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Kindled seizures activate both branches of the autonomic nervous system
Epilepsy Research 34 (1999) 169 – 176
Kindled seizures activate both branches of the autonomic nervous system Jeffrey H. Goodman a,c,*, Richard W. Homan a,c,1, Isaac L. Crawford a,b,c b
a Department of Neurology, Southwestern Medical Center, Dallas, TX, USA Department of Pharmacology, Southwestern Medical Center, Dallas, TX, USA c Department of Neurology, VA Medical Center, Dallas, TX 75219, USA
Received 25 June 1998; accepted 6 October 1998
Abstract Amygdaloid kindled seizures in the rat induce an abrupt elevation of blood pressure accompanied by a significant decrease in heart rate. The autonomic pharmacology of this response was examined in unanesthetized kindled rats. Muscarinic receptor blockade with atropine (1 mg/kg, intravenous (i.v.)) abolished the seizure-induced bradycardia. The seizure-induced hypertension was unaffected by b-adrenergic blockade with timolol (1 mg/kg, i.v.), but was reduced by phentolamine (5 mg/kg, subcutaneous (s.c.)), an a-adrenergic receptor antagonist. A chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood – brain barrier. This eliminated the pressor response but did not completely block the seizure-induced bradycardia. The effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.) an agent that releases endogenous catecholamines. These results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. The bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to a-adrenergic receptor activation. More important, these findings show that kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Amygdala; Autonomic nervous system; Blood pressure; Bradycardia; Epilepsy; Kindling; Seizures
1. Introduction * Corresponding author. Present address: Helen Hayes Hospital, Neurology Research Center, West Haverstraw, NY 10993, USA. Tel.: + 1-914-7864865. 1 Current address: Dept. of Neuropsychiatry and Behavioral Science, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA.
Clinical seizures are often accompanied by profound autonomic changes (Van Buren, 1958; Van Buren and Ajmone-Marsan, 1960; Meldrum and Horton, 1973; Metz et al., 1978; Elliot et al., 1982;
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Marshall et al., 1983; Coulter, 1984; Devinsky et al., 1986; Smaje et al., 1987; Galimberti et al., 1996; Reeves et al., 1996). Seizure-induced disruption of cardiovascular function is particularly significant since it may be related to the phenomenon of sudden, unexplained death that occurs in epileptic patients (Pritchett et al., 1980; Leestma et al., 1984; Dasheiff and Dickinson, 1986; Earnest et al., 1992; Tennis et al., 1995; Derby et al., 1996). Several experimental seizure models have been used to examine the effect of seizures on cardiovascular function: electroconvulsive shock (Plum et al., 1968; Wasterlain, 1974; Petito et al., 1977; Westergaard et al., 1978); pentylenetetrazol (Plum et al., 1968; Doba et al., 1975; Lathers and Schraeder, 1982; Lathers et al., 1987); bicuculline (Meldrum and Horton, 1973; Johanssen and Nilsson, 1977; Suzuki et al., 1984) and penicillin (Mameli et al., 1988). However, each of these models has inherent limitations due to the presence of anesthetics, paralytic agents, or widespread exposure of the CNS to chemical convulsants or electric current. The kindling seizure model is well suited for studies of the effect of seizures on the cardiovascular system. Cardiovascular function can be evaluated before, during and after a seizure in an unanesthetized, freely moving rat. We have characterized the cardiovascular changes that occur during kindling acquisition and during kindled seizures in the conscious rat (Goodman et al., 1990, 1991). The cardiovascular response during amygdaloid kindled seizure consists of an abrupt increase in mean arterial pressure. This change in blood pressure is accompanied by a dramatic decrease in heart rate along with a variety of arrhythmias (Goodman et al., 1990, 1991). It is likely that kindled seizures alter cardiovascular function by disruption of autonomic regulation of the heart, but direct pharmacologic evidence is lacking. In the present report we used pharmacologic manipulation of the autonomic nervous system to specifically determine the pharmacology underlying the seizure-induced cardiovascular changes that occur during kindled seizures in the rat.
2. Materials and methods
2.1. Animals All animals were individually housed with free access to food and water. Animal care and use followed guidelines determined by the National Institutes of Health. Twenty-four male Sprague– Dawley rats (275–325 g) were anesthetized by intramuscular injection of a combination of ketamine (90 mg/kg) and xylazine (15 mg/kg). Bipolar Teflon-coated, stainless steel electrodes (100 mm) were bilaterally implanted in the basolateral amygdalae according to previously reported methods used in our laboratory (Crawford, 1986; Homan and Goodman, 1988; Goodman et al., 1990). The stereotaxic coordinates for the amygdala electrodes were: A–P, + 4.8 mm from the interaural line; M–L, 9 5.3 mm from the sagittal suture; Vertical, + 2.4 mm from ear bar zero (Pellegrino et al., 1979). Each animal was allowed to recover a minimum of 1 week, at which time the kindling process was initiated. The afterdischarge threshold was determined for each electrode in each animal. Any animal with an afterdischarge (AD) threshold greater than 250 mA in both electrodes was not included in the study. The electrode with the lower threshold was selected for kindling. Animals were stimulated once daily (400 mA, 60 Hz, 1 ms pulse duration) until three consecutive stage 5 seizures were elicited. These animals were considered fully kindled. Since kindling-induced cardiovascular changes occur independent of which amygdala is kindled, animals kindled in the left amygdala and animals kindled in the right amygdala were included in the study (Goodman et al., 1991). Once fully kindled, each animal was anesthetized a second time as described above and chronic jugular vein and femoral artery catheters were surgically implanted. A catheter made out of silastic sheeting and tubing was inserted into the jugular vein and sutured in place. The distal end of the catheter was passed under the skin and externalized at the dorsal surface of the neck according to the methods of Harms and Ojeda (1974). The jugular catheter provided a route for i.v. drug administration.
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The femoral artery was surgically exposed and a catheter made out of polyethylene tubing (PE 90) was inserted into the femoral artery and sutured to the inner surface of the hindlimb so that it could not be dislodged by movement. The distal end of this catheter was also passed under the skin and externalized at the neck. Both the jugular and femoral catheters were filled with heparinized saline to maintain patency. The arterial catheter allowed for the measurement of cardiovascular changes during the seizure in an unanesthetized, freely moving rat. In 10 animals, additional electrodes were placed across the chest to measure the electrocardiogram (EKG).
2.2. Drugs Each animal was allowed to recover a minimum of 24 h before initiation of drug testing. All drugs were dissolved in saline and injected i.v. through the jugular catheter (except phentolamine). The base form of each drug was used in all dose calculations. Atropine sulphate (1 mg/kg) or timolol maleate (1 mg/kg) was injected 15 min before delivery of the kindling stimulus. Control animals were injected with saline. 6-Hydroxydopamine (6OHDA, 100 mg/kg) was injected 24 h before the kindled seizure. The effectiveness of the 6-OHDA treatment was tested by the injection of tyramine (0.5 mg/kg) immediately before and 28 h after injection of 6-OHDA. Phentolamine hydrochloride (5 mg/kg) was injected s.c. 30 min before the kindled seizure.
2.3. Data collection In these experiments EEG, blood pressure and heart rate were measured during a seizure in amygdaloid kindled rats. In 10 animals the EKG was also recorded. In most animals changes in heart rate could also be detected in the blood pressure tracing. Heart rate and blood pressure measurements were collected and averaged over 5 s epochs before, during and after a kindled seizure. The study focused on changes during the first 30 s of the seizure since this is when the maximum changes in cardiovascular function occur (Goodman et al., 1990, 1991). Changes in
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drug-treated animals were compared to saline-injected controls. Significance (P B 0.05) was determined by analysis of variance with one repeated measure.
3. Results In previous studies we characterized the cardiovascular response during a stage 5 generalized, amygdaloid kindled seizure (Goodman et al., 1990, 1991). The response consisted of an abrupt increase in blood pressure during the first 20–30 s of the seizure. Superimposed upon the pressor response was a profound bradycardia characterized by decreases in heart rate of up to 50% accompanied by ventricular arrhythmias (Goodman et al., 1990, 1991). This response was independent of which amygdala was kindled and was seizure-dependent (Goodman et al., 1991). These cardiovascular changes were limited to the first 30 s of the seizure even though the seizure lasted 60–90 s. The purpose of the present study was to examine the mechanism of seizure-induced changes in cardiovascular function. For this reason this study focused on the first 30 s of the kindled seizure after pharmacologic manipulation of the autonomic nervous system. We did not detect any effects of the pharmacologic agents used in the study on the kindled seizure. Atropine (1 mg/kg, i.v.), a muscarinic receptor antagonist, was injected into fully kindled rats (n= 5) 15 min before initiation of a kindled seizure. Atropine had no effect on the seizure-induced increase in blood pressure (data not shown); however the seizure-induced bradycardia was completely eliminated (Fig. 1). Atropine was effective throughout the first 30 s of the seizure, which is when the seizure appears to exert its maximum effect on the cardiovascular system (Fig. 2). Atropine significantly (PB 0.05) prevented the seizure-induced decrease in heart rate during the first 20 s of the seizure when compared to rats injected with saline (n= 5). We compared baseline heart rate before the seizure to the maximum change in heart rate (increase or decrease) during the seizure in control and atropine-treated
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Fig. 1. The effect of atropine sulfate (1 mg/kg, i.v.) on kindled seizure-induced changes in cardiovascular function. Pretreatment with atropine prevented the seizure-induced bradycardia. There was no change in the electrocardiogram (EKG) during the seizure. Atropine had no effect on the seizure-induced increase in blood pressure. The electroencephalogram (EEG) indicates the onset of the seizure afterdischarge. The up and down arrows indicate the beginning and end of the seizure-inducing stimulus.
rats. The maximum change in heart rate during the seizure in saline controls was a decrease of 242 9 40 beats/min (mean9 S.E.M) while the maximum change in heart rate during the seizure in animals treated with atropine was 4298 beats/ min (mean 9 S.E.M, P B0.001). These data further illustrate the magnitude of the seizureinduced bradycardia and the effectiveness of atropine in preventing it. Timolol (1 mg/kg, i.v.), a nonspecific b-adrenergic receptor antagonist, was injected 15 min be-
Fig. 2. Graphic comparison of the change in heart rate during kindled seizures in animals pretreated with atropine with animals pretreated with saline (control). Atropine significantly (*PB0.05) prevented the seizure-induced decrease in heart rate during the first 20 s of the kindled seizure.
Fig. 3. Effect of pretreatment with timolol maleate on the mean arterial blood pressure during the first 30 s after initiation of stage 5 amygdaloid kindled seizures. There was no difference in the seizure-induced increase in timolol-treated rats when compared with saline controls.
fore the seizure. Treatment with timolol did not affect the decrease in heart rate that occurred during the seizure (data not shown). It also did not prevent the increase in mean arterial pressure that occurred during the kindled seizure (Fig. 3). This suggested that the seizure-induced increase in blood pressure was mediated through a-adrenergic receptor activation. We tested this possibility by inducing a seizure after a-adrenergic blockade with phentolamine or chemical sympathectomy with 6-OHDA, an adrenolytic agent. Phentolamine (5 mg/kg, s.c., n=3), an a-adrenergic receptor antagonist, was injected 30 min before kindled rats were stimulated. Phentolamine decreased baseline mean arterial pressure as well as the increase in blood pressure that occurred during the kindled seizure. However, the seizureassociated bradycardia persisted despite the attenuated increase in blood pressure (Fig. 4). The bradycardia present in animals treated with phentolamine was delayed 15–20 s relative to what was observed in untreated animals (Goodman et al., 1990, 1991). A chemical sympathectomy was induced with 6-OHDA (100 mg/kg, i.v.). Twenty-four hours after 6-OHDA, resting systolic and diastolic pressure was decreased by approximately 50% (Fig. 5B, n= 3). The effectiveness of the 6-OHDA treatment was tested by injecting tyramine (0.5 mg/kg, i.v.), before the 6-OHDA treatment and
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then again after the kindled seizure. Tyramine causes the release of endogenous catecholamines from presynaptic terminals. The initial injection of tyramine resulted in a large increase in blood pressure (Fig. 5A). If the 6-OHDA treatment were ineffective then one would predict that an injection of tyramine after 6-OHDA would also result in a hypertensive response. The second tyramine injection had no effect on blood pressure (Fig. 5C) suggesting that the injection of 6-OHDA resulted in an effective chemical sympathectomy. In these animals, the seizure-induced pressure response was eliminated; however, in two animals a small bradycardic response was still present despite the absence of an increase in blood pressure (Fig. 5B). This bradycardic response (present in the blood pressure trace in Fig. 5B) was delayed relative to what occurred in untreated animals during the seizure. It was similar to what was observed in animals treated with phentolamine.
4. Discussion Cardiovascular changes that occur during amygdaloid kindled seizures result from activation of the sympathetic and parasympathetic branches of the autonomic nervous system. Our findings suggest the pressor component of the seizure-induced response results from central activation of sympathetic pathways. The bradycardia
Fig. 4. Effect of pretreatment with phentolamine hydrochloride (5 mg/kg, s.c.) on kindled seizure-induced changes in cardiovascular function. Phentolamine decreased blood pressure before initiation of the seizure. Phentolamine greatly attenuated the increase in blood pressure that occurred during the kindled seizure. Note the presence of the seizure-associated bradycardia in the absence of a profound increase in blood pressure. The up and down arrows indicate the beginning and end of the stimulus.
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that accompanies the seizure-associated increase in blood pressure is the result of baroreceptor activation of the parasympathetic system. Central activation of the parasympathetic system remains a possibility since the bradycardia was not completely eliminated by phentolamine or chemical sympathectomy. Seizure-induced hypertension has been reported to occur during several experimentally-induced seizures: electroconvulsive shock (Plum et al., 1968; Wasterlain, 1974; Petito et al., 1977; Westergaard et al., 1978), pentylenetetrazol (Plum et al., 1968; Doba et al., 1975; Lathers and Schraeder, 1982) and bicuculline (Meldrum and Horton, 1973; Johanssen and Nilsson, 1977; Suzuki et al., 1984). In all cases, activation of the sympathetic nervous system has been implicated as mediating this effect. In the present study, our data also give evidence that the hypertensive response associated with kindled seizures is mediated through activation of sympathetic pathways. The observations that treatment with the nonspecific b-adrenergic receptor blocker, timolol, had no effect on the pressor response while the response was completely eliminated by the adrenolytic agent 6OHDA, suggests the seizure-induced increase in blood pressure is due to a-adrenergic receptor activation. The 6-OHDA treatment was effective since posttreatment with tyramine, an agent that causes the release of endogenous catecholamines from presynaptic nerve terminals, had no effect in these animals. The observation that the bradycardia could be completely eliminated in kindled animals pretreated with atropine, a muscarinic antagonist, suggests the response is mediated by activation of the parasympathetic system. This increase in parasympathetic activity can be explained by baroreceptor activation secondary to the seizureinduced increase in blood pressure. There is also evidence of central activation of the parasympathetic system during the seizure. Animals treated with phentolamine and 6-OHDA exhibited a bradycardic response in the absence of a pressor response that would be necessary for baroreceptor activation. This bradycardic response was delayed, occurring 15–20 s after initiation of the seizure which also suggests a
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Fig. 5. (A) Effect of tyramine (0.5 mg/kg, i.v.) on blood pressure before injection of 6-OHDA in a kindled rat. Tyramine caused a rapid increase in blood pressure with no effect on the EEG. Arrow indicates time of tyramine injection. (B) Effect of chemical sympathectomy with 6-OHDA on blood pressure during a kindled seizure in the same rat as in (A). 6-OHDA (100 mg/kg, i.v.) was injected 24 h before initiation of the seizure. Note the decrease in baseline systolic and diastolic pressure before the seizure. Chemical sympathectomy completely eliminated the seizure-induced hypertensive response. Note the delayed bradycardia in the blood pressure recording, 15 s after initiation of the seizure, in the absence of an increase in blood pressure. Arrow indicates the onset of the kindling stimulus followed by the seizure afterdischarge in the EEG record. (C) Same rat as in (A) and (B). Effect of tyramine on blood pressure 28 h after injection of 6-OHDA. Tyramine had no effect on blood pressure indicating 6-OHDA induced an effective chemical sympathectomy. Arrow indicates time of tyramine injection. The time scale in this figure is different from previous figures.
different mechanism of activation. The delayed bradycardia would be masked in an untreated animal due to the presence of the baroreceptor mediated decrease in heart rate. Only by preventing the increase in blood pressure were we able to detect the delayed bradycardic event. During kindling acquisition, development of the bradycardic response was not coupled to the development of the pressor response (Goodman et al., 1990). These observations suggest central activation of the parasympathetic system was partially responsible for the seizure-induced bradycardia. This is significant given the number of clinical reports of ictal bradycardia (Coulter, 1984; Kiok et al., 1986; Howell and Blumhardt, 1989; Constantin et al.,
1990; Fincham et al., 1992; Wilder-Smith, 1992; Galimberti et al., 1996; Reeves et al., 1996). Our data from previous studies suggest that the cardiovascular changes associated with kindled seizures are not due to stimulation of the amygdala, a cardiovascular control center, but are seizure-dependent since the kindling stimulus in non-kindled animals failed to alter cardiovascular function (Goodman et al., 1990). We observed similar cardiovascular changes during spontaneous generalized seizures that occurred several minutes after the initial kindled seizure (Goodman et al., 1990, 1991). It is possible that kindled seizure activity travels from the seizure focus to the hypothalamus or brain stem structures that
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regulate cardiovascular function. The likelihood that a given seizure will disrupt autonomic regulation of the heart may be dependent on the location of the seizure focus (Galimberti et al., 1996; Massetani et al., 1997) and factors that determine seizure spread. Given the clinical phenomena of sudden, unexplained death in epileptic patients, the relationship between seizures and central regulation of cardiovascular function is of particular importance. Whether the cardiovascular changes associated with kindled seizures and the mechanism of activation are related to sudden, unexplained death requires further investigation. The kindling seizure model is well suited for future studies of this relationship since cardiovascular function can be evaluated before, during and after the seizure in an unanesthetized, freely moving rat. In addition, the kindling model allows for examination of the effect of partial as well as generalized seizures on the cardiovascular system.
Acknowledgements The authors acknowledge the untimely passing of our colleague and friend Isaac Crawford. He will be greatly missed.
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Massetani, R., Strata, G., Galli, R., Gori, S., Gneri, C., Limbruno, U., Di Santo, D., Mariana, M., Murri, L., 1997. Alteration of cardiac function in patients with temporal lobe epilepsy: Different roles of EEG–ECG monitoring and spectral analysis of RR variability. Epilepsia 38, 363– 369. Meldrum, B.S., Horton, R.W., 1973. Physiology of status epilepticus in primates. Arch Neurol 28, 1–9. Metz, S.A., Halter, J.B., Porte, D., Robertson, R.P., 1978. Autonomic epilepsy. Ann Intern Med 88, 189–193. Pellegrino, L.J., Pellegrino, A.S., Cushman, A.J., 1979. A Stereotaxic Atlas of the Rat Brain. Plenum, New York. Petito, C.K., Schaeffer, J.A., Plum, F., 1977. Ultrastructural characteristics of the brain and blood brain barrier in experimental seizures. Brain Res 127, 251–267. Plum, F., Posner, J.B., Troy, B., 1968. Cerebral metabolic and circulatory responses to induced convulsions in animals. Arch Neurol 18, 1 – 13. Pritchett, E.L.C., McNamara, J.O., Gallagher, J.J., 1980. Arrhythmogenic epilepsy: An hypothesis. Am Heart J 100, 683 – 688. Reeves, A.L., Nollet, K.E., Klass, D.W., Sharbrough, F.W., So, E.L., 1996. The ictal bradycardic syndrome. Epilepsia 37, 983 – 987. Smaje, J.C., Davidson, C., Teasdale, G.M., 1987. Sino-atrial
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.
Kindled seizures activate both branches of the autonomic nervous system Jeffrey H. Goodman a,c,*, Richard W. Homan a,c,1, Isaac L. Crawford a,b,c b
a Department of Neurology, Southwestern Medical Center, Dallas, TX, USA Department of Pharmacology, Southwestern Medical Center, Dallas, TX, USA c Department of Neurology, VA Medical Center, Dallas, TX 75219, USA
Received 25 June 1998; accepted 6 October 1998
Abstract Amygdaloid kindled seizures in the rat induce an abrupt elevation of blood pressure accompanied by a significant decrease in heart rate. The autonomic pharmacology of this response was examined in unanesthetized kindled rats. Muscarinic receptor blockade with atropine (1 mg/kg, intravenous (i.v.)) abolished the seizure-induced bradycardia. The seizure-induced hypertension was unaffected by b-adrenergic blockade with timolol (1 mg/kg, i.v.), but was reduced by phentolamine (5 mg/kg, subcutaneous (s.c.)), an a-adrenergic receptor antagonist. A chemical sympathectomy was induced with 6-hydroxydopamine (100 mg/kg, i.v.), an agent that does not cross the blood – brain barrier. This eliminated the pressor response but did not completely block the seizure-induced bradycardia. The effectiveness of 6-hydroxydopamine was tested with tyramine (0.5 mg/kg, i.v.) an agent that releases endogenous catecholamines. These results indicate amygdaloid kindled seizures activate both branches of the autonomic nervous system. The bradycardia was mediated by the parasympathetic system; the pressor response was caused by an increase in peripheral resistance due to a-adrenergic receptor activation. More important, these findings show that kindling is a useful seizure model for future studies on the effect of seizures on cardiovascular function and possible mechanisms of seizure-related sudden unexplained death. © 1999 Elsevier Science B.V. All rights reserved. Keywords: Amygdala; Autonomic nervous system; Blood pressure; Bradycardia; Epilepsy; Kindling; Seizures
1. Introduction * Corresponding author. Present address: Helen Hayes Hospital, Neurology Research Center, West Haverstraw, NY 10993, USA. Tel.: + 1-914-7864865. 1 Current address: Dept. of Neuropsychiatry and Behavioral Science, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, USA.
Clinical seizures are often accompanied by profound autonomic changes (Van Buren, 1958; Van Buren and Ajmone-Marsan, 1960; Meldrum and Horton, 1973; Metz et al., 1978; Elliot et al., 1982;
0920-1211/99/$ - see front matter © 1999 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 9 8 ) 0 0 1 2 0 - X
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Marshall et al., 1983; Coulter, 1984; Devinsky et al., 1986; Smaje et al., 1987; Galimberti et al., 1996; Reeves et al., 1996). Seizure-induced disruption of cardiovascular function is particularly significant since it may be related to the phenomenon of sudden, unexplained death that occurs in epileptic patients (Pritchett et al., 1980; Leestma et al., 1984; Dasheiff and Dickinson, 1986; Earnest et al., 1992; Tennis et al., 1995; Derby et al., 1996). Several experimental seizure models have been used to examine the effect of seizures on cardiovascular function: electroconvulsive shock (Plum et al., 1968; Wasterlain, 1974; Petito et al., 1977; Westergaard et al., 1978); pentylenetetrazol (Plum et al., 1968; Doba et al., 1975; Lathers and Schraeder, 1982; Lathers et al., 1987); bicuculline (Meldrum and Horton, 1973; Johanssen and Nilsson, 1977; Suzuki et al., 1984) and penicillin (Mameli et al., 1988). However, each of these models has inherent limitations due to the presence of anesthetics, paralytic agents, or widespread exposure of the CNS to chemical convulsants or electric current. The kindling seizure model is well suited for studies of the effect of seizures on the cardiovascular system. Cardiovascular function can be evaluated before, during and after a seizure in an unanesthetized, freely moving rat. We have characterized the cardiovascular changes that occur during kindling acquisition and during kindled seizures in the conscious rat (Goodman et al., 1990, 1991). The cardiovascular response during amygdaloid kindled seizure consists of an abrupt increase in mean arterial pressure. This change in blood pressure is accompanied by a dramatic decrease in heart rate along with a variety of arrhythmias (Goodman et al., 1990, 1991). It is likely that kindled seizures alter cardiovascular function by disruption of autonomic regulation of the heart, but direct pharmacologic evidence is lacking. In the present report we used pharmacologic manipulation of the autonomic nervous system to specifically determine the pharmacology underlying the seizure-induced cardiovascular changes that occur during kindled seizures in the rat.
2. Materials and methods
2.1. Animals All animals were individually housed with free access to food and water. Animal care and use followed guidelines determined by the National Institutes of Health. Twenty-four male Sprague– Dawley rats (275–325 g) were anesthetized by intramuscular injection of a combination of ketamine (90 mg/kg) and xylazine (15 mg/kg). Bipolar Teflon-coated, stainless steel electrodes (100 mm) were bilaterally implanted in the basolateral amygdalae according to previously reported methods used in our laboratory (Crawford, 1986; Homan and Goodman, 1988; Goodman et al., 1990). The stereotaxic coordinates for the amygdala electrodes were: A–P, + 4.8 mm from the interaural line; M–L, 9 5.3 mm from the sagittal suture; Vertical, + 2.4 mm from ear bar zero (Pellegrino et al., 1979). Each animal was allowed to recover a minimum of 1 week, at which time the kindling process was initiated. The afterdischarge threshold was determined for each electrode in each animal. Any animal with an afterdischarge (AD) threshold greater than 250 mA in both electrodes was not included in the study. The electrode with the lower threshold was selected for kindling. Animals were stimulated once daily (400 mA, 60 Hz, 1 ms pulse duration) until three consecutive stage 5 seizures were elicited. These animals were considered fully kindled. Since kindling-induced cardiovascular changes occur independent of which amygdala is kindled, animals kindled in the left amygdala and animals kindled in the right amygdala were included in the study (Goodman et al., 1991). Once fully kindled, each animal was anesthetized a second time as described above and chronic jugular vein and femoral artery catheters were surgically implanted. A catheter made out of silastic sheeting and tubing was inserted into the jugular vein and sutured in place. The distal end of the catheter was passed under the skin and externalized at the dorsal surface of the neck according to the methods of Harms and Ojeda (1974). The jugular catheter provided a route for i.v. drug administration.
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The femoral artery was surgically exposed and a catheter made out of polyethylene tubing (PE 90) was inserted into the femoral artery and sutured to the inner surface of the hindlimb so that it could not be dislodged by movement. The distal end of this catheter was also passed under the skin and externalized at the neck. Both the jugular and femoral catheters were filled with heparinized saline to maintain patency. The arterial catheter allowed for the measurement of cardiovascular changes during the seizure in an unanesthetized, freely moving rat. In 10 animals, additional electrodes were placed across the chest to measure the electrocardiogram (EKG).
2.2. Drugs Each animal was allowed to recover a minimum of 24 h before initiation of drug testing. All drugs were dissolved in saline and injected i.v. through the jugular catheter (except phentolamine). The base form of each drug was used in all dose calculations. Atropine sulphate (1 mg/kg) or timolol maleate (1 mg/kg) was injected 15 min before delivery of the kindling stimulus. Control animals were injected with saline. 6-Hydroxydopamine (6OHDA, 100 mg/kg) was injected 24 h before the kindled seizure. The effectiveness of the 6-OHDA treatment was tested by the injection of tyramine (0.5 mg/kg) immediately before and 28 h after injection of 6-OHDA. Phentolamine hydrochloride (5 mg/kg) was injected s.c. 30 min before the kindled seizure.
2.3. Data collection In these experiments EEG, blood pressure and heart rate were measured during a seizure in amygdaloid kindled rats. In 10 animals the EKG was also recorded. In most animals changes in heart rate could also be detected in the blood pressure tracing. Heart rate and blood pressure measurements were collected and averaged over 5 s epochs before, during and after a kindled seizure. The study focused on changes during the first 30 s of the seizure since this is when the maximum changes in cardiovascular function occur (Goodman et al., 1990, 1991). Changes in
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drug-treated animals were compared to saline-injected controls. Significance (P B 0.05) was determined by analysis of variance with one repeated measure.
3. Results In previous studies we characterized the cardiovascular response during a stage 5 generalized, amygdaloid kindled seizure (Goodman et al., 1990, 1991). The response consisted of an abrupt increase in blood pressure during the first 20–30 s of the seizure. Superimposed upon the pressor response was a profound bradycardia characterized by decreases in heart rate of up to 50% accompanied by ventricular arrhythmias (Goodman et al., 1990, 1991). This response was independent of which amygdala was kindled and was seizure-dependent (Goodman et al., 1991). These cardiovascular changes were limited to the first 30 s of the seizure even though the seizure lasted 60–90 s. The purpose of the present study was to examine the mechanism of seizure-induced changes in cardiovascular function. For this reason this study focused on the first 30 s of the kindled seizure after pharmacologic manipulation of the autonomic nervous system. We did not detect any effects of the pharmacologic agents used in the study on the kindled seizure. Atropine (1 mg/kg, i.v.), a muscarinic receptor antagonist, was injected into fully kindled rats (n= 5) 15 min before initiation of a kindled seizure. Atropine had no effect on the seizure-induced increase in blood pressure (data not shown); however the seizure-induced bradycardia was completely eliminated (Fig. 1). Atropine was effective throughout the first 30 s of the seizure, which is when the seizure appears to exert its maximum effect on the cardiovascular system (Fig. 2). Atropine significantly (PB 0.05) prevented the seizure-induced decrease in heart rate during the first 20 s of the seizure when compared to rats injected with saline (n= 5). We compared baseline heart rate before the seizure to the maximum change in heart rate (increase or decrease) during the seizure in control and atropine-treated
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Fig. 1. The effect of atropine sulfate (1 mg/kg, i.v.) on kindled seizure-induced changes in cardiovascular function. Pretreatment with atropine prevented the seizure-induced bradycardia. There was no change in the electrocardiogram (EKG) during the seizure. Atropine had no effect on the seizure-induced increase in blood pressure. The electroencephalogram (EEG) indicates the onset of the seizure afterdischarge. The up and down arrows indicate the beginning and end of the seizure-inducing stimulus.
rats. The maximum change in heart rate during the seizure in saline controls was a decrease of 242 9 40 beats/min (mean9 S.E.M) while the maximum change in heart rate during the seizure in animals treated with atropine was 4298 beats/ min (mean 9 S.E.M, P B0.001). These data further illustrate the magnitude of the seizureinduced bradycardia and the effectiveness of atropine in preventing it. Timolol (1 mg/kg, i.v.), a nonspecific b-adrenergic receptor antagonist, was injected 15 min be-
Fig. 2. Graphic comparison of the change in heart rate during kindled seizures in animals pretreated with atropine with animals pretreated with saline (control). Atropine significantly (*PB0.05) prevented the seizure-induced decrease in heart rate during the first 20 s of the kindled seizure.
Fig. 3. Effect of pretreatment with timolol maleate on the mean arterial blood pressure during the first 30 s after initiation of stage 5 amygdaloid kindled seizures. There was no difference in the seizure-induced increase in timolol-treated rats when compared with saline controls.
fore the seizure. Treatment with timolol did not affect the decrease in heart rate that occurred during the seizure (data not shown). It also did not prevent the increase in mean arterial pressure that occurred during the kindled seizure (Fig. 3). This suggested that the seizure-induced increase in blood pressure was mediated through a-adrenergic receptor activation. We tested this possibility by inducing a seizure after a-adrenergic blockade with phentolamine or chemical sympathectomy with 6-OHDA, an adrenolytic agent. Phentolamine (5 mg/kg, s.c., n=3), an a-adrenergic receptor antagonist, was injected 30 min before kindled rats were stimulated. Phentolamine decreased baseline mean arterial pressure as well as the increase in blood pressure that occurred during the kindled seizure. However, the seizureassociated bradycardia persisted despite the attenuated increase in blood pressure (Fig. 4). The bradycardia present in animals treated with phentolamine was delayed 15–20 s relative to what was observed in untreated animals (Goodman et al., 1990, 1991). A chemical sympathectomy was induced with 6-OHDA (100 mg/kg, i.v.). Twenty-four hours after 6-OHDA, resting systolic and diastolic pressure was decreased by approximately 50% (Fig. 5B, n= 3). The effectiveness of the 6-OHDA treatment was tested by injecting tyramine (0.5 mg/kg, i.v.), before the 6-OHDA treatment and
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then again after the kindled seizure. Tyramine causes the release of endogenous catecholamines from presynaptic terminals. The initial injection of tyramine resulted in a large increase in blood pressure (Fig. 5A). If the 6-OHDA treatment were ineffective then one would predict that an injection of tyramine after 6-OHDA would also result in a hypertensive response. The second tyramine injection had no effect on blood pressure (Fig. 5C) suggesting that the injection of 6-OHDA resulted in an effective chemical sympathectomy. In these animals, the seizure-induced pressure response was eliminated; however, in two animals a small bradycardic response was still present despite the absence of an increase in blood pressure (Fig. 5B). This bradycardic response (present in the blood pressure trace in Fig. 5B) was delayed relative to what occurred in untreated animals during the seizure. It was similar to what was observed in animals treated with phentolamine.
4. Discussion Cardiovascular changes that occur during amygdaloid kindled seizures result from activation of the sympathetic and parasympathetic branches of the autonomic nervous system. Our findings suggest the pressor component of the seizure-induced response results from central activation of sympathetic pathways. The bradycardia
Fig. 4. Effect of pretreatment with phentolamine hydrochloride (5 mg/kg, s.c.) on kindled seizure-induced changes in cardiovascular function. Phentolamine decreased blood pressure before initiation of the seizure. Phentolamine greatly attenuated the increase in blood pressure that occurred during the kindled seizure. Note the presence of the seizure-associated bradycardia in the absence of a profound increase in blood pressure. The up and down arrows indicate the beginning and end of the stimulus.
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that accompanies the seizure-associated increase in blood pressure is the result of baroreceptor activation of the parasympathetic system. Central activation of the parasympathetic system remains a possibility since the bradycardia was not completely eliminated by phentolamine or chemical sympathectomy. Seizure-induced hypertension has been reported to occur during several experimentally-induced seizures: electroconvulsive shock (Plum et al., 1968; Wasterlain, 1974; Petito et al., 1977; Westergaard et al., 1978), pentylenetetrazol (Plum et al., 1968; Doba et al., 1975; Lathers and Schraeder, 1982) and bicuculline (Meldrum and Horton, 1973; Johanssen and Nilsson, 1977; Suzuki et al., 1984). In all cases, activation of the sympathetic nervous system has been implicated as mediating this effect. In the present study, our data also give evidence that the hypertensive response associated with kindled seizures is mediated through activation of sympathetic pathways. The observations that treatment with the nonspecific b-adrenergic receptor blocker, timolol, had no effect on the pressor response while the response was completely eliminated by the adrenolytic agent 6OHDA, suggests the seizure-induced increase in blood pressure is due to a-adrenergic receptor activation. The 6-OHDA treatment was effective since posttreatment with tyramine, an agent that causes the release of endogenous catecholamines from presynaptic nerve terminals, had no effect in these animals. The observation that the bradycardia could be completely eliminated in kindled animals pretreated with atropine, a muscarinic antagonist, suggests the response is mediated by activation of the parasympathetic system. This increase in parasympathetic activity can be explained by baroreceptor activation secondary to the seizureinduced increase in blood pressure. There is also evidence of central activation of the parasympathetic system during the seizure. Animals treated with phentolamine and 6-OHDA exhibited a bradycardic response in the absence of a pressor response that would be necessary for baroreceptor activation. This bradycardic response was delayed, occurring 15–20 s after initiation of the seizure which also suggests a
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Fig. 5. (A) Effect of tyramine (0.5 mg/kg, i.v.) on blood pressure before injection of 6-OHDA in a kindled rat. Tyramine caused a rapid increase in blood pressure with no effect on the EEG. Arrow indicates time of tyramine injection. (B) Effect of chemical sympathectomy with 6-OHDA on blood pressure during a kindled seizure in the same rat as in (A). 6-OHDA (100 mg/kg, i.v.) was injected 24 h before initiation of the seizure. Note the decrease in baseline systolic and diastolic pressure before the seizure. Chemical sympathectomy completely eliminated the seizure-induced hypertensive response. Note the delayed bradycardia in the blood pressure recording, 15 s after initiation of the seizure, in the absence of an increase in blood pressure. Arrow indicates the onset of the kindling stimulus followed by the seizure afterdischarge in the EEG record. (C) Same rat as in (A) and (B). Effect of tyramine on blood pressure 28 h after injection of 6-OHDA. Tyramine had no effect on blood pressure indicating 6-OHDA induced an effective chemical sympathectomy. Arrow indicates time of tyramine injection. The time scale in this figure is different from previous figures.
different mechanism of activation. The delayed bradycardia would be masked in an untreated animal due to the presence of the baroreceptor mediated decrease in heart rate. Only by preventing the increase in blood pressure were we able to detect the delayed bradycardic event. During kindling acquisition, development of the bradycardic response was not coupled to the development of the pressor response (Goodman et al., 1990). These observations suggest central activation of the parasympathetic system was partially responsible for the seizure-induced bradycardia. This is significant given the number of clinical reports of ictal bradycardia (Coulter, 1984; Kiok et al., 1986; Howell and Blumhardt, 1989; Constantin et al.,
1990; Fincham et al., 1992; Wilder-Smith, 1992; Galimberti et al., 1996; Reeves et al., 1996). Our data from previous studies suggest that the cardiovascular changes associated with kindled seizures are not due to stimulation of the amygdala, a cardiovascular control center, but are seizure-dependent since the kindling stimulus in non-kindled animals failed to alter cardiovascular function (Goodman et al., 1990). We observed similar cardiovascular changes during spontaneous generalized seizures that occurred several minutes after the initial kindled seizure (Goodman et al., 1990, 1991). It is possible that kindled seizure activity travels from the seizure focus to the hypothalamus or brain stem structures that
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regulate cardiovascular function. The likelihood that a given seizure will disrupt autonomic regulation of the heart may be dependent on the location of the seizure focus (Galimberti et al., 1996; Massetani et al., 1997) and factors that determine seizure spread. Given the clinical phenomena of sudden, unexplained death in epileptic patients, the relationship between seizures and central regulation of cardiovascular function is of particular importance. Whether the cardiovascular changes associated with kindled seizures and the mechanism of activation are related to sudden, unexplained death requires further investigation. The kindling seizure model is well suited for future studies of this relationship since cardiovascular function can be evaluated before, during and after the seizure in an unanesthetized, freely moving rat. In addition, the kindling model allows for examination of the effect of partial as well as generalized seizures on the cardiovascular system.
Acknowledgements The authors acknowledge the untimely passing of our colleague and friend Isaac Crawford. He will be greatly missed.
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