Role of the autonomic nervous system in emetic and cardiovascular responses in Suncus murinus

Autonomic Neuroscience: Basic and Clinical 100 (2002) 32 – 40 www.elsevier.com/locate/autneu

Role of the autonomic nervous system in emetic and cardiovascular responses in Suncus murinus Masahiro Uchino a,*, Keiji Ishii a, Masayoshi Kuwahara a, Susumu Ebukuro b, Hirokazu Tsubone a a

Department of Comparative Pathophysiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan b Animal Resource Center, Central Institute for Experimental Animals, 1430 Nogawa, Miyamae, Kawasaki 216-0001, Japan Received 25 January 2002; received in revised form 14 May 2002; accepted 25 June 2002

Abstract To clarify the role of the autonomic nervous system in cardiovascular and emetic responses, we studied the influence of drugs that act on autonomic nervous function on emetic and cardiovascular responses induced by chemical or mechanical stimulation to the stomach in two strains of Suncus murinus, Jic:SUN-Her and Jic:SUN-Ler. Latency to the first retching in Jic:SUN-Her was significantly shorter than that in Jic:SUN-Ler to both mechanical and chemical stimulation. This result indicated that there are different sensitivities to mechanical and chemical stimulation to the stomach in these two strains of suncus. However, the numbers of emetic episodes were almost the same in these two strains. Mean blood pressure significantly increased from baseline prior to retching in both strains. Heart rate decreased in Jic:SUN-Her and increased in Jic:SUN-Ler prior to retching, suggesting that a different baroreflex responsiveness might exist in these two strains of suncus. Administration of acetylcholine and phenylephrine affected emetic response induced by mechanical and chemical stimulation. Although the baseline values of mean blood pressure and heart rate after administration of these drugs were different, changes in mean blood pressure and heart rate prior to retching were unaffected. This result suggested that the state of autonomic activity before the emetic response might be important in the development of the emetic response. Pretreatment with hexamethonium suppressed the cardiovascular response prior to retching and prolonged the latency to the first retching. This result indicated that there was an interaction between the mechanisms involved in cardiovascular and emetic responses. The change in autonomic function during the emetic response, especially enhancement of sympathetic activity prior to retching, may be relevant to emetic and cardiovascular responses. Moreover, these results suggest that different autonomic function or different baroreflex responsiveness in Jic:SUN-Her and Jic:SUN-Ler may be involved in emetic responses. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Autonomic nervous system; Retching; Heart rate; Arterial pressure; Suncus murinus

1. Introduction There are various reports on autonomic nervous function and cardiovascular response accompanied by emetic response. Schlegel et al. (2001) reported that the highfrequency spectral power of RR intervals increase after parabolic flight in human subjects with vomiting, compared with nonvomiters. In squirrel monkeys, the coefficient of variance of RR intervals increases during exposure to vestibulo-visual conflict (Ishii et al., 1987). On the contrary, Mullen et al. (1998) have reported that heart rate variability does not change during motion sickness in human subjects. Decreased heart rate variability has also been observed *

Corresponding author. Tel.: +81-3-5841-5390; fax: +81-3-5841-8182. E-mail address: [email protected] (M. Uchino).

during motion sickness (Doweck et al., 1997; Hu et al., 1999). On the other hand, Montastruc et al. (1996) reported a significant decrease of blood pressure and a marked increase of heart rate in emesis induced by apomorphine in dog. Graybiel and Lackner (1980) reported that blood pressure and heart rate increases, decreases or does not change during motion sickness in human subjects. Heart rate decreases during nausea and increases during emesis induced by cancer chemotherapy in humans (Morrow et al., 1992). An acute increase in arterial pressure preceding retching and vomiting has been reported in anesthetized ferrets (Andrews et al., 1990; Makale and King, 1992). However, it is unclear whether cardiovascular and emetic responses involve the same or different neural pathways. Recently, we have shown that two strains of suncus have different sensitivities to veratrine (Ebukuro et al., 2000) and

1566-0702/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 6 - 0 7 0 2 ( 0 2 ) 0 0 1 4 1 - 8

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motion stimuli (Uchino et al., 2001). There is a difference between the high-emesis group (Jic:SUN-Her) and lowemesis group (Jic:SUN-Ler) in the proportion of individuals with an emetic response and in the latency to the first emetic episode in response to these stimuli. Moreover, autonomic activity is relevant to the development and suppression of motion-induced emetic responses in these two strains of suncus (Uchino et al., 2001). Therefore, we thought that these animals could provide new insight into the relationship between autonomic activity and cardiovascular responses during the emetic response. In this study, we compared the emetic response and the cardiovascular response that precedes it in two strains of suncus, Jic:SUN-Her and Jic:SUN-Ler, because the emetic response can be induced under anaesthesia by mechanical stimulation of the stomach (Andrews et al., 1996) and intragastric administration of CuSO4 in ferret (Makale and King, 1992) and dog (Furukawa and Hatano, 1998; Kayashima et al., 1978). We thought that the contradiction in earlier reports was due to vagueness about whether the subjects developed vomiting or not, and in which phase of the emetic response the data were reported. Therefore, we focused on the cardiovascular response that precedes retching and vomiting. Moreover, to clarify role of the autonomic nervous system in the cardiovascular and emetic responses, we also studied the influence of drugs that affect autonomic activity.

2. Material and methods

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and analyzed by a data analysis system (ADInstruments, MacLab/4s, Japan). A balloon catheter and the gastric catheter were inserted into the stomach from the pylorus. Emetic responses were induced by distension of the balloon catheter (saline heated to 37 jC, 4 ml) and intragastric administration of CuSO4 (5% w/v, 0.5 ml, heated to 37 jC) via the gastric catheter. Retching and vomiting were recognized from the change of intratracheal pressure, which was continuous, and over twice as great as that without emetic stimuli. The following drugs were injected intraperitoneally into Jic:SUN-Her and Jic:SUN-Ler: phenylephrine hydrochloride (1.2 mg kg 1), acetylcholine chloride (4.0 mg kg 1), atropine sulfate (1.6 mg kg 1), hexamethonium chloride (0.8 mg kg 1) and vehicle (saline) as a control solution. The volume of the drug solution and saline injected were adjusted to 2.0 mg kg 1 body weight. After administration of these drugs, the emetic response was induced by mechanical (distension of balloon catheter) or chemical stimulation (5% of CuSO4, 0.5 ml) of the stomach. Values of mean blood pressure, heart rate and respiratory rate after administration of each drug or saline but before emetic stimuli, were considered as baseline value. 2.3. Statistical analysis Results are expressed as the means F S.E. The statistical analysis was performed by analysis of variance (ANOVA). Values for p < 0.05 were considered as significant differences.

2.1. Animals Jic:SUN-Her (male, 3 – 6 months old, 40 – 70 g body weight) and Jic:SUN-Ler (male, 3 – 8 months old, 40– 70 g body weight) were used for this study. The two strains of Suncus murinus were selectively bred at the Animal Resource Center, Central Institute for Experimental Animals. 2.2. Experimental procedure The animals were anesthetized with urethane (1.0 g kg 1, i.p.). Urethane was selected because it has only slight effect on reflex responses including emetic and cardiovascular responses (Maggi and Meli, 1986). The trachea and the carotid artery were cannulated (polyethylene tube diameter 1.6 and 0.6 mm, respectively). The tracheal catheter was connected to a differential pressure transducer (Nihon Koden, TP-602T, Japan) and a respiratory amplifier (Nihon Koden, AR-601G, Japan). The arterial pressure was measured by a blood pressure transducer (NEC, 45362-1, Japan) connected to a transducer amplifier (NEC, 1829, Japan). The limb lead II electrocardiogram was recorded by electrodes inserted into the skin connected to an adapter (NEC, 47396B, Japan) and amplified by a bioelectric amplifier (NEC, 4124, Japan). Data were recorded by an instrumentation cassette recorder (Sony Magnescale, PC 204, Japan),

3. Results 3.1. Emetic and cardiovascular responses to mechanical stimulation of the stomach in Jic:SUN-Her and Jic:SUN-Ler There was no significant difference between Jic:SUNHer and Jic:SUN-Ler in baseline values of mean blood pressure, heart rate and respiratory rate under anaesthesia without emetic stimuli (Table 1). Table 1 Change in mean blood pressure (MBP), heart rate (HR) and respiratory rate (RR) from baseline prior to retching induced by mechanical stimulation in Jic:SUN-Her and Jic:SUN-Ler MBP (mm Hg)

HR (bpm)

RR (min

Jic:SUN-Her Baseline Prodromal

96.2 F 6.6 113.3 F 9.6 *

448.1 F 14.5 433.7 F 10.7

84.6 F 8.2 78.1 F 9.7

Jic:SUN-Ler Baseline Prodromal

100.2 F 1.3 133.1 F 6.8 *

451.0 F 21.9 481.5 F 1.2

87.4 F 6.2 79.3 F 0.8

1

)

Values are means F S.E. of six experiments. * p < 0.05 compared with baseline value in anesthetized condition before emetic stimuli.

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Fig. 1. The record of intratracheal pressure (ITP) and arterial pressure (AP) in Jic:SUN-Her (A) and Jic:SUN-Ler (B). Retching (R) was induced by mechanical stimulation of the stomach (distention of balloon catheter, 4 ml). E: start of distending balloon catheter.

Emetic responses were induced by mechanical stimulation of the stomach (Fig. 1). Mean blood pressure significantly ( p < 0.05) increased from baseline prior to retching in Jic:SUN-Her and in Jic:SUN-Ler. Heart rate tended to decrease in Jic:SUN-Her and to increase in Jic:SUN-Ler

prior to retching. The respiratory rate decreased, but not significantly ( p> 0.05), in both strains (Table 1). The latency to the first retching was 69.3 F 15.1 s in Jic:SUN-Her and 116.3 F 7.5 s in Jic:SUN-Ler (Fig. 2A). The number of emetic episodes were 8.0 F 3.0 in Jic:SUN-

Fig. 2. The comparison between Jic:SUN-Her (5) and Jic:SUN-Ler (n) in latency to the first retching (A), the number of emetic episodes (B) and change of mean blood pressure (MBP) prior to retching (C) induced by mechanical stimulation of the stomach. The baseline value of mean blood pressure was considered as 100%. * p < 0.05 compared with Jic:SUN-Her.

M. Uchino et al. / Autonomic Neuroscience: Basic and Clinical 100 (2002) 32–40 Table 2 Change in mean blood pressure (MBP), heart rate (HR) and respiratory rate (RR) from baseline prior to retching induced by chemical stimulation in Jic:SUN-Her and Jic:SUN-Ler 1

MBP (mm Hg)

HR (bpm)

RR (min

Jic:SUN-Her Baseline Prodromal

108.0 F 7.5 130.5 F 10.1 *

464.2 F 20.9 452.3 F 16.2

90.5 F 12.2 81.0 F 3.5

Jic:SUN-Ler Baseline Prodromal

98.0 F 1.5 111.6 F 5.0 *

458.8 F 2.2 474.9 F 11.2

89.2 F 8.5 87.3 F 9.5

)

Values are means F S.E. of four experiments. * p < 0.05 compared with baseline value in anesthetized condition before emetic stimuli.

Her and 6.7 F 2.3 in Jic:SUN-Ler (Fig. 2B). The mean blood pressure increased prior to retching by 16.6 F 1.1% in Jic: SUN-Her and by 32.9 F 9.0% in Jic:SUN-Ler, when the baseline values considered as 100% (Fig. 2C). The latency

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in Jic:SUN-Her was significantly ( p < 0.05) shorter than that in Jic:SUN-Ler, but there was no significant difference between Jic:SUN-Her and Jic:SUN-Ler in the number of emetic episodes and change in mean blood pressure prior to retching. 3.2. Emetic and cardiovascular responses to chemical stimulation of the stomach in Jic:SUN-Her and Jic:SUN-Ler There was no significant difference between Jic:SUNHer and Jic:SUN-Ler in baseline values of mean blood pressure, heart rate and respiratory rate under anaesthesia without emetic stimuli (Table 2). Emetic responses were induced by chemical stimulation of the stomach in Jic:SUN-Her (Fig. 3A) and Jic:SUN-Ler (Fig. 3B). Changes in mean blood pressure, heart rate and respiratory rate from baseline that preceded retching were similar to those for mechanical stimulation (Table 2).

Fig. 3. The record of intratracheal pressure (ITP) and arterial pressure (AP) in Jic:SUN-Her (A) and Jic:SUN-Ler (B). Retching (R) was induced by chemical stimulation of the stomach (intragastric administration of CuSO4, 5%, 0.5 ml). E: start of intragastric administration.

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Fig. 4. The comparison between Jic:SUN-Her (5) and Jic:SUN-Ler (n) in latency to the first retching (A), the number of emetic episodes (B) and change of mean blood pressure (MBP) prior to retching (C) induced by chemical stimulation of the stomach. The baseline value of mean blood pressure was considered as 100%. * p < 0.05 compared with Jic:SUN-Her.

The latency to the first retching was 110.7 F 30.0 s in Jic:SUN-Her and 294.7 F 9.3 s in Jic:SUN-Ler (Fig. 4A). The number of emetic episodes was 4.4 F 1.0 in Jic:SUNHer and 2.3 F 1.3 in Jic:SUN-Ler (Fig. 4B). Mean blood pressure increased prior to retching by 20.9 F 4.1% in Jic:SUN-Her and by 13.8 F 4.7% in Jic:SUN-Ler (Fig. 4C). The latency in Jic:SUN-Her was significantly ( p < 0.05) shorter than that in Jic:SUN-Ler, but there was no significant difference between Jic:SUN-Her and Jic:SUN-Ler in the number of emetic episodes and change of mean blood pressure prior to retching. 3.3. Effect of autonomic agents on emetic and cardiovascular responses induced by mechanical and chemical stimulation There was no significant difference between Jic:SUNHer and Jic:SUN-Ler in baseline values of mean blood Table 3 Change in mean blood pressure (MBP) and heart rate (HR) from baseline prior to retching induced by mechanical stimulation after administration of acetylcholine (ACh), phenylephrine (PE) and hexamethonium (HM) in Jic:SUN-Her and Jic:SUN-Ler MBP (mm Hg)

Control Baseline Prodromal ACh Baseline Prodromal PE Baseline Prodromal HM Baseline Prodromal

Jic:SUN-Ler

Jic:SUN-Her

Jic:SUN-Ler

96.2 F 6.6 113.3 F 9.6 *

100.2 F 1.3 133.1 F 6.8 *

448.1 F 14.5 433.7 F 10.7

451.0 F 21.9 481.5 F 1.2

115.6 F 2.5 150.1 F 7.3 *

81.3 F 2.7 80.8 F 2.4

Table 4 Change in mean blood pressure (MBP) and heart rate (HR) from baseline prior to retching induced by chemical stimulation after administration of acetylcholine (ACh), phenylephrine (PE) and hexamethonium (HM) in Jic:SUN-Her and Jic:SUN-Ler MBP (mm Hg)

HR (bpm)

Jic:SUN-Her

81.9 F 2.6 100.5 F 2.5 *

pressure and heart rate after administration of each drug before emetic stimuli (Tables 3 and 4). Retching was induced by mechanical or chemical stimulation after administration of acetylcholine (4.0 mg kg 1, i.p.) in all individual Jic:SUN-Her and Jic:SUN-Ler. Mean blood pressure significantly ( p < 0.05) increased from baseline in both Jic:SUN-Her and Jic:SUN-Ler prior to retching induced by mechanical (Table 3) or chemical stimulation (Table 4), but there was no significant difference compared with control (2.0 mg kg 1 of saline, i.p.) in the change of mean blood pressure prior to retching induced by mechanical (Fig. 5A and B) or chemical stimulation (Fig. 6A and B). Heart rate did not significantly change from baseline prior to retching (Tables 3 and 4). The latency to the first retching induced by mechanical stimulation tended to be shortened in both Jic:SUN-Her (Fig. 5C) and Jic:SUN-Ler (Fig. 5D) compared to control. In response to chemical

84.0 F 2.7 99.1 F 6.5 *

116.2 F 1.2 140.6 F 3.2 *

83.6 F 2.9 86.6 F 2.1

418.2 F 29.2 412.7 F 11.2

448.3 F 19.6 437.8 F 22.0

458.0 F 15.5 459.9 F 23.5

428.6 F 26.3 440.4 F 19.3

452.6 F 12.4 460.5 F 20.3

443.3 F 24.1 440.6 F 30.7

Values are means F S.E. of six experiments. Value in condition before emetic stimuli after administration of each drug was considered as baseline value. * p < 0.05 compared with baseline value.

HR (bpm)

Jic:SUN-Her

Jic:SUN-Ler

Jic:SUN-Her

Jic:SUN-Ler

Control Baseline Prodromal

108.0 F 7.5 130.5 F 10.1 *

98.0 F 1.5 111.6 F 5.0 *

464.2 F 20.9 452.3 F 16.2

458.8 F 2.2 474.9 F 11.2

ACh Baseline Prodromal

83.0 F 3.6 94.8 F 2.0 *

89.4 F 8.5 102.5 F 6.8 *

409.0 F 25.7 401.7 F 26.1

430.6 F 23.0 422.7 F 42.0

PE Baseline Prodromal

117.1 F 1.6 138.0 F 4.5 *

116.7 F 0.8 131.6 F 1.8 *

462.3 F 12.5 448.4 F 12.0

464.8 F 14.8 477.4 F 10.2

HM Baseline Prodromal

89.9 F 7.9 93.1 F 8.5

91.0 F 7.3 92.5 F 7.2

447.9 F 15.3 445.1 F 7.6

447.6 F 15.1 446.2 F 7.3

Values are means F S.E. of four experiments. Value in condition before emetic stimuli after administration of each drug was considered as baseline value. * p < 0.05 compared with baseline value.

M. Uchino et al. / Autonomic Neuroscience: Basic and Clinical 100 (2002) 32–40

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Fig. 5. The effect of acetylcholine ( ), phenylephrine ( ) and hexamethonium (n) on change in mean blood pressure (MBP) prior to retching in Jic:SUN-Her (A) and Jic:SUN-Ler (B) and on latency to the first retching in Jic:SUN-Her (C) and Jic:SUN-Ler (D). Retching was induced by mechanical stimulation to the stomach. The baseline value of mean blood pressure in condition after administration of each drug before emetic stimuli was considered as 100%. * p < 0.05 compared with control (5).

stimulation, the latency showed a tendency to be shortened in Jic:SUN-Her (Fig. 6C) and was significantly ( p < 0.05) shortened from 294.7 F 9.3 s to 194.0 F 44.0 s in Jic:SUNLer (Fig. 6D). In emetic response induced by mechanical or chemical stimulation after administration of phenylephrine (1.2 mg kg 1, i.p.), no significant difference compared with control was observed in the number of individuals that exhibited retching. Mean blood pressure significantly ( p < 0.05) increased from baseline in Jic:SUN-Her and Jic:SUN-Ler prior to retching induced by mechanical (Table 3) or chemical stimulation (Table 4), but there was no significant difference compared with control in change of mean blood pressure prior to retching induced by mechanical (Fig. 5A and B) or chemical stimulation (Fig. 6A and B). Heart rate tended to decrease in Jic:SUN-Her and to increase in Jic:SUN-Ler from baseline prior to retching induced by mechanical (Table 3) and chemical stimulation (Table 4). Latency was prolonged, but not significantly ( p > 0.05) in Jic:SUN-Her (Fig. 5C), but was significantly ( p < 0.05) prolonged from 116.3 F 7.5 s to 143.0 F 4.0 s in Jic:SUN-

Ler (Fig. 5D) during the emetic response induced by mechanical stimulation. In response to chemical stimulation, the latency was significantly ( p < 0.05) prolonged from 110.7 F 30.0 s to 293.5 F 13.5 s in Jic:SUN-Her (Fig. 6C) and from 294.7 F 9.3 s to 459.5 F 33.5 s in Jic:SUN-Ler (Fig. 6D). After pretreatment with hexamethonium (0.8 mg kg 1, i.p.), the number of individuals which responded did not change in either Jic:SUN-Her or Jic:SUN-Ler. The increase in mean blood pressure and change in heart rate prior to retching induced by mechanical stimulation was abolished by hexamethonium (Table 3, Fig. 5A and B). In response to chemical stimulation, only a slight increase in mean blood pressure was seen in both Jic:SUN-Her (by 5.0 F 1.2%, Table 4 and Fig. 6A) and Jic:SUN-Ler (by 0.6 F 2.7%, Table 4 and Fig. 6B). The change in heart rate prior to retching was also abolished in both strains (Table 4). Latency was significantly (p < 0.05) prolonged to 128.7 F 4.5 s in Jic:SUNHer (Fig. 5C) and to 196.5 F 38.5 s in Jic:SUN-Ler (Fig. 5D) in response to mechanical stimulation. A significant (p < 0.05) prolongation of latency was also seen in both

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Fig. 6. The effect of acetylcholine ( ), phenylephrine ( ) and hexamethonium (n) on change in mean blood pressure (MBP) prior to retching in Jic:SUN-Her (A) and Jic:SUN-Ler (B) and on latency to the first retching in Jic:SUN-Her (C) and Jic:SUN-Ler (D). Retching was induced by chemical stimulation of the stomach. The baseline value of mean blood pressure in condition after administration of each drug before emetic stimuli was considered as 100%. * p < 0.05 compared with control (5).

Jic:SUN-Her (to 311.0 F 2.0 s, Fig. 6C) and Jic:SUN-Ler (to 470.0 F 123.0 s, Fig. 6D) in response to chemical stimulation. After pretreatment with atropine (1.6 mg kg 1, i.p.), neither mechanical nor chemical stimulation induced retching in Jic:SUN-Her and Jic:SUN-Ler.

4. Discussion This study shows that mechanical and chemical stimulation of the stomach can induce an emetic response in the two strains of S. murinus, Jic:SUN-Her and Jic:SUN-Ler. The latency in Jic:SUN-Her was significantly shorter than that in Jic:SUN-Ler in response to both mechanical and chemical stimulation, but the number of emetic episodes was almost the same between these two strains of suncus. Mean blood pressure significantly increased from baseline prior to retching in both strains. Heart rate decreased in Jic:SUN-Her and increased in Jic:SUN-Ler prior to retching.

Moreover, autonomic drugs modified both emetic and cardiovascular responses induced by mechanical and chemical stimulation. These results suggest that there are different sensitivities to mechanical and chemical stimulation of the stomach in these two strains of S. murinus. Gastric stimulation by CuSO4 and passive distension of stomach can induce nausea and vomiting through the afferent fibres of chemoreceptors and mechanoreceptors that send their nerve fibers to the vagal afferents and the sympathetic afferents (Willems and Lefebvre, 1986; Lang, 1999). These afferent fibres activate a vomiting center. These gastric stimuli can induce emetic responses without involving the area postrema (Wang and Borison, 1951). In this study, there were significant differences between Jic:SUN-Her and Jic:SUN-Ler in the latency to the first retching. Because there is also a differential sensitivity to veratrine (Ebukuro et al., 2000), which activates area postrema (Torack and LaValle, 1973), in these two strains, it is apparent that central mechanisms including the vomiting center might be congenitally different. On the other hand,

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the result that the number of emetic episodes and the change in mean blood pressure were similar between the two strains of suncus indicated that outputs from vomiting center might not be different. We suggest that there might be differences in threshold of vomiting center rather than in efferent pathways of emetic and cardiovascular responses. An acute increase in arterial pressure prior to retching has been reported in the emetic response induced by electrical stimulation of vagal afferents in anaesthetised ferrets (Andrews et al., 1990). Makale and King (1992) also reported an increase in arterial pressure prior to retching induced by intragastric CuSO4. Although bilateral abdominal vagotomy significantly reduced the number of vomiting animals, the cardiovascular response was not affected. Therefore, they suggested that separate mechanisms are involved in the genesis of cardiovascular and emetic responses. In the present study, however, pretreatment with hexamethonium suppressed the cardiovascular response prior to retching and prolonged the latency to the first retching. This result indicated that there is an interaction between the mechanisms that are involved in the cardiovascular and emetic responses. The change of autonomic activity during the emetic response, especially enhancement of sympathetic activity prior to retching, may be relevant. This possibility is supported by reports that emesis is accompanied by enhancement of sympathetic activity. Tang and Gernandt (1969) reported that vestibular stimulation causes a pronounced sympathetic response during fictive vomiting. During emesis induced by cancer chemotherapy, sympathetic activity is enhanced (Morrow et al., 1992). On the other hand, Willems and Lefebvre (1986) have suggested that chemoreceptors and mechanoreceptors and their afferent fibres play a role in reflexes regulating sympathetic and parasympathetic activity, affecting the cardiovascular response. Cardiovascular responses may be specific to the emetic stimuli mediated by vagal afferents and afferents related to sympathetic activity. Administration of acetylcholine and phenylephrine affected the emetic response induced by mechanical and chemical stimulation, but did not affect the changes in mean blood pressure and heart rate prior to retching. Nevertheless, the baseline values of mean blood pressure and heart rate after administration of these drugs were different. This result suggested that autonomic balance before the emetic response is important in the development of the emetic response. We thought that the predominance of parasympathetic activity is related to the enhancement of the emetic response induced by mechanical and chemical stimulation and that the predominance of sympathetic activity suppresses the emetic response. Moreover, we thought that autonomic balance might modulate the threshold or the sensitivity of vomiting center. This suggestion is coincident with our previous report on motion stimuli-induced emesis (Uchino et al., 2001) and the report of evaluation of peripheral autonomic nervous func-

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tion by heart rate variability during motion sickness (Ishii et al., 1987; Schlegel et al., 2001). Morrow et al. (1992) also reported nausea induced by cancer chemotherapy is related to parasympathetic effects such as decrease of heart rate. The congenitally different sensitivity to diverse emetic stimuli (veratrine, motion, and mechanical or chemical stimulation of the stomach) of Jic:SUN-Her and Jic:SUNLer may be attributed to different levels of the autonomic activity. Furthermore, it seems that autonomic responses induced by emetic stimuli are independent of the type of stimuli. Hexamethonium, however, enhances motion-induced emesis in conscious suncus, whereas pretreatment with hexamethonium prolonged the latency to the first retching induced by mechanical or chemical stimulation of the stomach under anaesthesia. There is no simple explanation for this discrepancy. Possibly, the autonomic activity may differ between the conscious and anaesthetised conditions or between emetic responses induced by these stimuli, though it is impossible to compare these conflicting results simply because of difference of emetic stimuli and experimental conditions. In consideration of similar response of mean blood pressure and different response of heart rate prior to retching between these two strains of suncus nevertheless there was no significant difference in baseline of mean blood pressure and heart rate under anaesthesia, a different baroreflex responsiveness may exist in these two strains. Emesis changes the respiratory pattern because of a coordinated recruitment of muscles involved in respiration (Abe et al., 1994) and arterial blood CO2 tension increases during retching (Fukuda and Koga, 1993), thought to be induced by an interaction between the vomiting center and the respiratory pattern generator (Abe et al., 1994). Hypercapnia reduces baroreflex sensitivity (Bristow et al., 1974) and baroreflex sensitivity is also changed by parabolic flight (Schlegel et al., 2001) and vestibular and oculomotor stimulation (Convertino et al., 1997). Therefore, the vomiting center might directly or indirectly modulate baroreflex responsiveness in the emetic response. Furthermore, a secondary increase of parasympathetic nervous activity may be involved in the development of emetic responses. This study has shown the different sensitivity to mechanical and chemical stimulation to the stomach between Jic:SUN-Her and Jic:SUN-Ler. This study also demonstrated the role of autonomic activity in emetic and cardiovascular responses induced by mechanical and chemical stimulation of the stomach. The predominance of parasympathetic function is relevant to the enhanced emetic response, whereas a predominance of sympathetic function suppresses emetic response. On the other hand, the enhancement of sympathetic activity prior to retching is important to the emetic response. Moreover, these results suggest that autonomic activity and baroreflex responsiveness differ in the emetic responses in Jic:SUN-Her and Jic:SUN-Ler.

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