Cardiac neural discharge and epileptogenic activity in the cat: An animal model for unexplained death

This study developed an animal model to explore the hypothesis that altered automatic function may be one cause for unexplained sudden epileptic deaths. After α-chloralose anesthesia, 9 cats received a tracheostomy and a thoracotomy. Intravenous gallamine was used to paralyze the cats. Blood pressure, arterial blood gases, electrocardiogram, and rectal temperature were monitored. Simultaneous monitoring of the neural discharge in postganglionic cardiac sympathetic branches and the vagus nerve was combined with a bilateral craniectomy and electrocorticography. Pentylenetetrazol was given intravenously at 10 min intervals in 10, 20, 50, 100, 200, and 2000 mg/kg doses. Epileptiform discharges were categorized as a prolonged ictal (duration of 10 sec or more), brief ictal (duration of less than 10 sec mixed with suppression), and interictal spike activity. The two types of ictal activity were quantified by duration in seconds for the 10 min interval after each dose of pentylenetetrazol; the number of interictal spikes/min was determined for each minute of the entire experiment. This study developed a model which quantified the degree of epileptiform activity and correlated it with changes in cardiovascular function and autonomic cardiac neural discharge. An imbalance within and between sympathetic and parasympathetic cardiac neural discharges was found, as was a significant disruption of the physiological relationships between heart rate and blood pressure. Frequent and varied electrocardiogram abnormalities occurred. All of the above changes occurred during minimal (interictal) subconvulsant as well as during maximal (ictal) convulsant epileptogenic activity.     

The effect of acute and chronic administration of timolol on cardiac sympathetic neural discharge, arrhythmia, and beta adrenergic receptor density associated with coronary occlusion in the cat

The effect of timolol (5 mg/kg, p.o., b.i.d. 7 or 14 days) on cardiac beta adrenergic receptor density, the times to arrhythmia (AR) and death (D), heart rate, mean arterial blood pressure, and postganglionic cardiac sympathetic neural discharge after acute coronary occlusion in cats was examined. In the control animals, receptor densities in the left and right atria did not differ, but were lower than the right ventricle. Left ventricle and septum receptor densities were higher, with the left ventricle the highest. The importance of the gradation of beta receptors with increasing density from base to apex appears to be its relation to cardiac contractile function. Occlusion in cats not treated with timolol did not alter the cardiac beta receptor densities. After timolol for 7 or 14 days, no occlusion, receptor density increased in left ventricle and septum although the increase was only significant after 14 days. A comparison of the beta adrenergic receptor densities in cats pretreated with timolol for 7 or 14 days with or without occlusion revealed that, in general, a decrease (p greater than 0.05) occurred for the occlusion group. Timolol decreased heart rate and blood pressure prior to occlusion. The mean times to AR and D were not significantly increased by either dosing regimen of timolol, although the trend was for an increase in the time to D after 7 days of timolol and an increase in the time to AR and D after 14 days of timolol. When compared with data obtained in saline cats, chronic timolol produced minimal changes in postganglionic cardiac sympathetic neural discharge. Timolol given chronically (p.o.) or acutely (5 mg/kg, i.v. given 15 min prior to occlusion) also did not prevent the cardiac sympathetic discharge associated with the development of AR. The time to AR and D in the acutely treated cats was increased but not significantly. Since cardiac sympathetic neural discharge increased as blood pressure fell in the control period but did not increase after occlusion in the timolol treated animals, the combination of timolol and occlusion may have modified neural discharge via an action on the baroreceptor mechanism. That chronic administration of timolol produces an effect not present in cats in which only occlusion was done is supported by the observation that chronic treatment produced an occlusion-induced decrease in beta adrenergic receptor density.(ABSTRACT TRUNCATED AT 400 WORDS)     

The effect of intracerebroventricular D-ALA2 methionine enkephalinamide and naloxone on cardiovascular parameters in the cat

Lathers and Schraeder (1) have shown that autonomic dysfunction is associated with epileptogenic activity induced by pentylenetetrazol while Vindrola et al (2) found increased D-ALA2 methionine-enkephalinamide (DAME) levels in the rat brain after pentylenetetrazol-induced epileptogenic activity. Thus, this study was designed to determine whether DAME could have contributed, at least in part, to the autonomic dysfunction associated with pentylenetetrazol-induced epileptogenic activity in the study of Lathers and Schraeder (1). DAME (500 micrograms/kg, icv) was given to 9 cats anesthetized with alpha chloralose. Epileptogenic activity and hypotension occurred in all cats (maximum fall ranging from 6 to 46 mmHg; duration of 6 to 35 min). In 6 cats the heart rate decreased, in 2 it increased, and in 1 it showed little or no change. The duration of heart rate changes varied from 18 to 76 min. Naloxone (100 micrograms/kg, iv) was given to 6 cats after DAME. Naloxone suppressed or abolished the epileptogenic activity in all 6 cats, reversed the DAME-induced hypotension and increased the heart rate in 3 cats, decreased it in 2, and produced no change in 1. These results indicate that DAME may produce epileptogenic activity and cardiovascular changes through an action on central opiate receptors. It is hypothesized that: 1) increased levels of DAME inhibit the release of gamma aminobutyric acid; 2) this then increases vagal bradycardia and hypotension; and 3) step 2 causes an imbalance in peripheral autonomic cardiac neural discharge which may cause arrhythmias and/or sudden unexplained death in the epileptic person.     

Chlorpromazine: cardiac arrhythmogenicity in the cat

To determine the effect of chlorpromazine on ouabain-induced arrhythmia and death, dial-urethane anesthetized cats were pretreated with chlorpromazine (5, 10, 20, 30, 40, or 60 mg/kg, i.v.) and then administered ouabain (2 microgram/kg/min, i.v.). Blood pressure, heart rate and lead II electrocardiogram (ECG) were monitored. The dosages of ouabain necessary to induce premature ventricular contractions, ventricular tachycardia and death were determined. No significant correlation between the dose of chlorpromazine given and the dose of ouabain required to produce arrhythmia or death was found. These doses of chlorpromazine could, therefore, be considered neither arrhythmogenic nor antiarrhythmic in the ouabain model. To determine whether chlorpromazine produced arrhythmia in the dial-urethane anesthetized cat model, the drug was infused at a rate of 1 mg/kg/min, i.v. Chlorpromazine produced arrhythmia at 185 +/- 4.3 minutes and death via cardiovascular collapse at 128 +/- 4.7 minutes. Bilateral adrenal vein ligation, employed to eliminate the influence of adrenal catecholamines, decreased the dosage of chlorpromazine necessary to produce arrhythmia and death to 67.8 +/- 17.7 and 84.7 +/- 15.7 mg/kg, respectively. Thus, adrenal catecholamines did not appear to contribute to chlorpromazine-induced arrhythmia, although the procedure of bilateral adrenal vein ligation appeared to be deleterious in combination with chlorpromazine. In all experiments, chlorpromazine depressed blood pressure without producing the reflex tachycardia normally seen with hypotension. This suggests that the drug may be interfering with the baroreceptor reflex arc. As chlorpromazine modifies the autonomic parameters of blood pressure, heart rate, and cardiac electrophysiology, sudden unexplained death in patients managed with this agent may be due to drug-induced arrhythmia.     

Effects of cocaine alone and in combination with haloperidol and SCH 23390 on cardiovascular function in squirrel monkeys

The potential involvement of D1 and D2 dopamine receptors in the effects of cocaine on cardiovascular function in squirrel monkeys was evaluated. A low dose of cocaine (0.1 mg/kg i.v.) produced increases in both blood pressure and heart rate. At the higher doses of cocaine (1.0-3.0 mg/kg) the heart rate response was biphasic, consisting of an early decrease followed by an increase in heart rate 10-20 min following injection. The dopamine D2 antagonist haloperidol (0.1 mg/kg i.m.) attenuated the heart rate increasing effect of cocaine, but doses as high as 0.03 mg/kg did not alter the blood pressure increase. The D1 antagonist SCH 23390 (0.01-0.03 mg/kg i.m.) did not attenuate either the blood pressure or heart rate increasing effects of cocaine. The D2 agonist quinpirole (1.0 mg/kg i.v.) produced increases in heart rate similar to cocaine, with little effect on blood pressure. Although effective against the heart rate increasing effect of cocaine, haloperidol (0.01 mg/kg) did not antagonize the heart rate increasing effects of quinpirole. The D1 agonist SKF 38393 (3.0 mg/kg i.v.) decreased heart rate and increased blood pressure. The blood pressure increasing effect of SKF 38393 was antagonized by 0.01 mg/kg SCH 23390. Haloperidol's ability to partially antagonize the tachycardiac response to cocaine suggests the involvement of D2 receptors in that response. However, the failure of haloperidol to antagonize quinpirole's tachycardiac effect suggests that non-dopaminergic mechanisms may also be involved in haloperidol's antagonism of cocaine's tachycardiac effect. The pressor effects of cocaine do not appear to be controlled by selective dopamine receptors.     

Cardiovascular effects of the essential oil of Mentha x villosa in DOCA-salt-hypertensive rats.

The present study investigated the effects of chronic treatment with deoxycorticosterone-acetate (DOCA)-salt on cardiovascular responses to intravenous (i.v.) injection of the essential oil of Mentha x villosa (EOMV) in conscious rats. In both DOCA-salt-hypertensive and uninephrectomized control, conscious rats, i.v. bolus injections of EOMV (1 to 20 mg/kg body wt.) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-dependent manner. Treatment with DOCA-salt significantly enhanced EOMV-induced decreases in MAP, without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. injection of the ganglion blocker, hexamethonium (30 mg/kg body wt.), were significantly greater in DOCA-salt-hypertensive than in control rats. In DOCA-salt-hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg body wt.) reduced the bradycardia elicited by EOMV (1 to 20 mg/kg body wt.) without affecting the enhancement of EOMV-induced hypotension. These results show that i.v. treatment with EOMV decreases blood pressure in conscious DOCA-salt-hypertensive rats dose-dependently, and that this action is enhanced when compared with uninephrectomized controls. This enhancement could be related mainly to an increase in EOMV-induced vascular smooth muscle relaxation, rather than to enhanced sympathetic nervous system activity in this hypertensive model.     

Effect of D-Ala-2-Me-Phe-4-Gly-ol-5 enkephalin on epinephrine-induced arrhythmias in the rat and the interrelationship to the parasympathetic nervous system

The purpose of this study was to evaluate the effects of the millimicrons opioid agonist D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) on catecholamine-induced arrhythmias. Arrhythmias were produced, in the rat, by continuous infusion of epinephrine until the development of fatal arrhythmias that were usually ventricular fibrillation. Intracerebroventricular (ICV) administration of DAGO, 3 nmol, significantly (p less than 0.05) shifted to the right the relationship between epinephrine and both the onset of ventricular arrhythmias and the development of fatal arrhythmias. Naloxone, 1 mg/kg i.v., prevented these effects of DAGO. Atropine, 1 mg/kg i.v. or 20 micrograms/kg ICV, prevented the shift in these dose response relationships. Antagonism of DAGO's effects on arrhythmias could not be explained by an alteration of the blood pressure response to epinephrine. However, DAGO significantly increased blood pressure and decreased heart rate in separate experiments in animals that did not receive epinephrine and atropine prevent the heart rate and blood pressure effects of DAGO. These data show that 1) the millimicrons opioid receptor agonist DAGO suppresses epinephrine-induced arrhythmias, 2) the site of action can be within the CNS, 3) there is a role for the central parasympathetic nervous system to mediate the effect of DAGO and 4) endogenous opioids could modulate catecholamine-induced cardiac arrhythmias.     

Central benzodiazepine involvement in clonidine cardiovascular actions

It is well known that the GABAergic and noradrenergic systems play an important role in blood pressure and heart rate regulation. Benzodiazepines and beta-carbolines, respectively, increase or decrease the probability of chloride-channel opening induced by GABA. The aim of this study was to determine, in conscious rats, the interaction existing between the central alpha2-adrenoceptor stimulation induced by clonidine and the facilitation or impairment of benzodiazepine receptor activity through the administration of either diazepam, a benzodiazepine receptor agonist, or methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), an inverse benzodiazepine agonist. Clonidine (5-10 microg, intracerebroventricularly) reduced heart rate and increased mean blood pressure by activation of central alpha2-adrenoceptors. Diazepam (2 mg/kg, intravenously (i.v.)) induced an increase in heart rate, while DMCM (0.3 mg/kg, i.v.) elicited a bradycardic effect. The bradycardic effects induced by both clonidine and DMCM were antagonized by the prior administration of methylatropine (1.5 mg/kg, i.v.). DMCM (0.3 mg/kg, i.v.) prevented the clonidine effects on heart rate and mean blood pressure, while diazepam (2 mg/kg, i.v.) failed to modify these effects. Our results suggest that the bradycardic effects of clonidine are mediated by a vagal stimulation and are related to the activation of a GABAergic pathway.     

Vagus nerve stimulation suppresses generalized seizure activity and seizure-triggered postictal cardiac rhythm changes in rats

In the present study, we investigated the effects of vagus nerve stimulation (VNS), a proposed treatment for patients with intractable epilepsy, on cardiac rhythm following seizures induced by pentylenetetrazole (PTZ) in Wistar rats. After a baseline recording of electroencephalogram (EEG), electrocardiogram (ECG) and blood pressure (BP), rats in the first group received a single convulsive dose of PTZ (70 mg/kg) (Group 1). In the other two groups, the Wistar rats were implanted with a cuff electrode on the left cervical vagus nerve. One day after surgery, rats in the second group were treated with VNS (Group 2), whereas rats in the third group were connected to the stimulator but did not receive VNS (Group 3). Ten minutes after VNS onset, 70 mg/kg dose of PTZ was injected. EEG, ECG and BP were continuously recorded during post-injection period. Seizure severity was scored behaviorally. Then, baseline, ictal and postictal periods were analyzed for cardiac rhythms, seizure severity and blood pressure variability. PTZ treatment induced tonic-clonic seizure activity in all animals of Group 1 and Group 3. In these groups a marked increase of mean arterial blood pressure (MABP) but a significant decrease in heart rate and PP interval fluctuations was observed at postictal period. However, in the VNS-treated group the seizure scores and cardiac parameter returned to the baseline level. Present results emphasize that VNS effectively reduces seizure severity and suppress the seizure-induced cardiac rhythm changes.     

Pentobarbital versus medetomidine-ketamine-fentanyl anaesthesia: effects on haemodynamics and the incidence of ischaemia-induced ventricular fibrillation in swine

The present study was performed to compare haemodynamic variables at baseline and the incidence of ventricular fibrillation during the early phase of ischaemia in swine during pentobarbital or medetomidine-ketamine-fentanyl anaesthesia. Twenty-two swine (mean +/- SD: 29+/- 3 kg) were anaesthetized with sodium pentobarbital (induction with 36 mg/kg intraperitoneally, and maintenance with 5-20 mg/kg/h intravenously [i.v.]) and 6 swine (27+/- 3 kg) were anaesthetized with ketamine and fentanyl (premedicated with medetomidine 0.1 mg/kg and ketamine 10 mg/kg intramuscularly, induction with ketamine 20 mg/kg and fentanyl 0.025 mg/kg i.v., and maintenance with ketamine 20 mg/kg/h and fentanyl 0.025 mg/kg/h i.v.). After a stabilization period of 30 min, the left anterior descending coronary artery (LAD) was occluded for 10 min. Haemodynamic data and occurrence of ventricular fibrillation were recorded. The ischaemic area was measured by fluorescing microspheres. Swine anaesthetized with medetomidine-ketamine-fentanyl had significantly lower heart rate, myocardial contractility, peak left ventricular pressure, arterial blood pressure, aortic blood flow, myocardial blood flow and cardiac index at baseline, than swine anaesthetized with pentobarbital. Whereas none of the swine anaesthetized with pentobarbital fibrillated during the LAD occlusion, ventricular fibrillation occurred in 83% of the animals anaesthetized with medetomidine-ketamine-fentanyl (P< 0.001). No significant difference was found in size of ischaemic area between the two groups. Thus, we show a depression in haemodynamic variables at baseline and a higher incidence of ventricular fibrillation during the early phase of ischaemia in swine anaesthetized with medetomidine-ketamine-fentanyl compared to swine anaesthetized with pentobarbital.     

Anti-epileptic effect of the new calcium channel blocker IOS-1.1212]

In experiments on freely moving male Wistar rats it was shown that IOS-1.1212 (1,4-dihydropyridine) in a dose 2 and 10 mg/kg (i. p.) suppressed the penicillin-induced focal epileptic activity in cerebral cortex. Similar suppressing effect of IOS-1.1212 was shown on acute generalized tonic-clonic pentylenetetrazol (PTZ) seizures (75 mg/kg i. p.) and on chronic PTZ administration (PTZ-kindling, 30 mg/kg i. p. during 30 days): when injected 30 min before each PTZ administration it delayed the development of kindling-induced seizures susceptibility in randomized animals (series 1) and attenuated the severity of seizures in PTZ-sensitive animals (series 2). However, IOS-1.1212 had no effect on the strychnine-induced focal epileptic activity. In male Icr:Icl mice IOS-1.1212 in a dose 1.5 and 5 mg/kg also influenced the PTZ convulsions (i. v. titration of 1% solution at a rate of 0.01 ml/s) and had no effect on the strychnine convulsions (i. v. titration of 0.01% solution at a rate of 0.01 ml/s) and on maximal electroshock. In addition, IOS-1.1212 significantly increased antiepileptic effect of phenobarbital on maximal electroshock.     

The cardiac effects of amitraz in the guinea-pig in vivo and in vitro

Intravenous amitraz caused significant hypotension and bradycardia in pentobarbitone anaesthetized guinea-pigs. Depression of blood pressure reached a plateau with a dose of 10 mg/kg but heart rate continued to fall in a dose-dependent manner, up to a fall of 90 beats per minute after a total of 160 mg/kg/min. Amitraz was then tested on spontaneously beating guinea-pig isolated atria. The maximum bath concentration approximated a blood concentration produced by 5 mg/kg amitraz in the guinea-pig (2.3 X 10(-4) M). Amitraz did not significantly shift the dose-response curve to isoprenaline or acetylcholine but antagonized histamine rate responses competitively in the presence of propranolol (2 X 10(-6) M). Propranolol unmasked a dose-dependent depressant effect of amitraz on atrial rate, an effect abolished with atropine (1 X 10(-5) M). Amitraz increased atrial force of contraction, an effect which was not seen when propranolol was present in the bath solution. Amitraz also depressed atrial rate directly, but this effect was minor in comparison to bradycardia seen in the guinea-pig. It is likely that the cardiovascular depression seen in the guinea-pig following amitraz i.v. is caused by an alteration in autonomic drive rather than a significant direct cardiac effect.     

Abolition of clonidine's effects on ventricular refractoriness by naloxone in the conscious dog

The interaction between opiate and adrenergic receptors on cardiac electrophysiologic function in the conscious dog was addressed in our study. We examined the effects of opiate receptor blockade with naloxone on clonidine-induced changes in refractoriness of the cardiac ventricle. Nine dogs were chronically instrumented for recording mean arterial blood pressure, administration of drugs and for measurement of effective refractory period of the ventricle. Clonidine (10 micrograms/kg, i.v.) significantly (p less than 0.05) decreased heart rate to 72 +/- 5 beats/minute from 108 +/- 8 beats/minute; mean arterial pressure decreased significantly (p less than 0.05) to 83 +/- 3 mmHg from 91 +/- 4 mmHg. Ventricular refractoriness was increased significantly (p less than 0.05) at current levels of 7 and 10 mA and pacing rates 180 and 200 beats/minute. Naloxone (3-10 mg/kg, i.v.) abolished clonidine's effects on heart rate, mean arterial pressure and ventricular refractoriness. We conclude that ventricular refractoriness may be regulated in part by interactions between central adrenergic and opioidergic systems.     

The effects of acebutolol alone and in combination with furosemide or hydralazine in experimentally induced hypertensive G-minipigs

Experimentally induced hypertensive G-minipigs were used for assessing the antihypertensive effects of acebutolol, a cardioselective beta-adrenergic blocking agent. In the acute experiment, six females were used. Acebutolol (3 mg/kg, i.v.) alone or in combination with furosemide (1 mg/kg, i.v.) or hydralazine (1 mg/kg, i.v.) was administered through an implanted catheter. In the chronic experiments, five females received oral acebutolol (100-200 mg/day). The blood pressure, heart rate, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were used as parameters. In the acute experiment, there were no marked changes in the blood pressure or heart rate during the nondosing period. Acebutolol alone caused a marked decrease in the blood pressure and heart rate. In the two combination tests, combined administration with acebutolol and furosemide had a greater effect on the blood pressure and heart rate than did acebutolol alone. A combined acebutolol and hydralazine regimen caused a slight reduction not only in the blood pressure, but also in the heart rate compared with acebutolol alone. PRA and PAC remained essentially constant, with minor fluctuations, throughout the nondosing period. Following the injection of acebutolol alone, PRA showed an elevation with a significant rise after three hours and PAC showed a tendency to increase. PRA and PAC generally tended to increase in the case of combined administration with furosemide or hydralazine, but these tendencies were less conspicuous than with acebutolol alone. On the other hand, chronic treatment with acebutolol produced a significant decrease in the heart rate from two weeks after the administration and in the blood pressure from four weeks.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of long-term pretreatment with isoproterenol on bromocriptine-induced tachycardia in conscious rats

It has been shown that bromocriptine-induced tachycardia, which persisted after adrenalectomy, is (i) mediated by central dopamine D2 receptor activation and (ii) reduced by 5-day isoproterenol pretreatment, supporting therefore the hypothesis that this effect is dependent on sympathetic outflow to the heart. This study was conducted to examine whether prolonged pretreatment with isoproterenol could abolish bromocriptine-induced tachycardia in conscious rats. Isoproterenol pretreatment for 15 days caused cardiac hypertrophy without affecting baseline blood pressure and heart rate. In control rats, intravenous bromocriptine (150 microg/kg) induced significant hypotension and tachycardia. Bromocriptine-induced hypotension was unaffected by isoproterenol pretreatment, while tachycardia was reversed to significant bradycardia, an effect that was partly reduced by i.v. domperidone (0.5 mg/kg). Neither cardiac vagal nor sympathetic tone was altered by isoproterenol pretreatment. In isolated perfused heart preparations from isoproterenol-pretreated rats, the isoproterenol-induced maximal increase in left ventricular systolic pressure was significantly reduced, compared with saline-pretreated rats (the EC50 of the isoproterenol-induced increase in left ventricular systolic pressure was enhanced approximately 22-fold). These results show that 15-day isoproterenol pretreatment not only abolished but reversed bromocriptine-induced tachycardia to bradycardia, an effect that is mainly related to further cardiac beta-adrenoceptor desensitization rather than to impairment of autonomic regulation of the heart. They suggest that, in normal conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at peripheral dopamine D2 receptors.     

The effect of an alerting acoustic stimulus on the heart rate, sympathetic activity and aortic baroreceptor discharge in conscious rabbits before and after naloxone administration

Blood pressure, heart rate, aortic nerve activity and cervical sympathetic discharge were recorded simultaneously in 10 rabbits. Chronic recordings were made with electrodes implanted to the uncut aortic and cervical sympathetic nerves. 1. The alerting acoustic stimulus produced a short lasting decrease in sympathetic activity with a transient bradycardia. 2. In 6 out of 8 rabbits i.v. administration of naloxone chloride (100 mg/kg) diminished or abolished early inhibitory effects evoked by acoustic stimulus. 3. The sympatho-inhibitory system involved in the startling response appears to be independent of the baroreceptor inhibitory reflex and has opposite responsiveness to naloxone. 4. A decrease in efferent sympathetic activity with no accompanying change in the aortic nerve activity suggests some central resetting of the baroreceptor-sympatho-inhibitory reflex. 5. We suggest that the observed autonomic effects following an alerting stimulus are typical for a fear-anxiety drive.     

Participation of the autonomic nervous system in the cardiovascular effects of milrinone

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.     

A comparison of medetomidine-propofol and medetomidine-midazolam-propofol anesthesia in rabbits.

We evaluated and compared the effects of medetomidine-propofol and medetomidine-midazolam-propofol anesthesia in rabbits. Fourteen New Zealand White rabbits were randomly assigned to receive either medetomidine (0.25 mg/kg, i.m.)-atropine (0.5 mg/kg, i.m.)-propofol (4 mg/kg, i.v.) (n = 7) or medetomidine (0.25 mg/kg, i.m.)-atropine (0.5 mg/kg, i.m.)-midazolam (0.5 mg/kg, i.m.)-propofol (2 mg/kg, i.v.) (n = 7). Five minutes after medetomidine-atropine or medetomidine-atropine-midazolam i.m. injection, propofol was administered i.v. Both medetomidine and medetomidine-midazolam rapidly (within 5 minutes) immobilized all rabbits and greatly eased the i.v. administration of propofol. Endotracheal intubation was accomplished easily after propofol injection in both groups. There was no significant difference between medetomidine-propofol and medetomidine-midazolam-propofol-treated rabbits in heart rate, respiratory rate, mean arterial pressure, or end-tidal CO2. The addition of midazolam to the medetomidine-propofol regimen significantly (P < 0.05) prolonged the duration of ear-pinch analgesia (25.0 +/- 7.1 vs. 36.7 +/- 8.9 minutes), the time from extubation to sternal recumbency (0.0 vs. 26.7 +/- 8.1 minutes), and the time from extubation to standing (0.0 vs. 39.5 +/- 11.3 minutes) without inducing significant changes in arterial blood pressure and end-tidal alveolar CO2. We consider both medetomidine-propofol and medetomidine-midazolam-propofol combinations to be safe and effective regimens for induction and short-term anesthesia in rabbits.     

Assessment of autonomic cardiovascular indices in non-stationary data in rats

The analysis of heart rate in the frequency domain has become increasingly important in physiological studies, and supports the use of heart rate variability as an index of autonomic cardiovascular control. A new index, the instant centre frequency (ICF) has been proposed as a global index of the instantaneous relationship between sympathetic and vagal modulation. The aim of this study was to assess ICF, RR intervals, and heart rate variability measures as indices of sympathovagal balance during a pharmacological blockade of the autonomic nervous system in normotensive rats. RR intervals and arterial blood pressure of 10 conscious Wistar rats equipped with telemetry probes, were evaluated before, during, and after injection of: (1) saline (100 microl kg(-1) i.v.); (2) phentolamine (5 mg kg(-1) i.v.); (3) atropine methyl nitrate (0.5 mg kg(-1) i.v.); and (4) atenolol (1 mg kg(-1) i.v.). RR interval series were analysed by the smoothed pseudo-Wigner-Ville distribution. A general linearised model was used to evaluate the parameters. ICF was calculated in the same way as the peak power frequency by use of the first moment of instant spectrum. We calculated the ICF of the whole spectrum (ICF(T)), ICF in high frequency (ICF(H)) and ICF in low frequency (ICF(L)). The RR intervals and ICF indexes varied similarly and presented the lowest coefficient of variation among animals exposed to the same autonomic conditions. ICF(T)-ICF(L) and ICF(H)-ICF(T) were strongly correlated with normalised HF and normalised LF. In normotensive rats, RR intervals and ICF indices may reliably capture the effects of the sympathetic and parasympathetic nervous system on the sinus node.     

Pharmacological effects of 1,2,3,5,6,10b-hexahydropyrido[2,3g]indolizine, a bridged-nicotine analog

The racemate of a bridged-nicotine (BN) analog was synthesized and resolved into its enantiomers for pharmacological comparisons to (+)- and (-)-nicotine. The EC50 values for (-)- and (+)-nicotine and (-)- and (+)-BN were 4, 170, 53 and 400 microM, respectively, for producing contractions of guinea-pig ilea. (-)-Nicotine was an effective antinociceptive agent in the mouse tail-flick procedure at i.v. doses of 0.1-0.3 mg/kg, whereas the isomers of BN failed to alter tail-flick response in doses up to 5 mg/kg. (-)-Nicotine (0.01-0.3 mg/kg, i.v.) increased blood pressure and decreased heart rate in anesthetized rats. Neither (+)- nor (-)-BN altered blood pressure and heart rate in rats in this dosage range. At doses of 3-100 mg/kg, (+)-BN produced an increase in blood pressure without changing heart rate, while (-)-BN decreased both blood pressure and heart rate. Bridging the pyrrolidine and pyridine rings decreased biologic activity and did not result in stereoselectivity greater than that observed with (+)- and (-)-nicotine. It appears that there may be subpopulations of nicotine receptors to which the isomers of BN do not interact.