blood pressure of the femoral artery (blood p.), CO2 concentration in tracheal air (CO2(%)), intra-tracheal pressure (intratracheal p.) and downward pulses representing stimulating pulses (10 Hz, 20V, 0.5 ms in duration) which were applied to vagal afferents. The pulses were fused by the pen recorded and appear as the thickened part of the bottom trace. Thus, the thickened part indicates the period of stimulation. Concomitant increases in discharges of the phrenic and abdominal muscle nerves represent fictive retches. Ordinal numbers of retches are indicated. Vagal afferent stimulation induced fictive retching, but not fictive expulsion at an end-tidal CO~ of 3.4% (A). Artificial ventilation was discontinued during the period indicated by the intra-tracheal pressure trace in B. TrCO 2 increased to 7.3% and 2 episodes of fictive expulsion (E) were induced. Traces of 19 and 20 s were omitted at the interrupted regions of A and B, respectively. These explanations also apply to the following figures.
A
blOOd
1
p.
,
5
10
15
20
25
29
....................,..............................~.............., ...........~,..~l.,,,litt,u,am~,~twlI,L]
vagus n. l OH=, ~I)V
B
1
5
10
5,see: 15
,
"
20 ~ ~ ;'~ ~
50Imp/bin
E,,,alJJ~,~., 1 1 S 0 m m H g
2::7~""i!"'-"!,':' ' ~ ! ' ' ~ ! = ~ ~,.~.z~.~_p. ~ ~ ~ J ~ F ~ ] ( ~
"~1 s) */*
M m m n. 2 0 H z . l § V
discontinued at the beginning of retching in the dog from which the traces in Fig. 1 were obtained, fictive expulsion was induced after the 19th retch, upon which TrCO 2 increased to 7.3%. A transition from the retching phase to the expulsion phase was also induced by interrupting artificial ventilation in 4 other dogs, and TrCO 2 was monitored in 2 of the 4 dogs. The mean
Fig. 3. Effects of stimulation of sinus nerve afferents on fictive retching. Fictive retching without fictive vomiting was induced by vagal afferent stimulation at an end-tidal CO 2 of 2.6% (A). Fictive expulsion was induced by stimulation (20 Hz, 15 V, 0.5 ms) of left sinus nerve afferents which was superimposed on vagal afferent stimulation (B). Pulses stimulating sinus nerve afferents are represented in the bottom trace by upward pulses, which have been fused by the pen recorder to appear as the thickest part. Traces of 7 and 15 s were omitted at the interrupted regions in A and B, respectively.
211 stimulation applied earlier (at the 15th retch) during the fictive retching phase transiently interrupted the retching, but did not induce fictive expulsion. However, an intensified sinus nerve stimulation (8 V, 40 Hz) applied at a similar time did induce fictive expulsion. Phase transitions were also induced by sinus nerve stimulation in 7 other dogs and the threshold frequency of the sinus nerve stimulation which induced the transitions similarly decreased as fictive retching progressed in all 3 of the other dogs in which this phenomenon was observed.
A phrenlc costal br.
1
10
15
17
,ck/'~rkA.
dlgastrlc i x .
j
blood p
IIIIIIIIIIIIM
..........
Is fictive expulsion induced by interrupting artificial ventilation or stimulating sinus nerve afferents the same as actual expulsion ? To determine whether fictive expulsion in paralyzed dogs and actual expulsion in nonparalyzed dogs are identical, activities of the motor nerves to the hiatal region of the crural diaphragm and to the digastric muscle were observed during fictive vomiting in 2 and 5 paralyzed decerebrate dogs, respectively. These nerves were selected because the mouth opens with actual expulsion in nonparalyzed dogs and cats, but not with actual retching (Borison and Wang, 1953; McCarthy and Borison, 1974) and because the hiatal diaphragm contracts with each actual retch, but not with actual expulsion (Monges et al., 1978; Tan and Miller, 1986; Miller et al., 1988). In the experiment shown in Fig. 4, a hiatal branch of the phrenic nerve exhibited a characteristic activity pattern with each fictive retch: its discharge frequency reached a maximum at an early phase of each fictive retch and then promptly decreased. Discharge of the hiatal branch completely disappeared during fictive expulsion without regard to the stimuli which were used to elicit fictive expulsion, i.e, an interruption of artificial ventilation (Fig. 4A) or stimulation of sinus nerve afferents (Fig. 4B). These discharge patterns during fictive retching and fictive expulsion are quite similar to the electromyograms recorded from the hiatal diaphragm during actual vomiting in dogs (Monges et al., 1978) and cats (Tan and Miller, 1986; Miller et al., 1988). In contrast, the digastric muscle branch did not discharge with each fictive retch, but exhibited characteristic discharges with fictive expulsions which were induced by either of the stimuli: inspiratory burst discharge(s) just be-fOte'lxpulsion, a high frequency discharge which started during fictive expulsion and stopped at the beginning of the next expiratory phase, and inspiratory discharges during several subsequent breaths (Fig. 4A, B).
5
!
II
!
~ I~UU ~
~lll
~ IIIIIIl
/
Intratracheal p,~
vagus n. lOHz, 2 0 V
Se~
S
5
.
.
.
.
10
14
Lo
;
~SOmmHg .....
"
"""J 50
.4_iU~U_?s% _L? U~ULC ~~ ULLA~ULFU Z U_kj~k ULILi]~° ~ ° t
slnus n, i O l ~
Fig. 4. Discharge patterns of the phrenic costal branch> the phrenic crural branch innervating the hiatal region of the diaphragm, and the digastric muscle branch of the trigeminal nerve during fictivevomiting. Fictive retching was induced by vagal afferent stimulation and fictive expulsionwas induced by interrupting artificial ventilation (A) or by stimulating left sinus nerve afferents (B). Stimulationof the left sinus nerve (10 Hz> 8 V, 0.5 ms) was applied immediately after the vagal afferent stimulation was discontinued. Pulses of sinus nerve stimulation are represented as upward pulses on the bottom trace. Traces of 8 s were omitted at the interrupted region in B.
Similar activity patterns of the phrenic branch to the hiatal diaphragm and the digastric muscle nerve were observed during fictive retching and fictive expulsion in 1 and 4 other paralyzed decerebrate dogs, respectively.
Role of central chemoreceptors in the transition from retching to expulsion To clarify the role of central chemoreceptors in the phase transition from retching to expulsion, we performed sino-aortic denervation in 5 paralyzed decerebrate dogs and examined whether or not the phase transition could be induced by an increase in TrCO z even after denervation. When a higher level of end-tidal TrCO 2 was maintained, continuous stimulation of abdominal vagal af-
212 (%)
which only fictive r e t c h i n g was i n d u c e d was significantly (p < 0.02) i n c r e a s e d from 3.7 _+ 0.7% (n = 5) to 5.0 + 1.32% (n = 5) by the d e n e r v a t i o n ( o p e n c o l u m n in Fig. 5). Similarly, the m e a n m i n i m u m e n d - t i d a l T r C O 2 at which fictive r e t c h i n g a n d s u b s e q u e n t fictive expulsion w e r e i n d u c e d was significantly (p < 0.01) inc r e a s e d from 4.6 _+ 0.7% (n - - 5 ) to 6.2 + 1.2% (n = 5) ( h a t c h e d column). T h e role of the c e n t r a l c h e m o r e c e p t o r s was also e x a m i n e d in fictive r e t c h i n g a n d fictive expulsion which w e r e i n d u c e d by s t i m u l a t i n g t h e solitary tract a n d its nucleus (the solitary complex). U s i n g l a c q u e r - c o a t e d p l a t i n u m wire (0.5 m m in d i a m e t e r ) as a m o n o p o l a r c a t h o d e , the solitary c o m p l e x was s t i m u l a t e d from t h e surface of the vagal t r i a n g l e on the floor of the 4th ventricle in 4 p a r a l y z e d d e c e r e b r a t e dogs in which the sinus nerves h a d b e e n cut. S t i m u l a t i o n of the rostral p o r t i o n of the vagal triangle (Fig. 6C, a) elicited fictive r e t c h i n g a n d fictive expulsion, as shown in Fig. 6A. H o w e v e r , t h e s a m e s t i m u l a t i o n a p p l i e d to m o r e c a u d a l sites of the t r i a n g l e (Fig. 6C, b) i n d u c e d only fictive r e t c h i n g (Fig. 6B). Interestingly, s t i m u l a t i o n which was a p p l i e d to m o r e rostral sites c a u s e d l a r g e r i n c r e a s e s o f arterial b l o o d p r e s s u r e . Similar r e g i o n a l d i f f e r e n c e s in t h e s e effects of s t i m u l a t i o n w e r e also o b s e r v e d in 3 o t h e r dogs. However, fictive r e t c h i n g a n d fictive expulsion responses to s t i m u l a t i o n of a site in t h e vagal t r i a n g l e v a r i e d a c c o r d i n g to the levels of e n d - t i d a l T r C O 2 even
7.0
I
i
6.0
o"
o m 'o
i "0 p, UJ
5.0 4.0
3,0
],. before after slno-aortlc denervatlon
Fig. 5. Effects of sino-aortic denervation on the maximum end-tidal TrCO2 levels at which vagal afferent stimulation induced fictive retching alone (open column), and on the minimum end-tidal CO2 levels at which vagal afferent stimulation induced both fictive retching and fictive expulsion (hatched column). Data represent averages of the maximum and minimum end-tidal TrCO~ levels observed before and after sino-aortic denervation in 5 dogs (mean _+SD). * P <0.02, ** P < 0.01. f e r e n t s e l i c i t e d fictive r e t c h i n g a n d s u b s e q u e n t fictive expulsion b e f o r e , as well as after, s i n o - a o r t i c d e n e r v a tion. H o w e v e r , the m e a n m a x i m u m e n d - t i d a l T r C O 2 at
A
B
phrenlc n.
,
~ L~.n~,~ ~
.
a l x l o m l m l l m. n.
E
t'2 -°
L. solitary complex 10Hz, 400pA a
b
sff
1ram Fig. 6. Regional differences in the effects of stimulation of the solitary complex in a paralyzed decerebrate dog in which the bilateral sinus nerves had been severed. End-tidal TrCO 2 was maintained at a low level of 2.9% in A and B. Stimulation of the solitary complex at site "a" in C induced fictive retching, fictive expulsion and an increase in blood pressure (A). However, the same stimulation applied to site "b" did not elicit fictive expulsion (B). Pulses stimulating the solitary complex are represented by downward pulses on the bottom trace.
213 after sino-aortic denervation, as shown in Fig. 7. In this example, stimulation of a site in the rostral vagal triangle induced both fictive retching and fictive expulsion at an end-tidal TrCO 2 of 3.0% (Fig. 7A), but only fictive retching at 1.5% (Fig. 7B). Similar changes were observed in 6 trials in 4 paralyzed decerebrate dogs in which sino-aortic denervation had been performed. In the 6 trials, the mean maximum end-tidal TrCO z at which only fictive retching was induced was 3.7 + 1.6%, and a mean minimum TrCO 2 at which fictive expulsion followed fictive retching was 4.3 + 1.7%,
Discussion
Similarity between fictive vomiting induced by activating chemoreceptor afferents and actual vomiting Borison and Wang (1953) have described retching and vomiting (expulsion) by noting that "movements suggestive of vomiting are not equivalent to retching since retching is not ordinarily accompanied by opening of the mouth. The mouth opens immediately preceding the evacuation of the stomach whether vomiting is projectile or labored". We also frequently observed similar mouth opening during actual expulsion in awake and nonparalyzed decerebrate dogs. The activity pat-
terns of the digastric nerve, which were observed in this study during fictive expulsion (Fig. 4), are believed to correspond to the opening of the mouth. Activities of the hiatal region of the diaphragm have been observed during actual retching and actual expulsion by electromyography in dogs (Monges et al., 1978) and cats (Tan and Miller, 1986; Miller et al., 1988). These studies clearly demonstrated that the hiatal region, in contrast to the costal region, is quiescent during actual expulsion, but exhibits a characteristic activity pattern with each actual retch: i.e., its activity reaches a maximum at an early phase of each actual retch and then promptly decreases. Discharge patterns similar to the previous electromyograms were exhibited in the present study by the phrenic branch to the hiatal region during fictive retching and fictive expulsion (Fig. 4). These activity patterns of the digastric muscle nerve and the phrenic hiatal branch indicate that the fictive expulsion which was induced in this study corresponds to actual expulsion in spontaneously breathing animals.
Participation of arterial and central chemoreceptor afferents in the transition from retching to expulsion Before the first episode of actual vomiting was induced by stomach distention in nonparalyzed, spontaneously breathing decerebrate dogs in this study, the
A phrenic n.
/L;-7
abdominal m.n. b l o o d p.
1o ,,**, •. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
COd%)
.~
~,~E
Osommttg 150
3.o~ ~
~
I- smlllary complex 10Hz,
o
3%
200pA
B
.... ih,.,lh..,,I ...............
~,llh,,UlhlJiUl,,~h,ullh,dJl"ll~lll[[ll'"¢h'¢lJlll'll~'*~lllfl
~lli~Uil~ltlllh'*ll
I
,
i
1.5%
Fig. 7. Effects of end-tidal Tr(~,O 2 levels on fictive retching and fictive expulsion responses to stimulation of the solitary complex in a paralyzed decerebrate dog m which smo-aortlc denervatlon had been performed. The solitary complex was stimulated at a site in the rostral region of the vagal triangle in A and B. Fietqve retching and fictive expulsion were induced at an end-tidal TrCO a level of .3.0% (A), but only fictive retching was induced when the end-tidal C O : level was lowered to 1.5% by increasing the frequency of artificial ventilation (B). Traces of 8 and 15 s were omitted at the interrupted regions in A and B, respectively. .
.
.
r ) h
.
214 dogs exhibited respiratory rates and end-tidal TrCO 2 and TrO 2 levels which were thought to be ordinary (Table 1). These values are comparable to those which have been previously reported in dogs (Bainton and Mitchel, 1971; Berger, 1979). A long-lasting tachypnea phase followed each episode of actual vomiting, and the tachypnea did not completely recover during the 25 min interval between episodes of actual vomiting (Table 1). As a result, PaCO 2 reached an extraordinarily low value during the period between vomiting episodes (Table 1). However, during these episodes, actual vomiting always consisted of actual retching and subsequent actual expulsion. Pulmonary ventilation was completely interrupted during the 1st phase of actual retching and was depressed during the 2nd phase (Fig. 1). Consequently, PaCO 2 and PaO 2 steadily increased and decreased, respectively, during actual retching (Fig. 1, Table 1). These changes in PaCO 2 and PaO 2 suggest that activity of arterial and central chemoreceptors gradually increases as actual retching progresses (Eyzaguirre and Lewin, 1961). Stimulation of abdominal vagal afferents induced fictive retching in paralyzed decerebrate dogs, but the fictive retching was not followed by fictive expulsion when end-tidal TrCO 2 was below 3.7 + 0.7%. In contrast, fictive expulsion always followed fictive retching when end-tidal TrCO 2 was higher than 4.6 + 0.7%. Both results are consistent with previous observations: i.e., fictive retching was always followed by fictive expulsion in paralyzed decerebrate cats in which end-tidal TrCO 2 was maintained at 3.5-6.0% (Tan and Miller, 1986; Miller et al., 1988; Bianchi and Gr61ot, 1989; Gr61ot et al., 1990; Cohen et al., 1992; Miller and Ezure, 1992), while fictive retching was only occasionally followed by fictive expulsion in paralyzed decerebrate dogs in which end-tidal TrCO 2 was maintained at 2.0-3.5% (Koga and Fukuda, 1990, 1992; Koga, 1991; Fukuda and Koga, 1991, 1992). Although end-tidal TrCO 2 was maintained at a low level, fictive expulsion could be induced by interrupting artificial ventilation during the fictive retching phase (Figs. 2 and 4A), and by stimulating sinus nerve afferents later during the fictive retching phase (Figs. 3 and 4B). Even after sino-aortic denervation, fictive retching and fictive expulsion could be induced by stimulating abdominal vagal afferents and the solitary complex. However, the end-tidal TrCO 2 levels at which fictive expulsion followed fictive retching increased after denervation (Figs. 5 and 7). These results indicate that the activity of arterial a n d / o r central chemoreceptors must exceed some critical level to induce the transition from the retching
phase to the expulsion phase. However, this dose not exclude the possibility that sensory cells a n d / o r neurons, which are sensitive to changes in PaCO 2 a n d / o r PaO 2, and which exist in tissue other than the carotid and aortic bodies and the ventral medulla chemosensitire areas, are participate in the phase transition. As mentioned above, stimulation of sinus nerve afferents during fictive retching induced the transition from fictive retching to fictive expulsion in paralyzed, artificially ventilated decerebrate dogs. Interestingly, the threshold intensity of the stimulation gradually decreased as retching progressed. PaCO 2 and PaO 2 may not have changed during the fictive retching phase because constant artificial ventilation was maintained. Therefore, the change in this threshold suggests that the pattern generator of the emetic act (Fukuda and Koga, 1991, 1992; Koga and Fukuda, 1992) progressively increases its responsiveness to arterial and central chemoreceptor afferents during the retching phase. Based on these results, the transition from actual retching to actual expulsion in nonparalyzed spontaneously breathing dogs is believed to occur as follows: PaCO 2 and PaO 2 gradually increase and decrease, respectively, during cessation of pulmonary ventilation in the actual retching phase, thereby activating arterial and central chemoreceptor afferents. In parallel with these changes, the pattern generator for the emetic act (Fukuda and Koga, 1991, 1992; Koga and Fukuda, 1992) progressively increases its responsiveness to the chemoreceptor afferents and the threshold activity level of the afferents which enables the transition from retching to expulsion decreases. Consequently, the retching phase is changed to the expulsion phase by the increasing afferent activity when the activity exceeds the decreasing threshold level. Fictive expulsion after fictive retching was induced by stimulation of the rostral region of the solitary complex, although end-tidal TrCO 2 was at a very low level (Figs. 6 and 7). Sinus and aortic nerve afferents distribute primarily to the lateral region of the medial subnucleus of the solitary tract (Davis and Edwards, 1973; Berger, 1979; Katz and Karten, 1979; Panneton and Loewy, 1980; Wallach and Loewy, 1980), whereas most vagal gastric afferents terminate in the medial region (Gwyn et al., 1979; Kalia and Mesulam, 1980). However, both distributions extend rostro-caudally and overlap. In the present study, when stimulation was applied to the surface of the Vagal triangle to activate the solitary complex, arterial blood pressure increased, along with fictive retching and fictive expulsion responses. Therefore, stimulation seems to activate both arterial chemoreceptor and vagal abdominal afferents,
215 and, consequently, it can induce fictive expulsion despite very low end-tidal TrCO 2 levels. Thus, the findings observed during solitary complex stimulation are not thought to contradict the conclusions mentioned above. Acknowledgment This work was supported in part by Project Research Grants from Kawasaki Medical School.
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