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Experiments were performed on pentobarbital-anesthetized cats to test the hypothesis that hypovolemia rather than cardiac failure is responsible for the acute lethal toxicity of the trichothecene mycotoxin, T-2 toxin (T2T). Measurements were made on mean arterial blood pressure (MAP), arterial pulse pressure (PP), and heart rate (HR) in eight otherwise untreated cats given T2T (2 mg/kg iv) and in three cats similarly injected with T2T but then transfused with plasma and blood. The transfusions to their available extent significantly delayed or counteracted the development of mycotoxic shock (i.e., depressed MAP and PP) and prevented or reversed a rise in the hematocrit. HR remained stable under all conditions. Plasmapheresis followed by whole-blood removal was found best to simulate mechanistically the mycotoxic shock syndrome in six blood donor cats free of T2T. It is concluded that hypovolemia with polycythemia resulting from plasma leakage and internal bleeding accounts for acute lethal T-2 mycotoxicosis.

Studies were conducted in cats to determine whether this species could serve as an animal model for the therapeutic toxicity of recombinant interleukin-2 in humans, and to establish the role of the area postrema in the causation of recombinant interleukin-2-induced vomiting. Injections of recombinant interleukin-2 (3.6 x 10(6) IU/kg, i.m.), given once every 24 hr for one to three days, evoked repeated vomiting in 4 out of 6 area postrema intact cats and in 3 out of 3 area postrema-ablated cats. These results suggest that the area postrema is not essential for the emetic action of recombinant interleukin-2. In anesthetized intact cats, no remarkable changes in ventilation, blood pressure, heart rate or blood pH were observed over 4.5 to 54 hr of continuous physiological recording after i.v. injections of recombinant interleukin-2 to a total dose as high as 27 x 10(6) IU/kg. Cat lymphocytes responded appropriately to the cytokinetic action of human recombinant interleukin-2.

Hindbrain morphology is compared in a variety of animals representing species that vomit and those that do not. Special attention is given to the nucleus of the tractus solitarius (NTS) and its synaptic connections with surrounding structures. The role of the area postrema is examined from the standpoints of containing the chemoreceptor trigger zone (CTZ) for vomiting, of its functional relationship to the blood-brain barrier, and of its significance as part of the circumventricular organ system. A survey is made of the manifold behavioral contributions of NTS to cardiovascular and respiratory regulation, appetite control, arousal, water balance, and digestive and neuroendocrine functions. An overview is presented of neurochemical distribution in the brain stem with respect to aminergic, cholinergic, and peptidergic substances. Finally, causes and prevention of vomiting are discussed in light of the above considerations.

Before 1949, the vomiting center was said to be located in the dorsal vagal nuclei of the medulla, but it was uncertain whether two centers existed separately for the control of direct and reflex actions of emetic agents. Borison and Wang then used a stereotaxic technique with electrical stimulation to localize the vomiting center in the reticular formation at a measurable distance from the dorsal vagal nuclei. They also formulated the concept of a separate emetic chemoreceptor trigger zone (CTZ) so that the vomiting center itself is not sensitive to emetic agents and serves solely to coordinate the reflex process. The CTZ was soon identified with the area postrema (AP), but the question remains unanswered whether the CTZ constitutes part or all of tht circumventricular organ. Furthermore, different chemosensory functions, as for defecation and certain forms of autonomic expression, may be represented regionally within the AP. Species that are unable to vomit, e.g., rodents, show other postrema-mediated effects as radiation-induced gastric stasis and drug-induced conditioned taste aversion. In sheep, digitalis-induced arrest of rumination is prevented by postremectomy. It is suggested that these behavioral end points in nonvomiting species may serve for biological assay of antinauseant drugs. Finally, a tabular summary is given of known causes of vomiting in which the AP has been implicated.

Cyclophosphamide and phosphoramide mustard produce significant vomiting. Cyclophosphamide is metabolized to phosphoramide mustard, which may ultimately contribute to vomiting after cyclophosphamide administration. The role of the chemoreceptor trigger zone (CTZ) in vomiting caused by these agents is unknown. We studied the emetic syndromes produced by iv and intracerebroventricular cyclophosphamide and phosphoramide mustard in unanesthetized normal and CTZ-ablated cats. Iv cyclophosphamide produced vomiting unpredictably, with a mean latency of 54 +/- 9 mins (mean +/- SE) in cats that vomited. A dose-response relationship was found for phosphoramide mustard-induced emesis. A dose of 200 mg/kg was consistently effective, with a mean latency of 127 +/- 6 mins. Neither agent produced predictable emesis by the intracerebroventricular route of administration. One of four CTZ-ablated cats vomited after 300 mg/kg of cyclophosphamide. Since cyclophosphamide was an unpredictable emetic stimulus, it was not possible to further evaluate the effect of CTZ ablation on cyclophosphamide-induced vomiting. However, CTZ-ablated cats given 200 mg/kg of phosphoramide mustard vomited significantly less frequently (P = 0.05 by chi-square test) and with a longer latency than nonablated animals. A temporary, severe neurotoxic reaction was observed in cats receiving greater than or equal to 3400 mg/kg of cyclophosphamide, which may have had an inhibitory effect on emesis. Phosphoramide mustard was found to be a potent emetic stimulus in cats and may contribute to the emetic response following cyclophosphamide administration. Analysis of latency data suggests that in the cat other cyclophosphamide metabolites may also contribute to the emetic syndrome.

Isolated control of pressure in the carotid sinus was exercised bilaterally by means of pump-driven autoperfusion in anaesthetized heparinized cats breathing 100% O2. In cats with vagus nerves intact, a rise of intrasinus pressure resulted in a non-adapting fall in arterial blood pressure and a short-lasting depression in tidal volume and frequency of breathing that adapted fully in the steady state. Vagotomy increased the steady-state gain of the intrasinus pressure-vasodepressor relationship and resulted sometimes in a measurable sustained inhibition of breathing, following its initial adaptation, at the upper levels of intrasinus pressure tested. Pharmacological stabilization of the blood pressure with the use of guanethidine plus phenylephrine did not detectably affect the adapting character of the sinus reflex respiratory response. Denervation of the carotid sinuses abolished all responses previously evoked by shifts of intrasinus pressure. It is concluded that the reflex effects of carotid sinus autoperfusion are produced by selective activation of the baroreceptors and that the respiratory adaptation results from signal processing in the central nervous system different from the processing involved in the non-adapting vasodepressor effect.

T-2 toxin, a trichothecene mycotoxin, was injected iv or ip in the single lethal dose of 2 mg/kg. Vomiting was elicited in normal and decerebrate cats with an average onset time of 26.6 min. Chronic ablation of the area postrema significantly delayed the emetic latency to 304 min. Polygraph recording revealed a steady decline in mean arterial blood pressure and pulse pressure to an extreme shock level resulting in death after 5 to 15 hr. Heart rate varied unremarkably throughout the course of circulatory failure, and the cardiac beat persisted after respiratory arrest. No protection against the lethal response was afforded by midbrain decerebration, area postrema ablation, section of the carotid sinus and vagus nerves, and high spinal cord transection supported with artificial ventilation. Effects of T-2 toxin on central and reflex control of breathing were evaluated through changes in VT/FACO2 and f/VT relationships generated by delivery of CO2 enriched gas for inhalation. Central CO2 responsiveness was well maintained under all tested neurological conditions up to the stage of terminal collapse with late decreases in delta VT/delta FACO2 gain and FACO2 setpoint. A toxin-induced progressive increase in resting frequency and an associated decrease in delta f/delta VT gain was found in unanesthetized decerebrate cats, though resting f did not change remarkably in the anesthetized brain-intact cats. In vagotomized brain-intact cats, the delta f/delta VT gain was sustained at zero. These findings indicate that T-2 toxin exercised minimal influence on the brain stem CO2-VT regulator but it caused an acceleration of the central respiratory oscillator after interruption of forebrain connections.

Space sickness is generally considered a variant of motion sickness although not fully proved as such. Understanding space sickness requires objective and quantitative characterization of the disorder. Vomiting is a quantifiable physiological event performed by the respiratory muscles which generate the pressures that evacuate the gut. Vomiting from all causes is coordinated by the vomiting center in the medulla oblongata. The emetic chemoreceptor trigger zone (CTZ) in the area postrema is thought to be an indispensable element in the afferent pathway of motion sickness. About 30 potential neurotransmitters exist in the vomiting control mechanism which includes at least eight chemical transmission steps through the reflex pathway of motion sickness. Individual synaptic transmitters do not likely mediate specific functions, but particular combinations of those transmitters might well serve distinct functions. Adaptation to the cause of space sickness probably results from readjustment of a cerebellar circuit or of a humoral factor acting on the CTZ, rather than from stimulus-receptor desensitization. Space sickness must, for purposes of investigation, be treated as a unique disorder engendered by weightlessness until proved equivalent to any emetic syndrome that occurs on earth.

Morphine, levorphanol, fentanyl and methadone given by intracerebroventricular (i.c.v.) injection blocked the vomiting response to a standard emetic test dose of apomorphine subsequently injected i.c.v. Of these narcotics, only morphine initially evoked vomiting. Systemic pretreatment with naloxone (5 mg/kg i.p. or i.v.) uniformly abolished the antiemetic activity of all the represented narcotic agents, moreover, naloxone thus administered was followed consistently by emetic responses to those narcotics which separately failed to evoke vomiting. When naloxone was injected i.c.v. in addition to being given systemically, both antiemetic and emetic activities of the narcotic agents were essentially abolished, whereas apomorphine continued to evoke vomiting. In the presence of systemic naloxone, given to counteract self-blockade of vomiting, the narcotics were shown to induce vomiting through excitation of the medullary emetic chemoreceptor trigger zone and emetic receptor tolerance as well as cross-tolerance developed acutely. The present differentiation by naloxone of the emetic and antiemetic properties of narcotic agents placed in the cerebrospinal fluid indicates that the opposing narcotic actions are exercised at different sites in the brain and that the narcotic receptor specificity of the chemoreceptor trigger zone does not encompass the emetic action of apomorphine.

Observations were made on respiration, alveolar concentration of CO2, arterial blood pressure and heart rate in barbiturate-anesthetized cats subjected routinely to section of the vagus and carotid sinus nerves and maintained with pure O2 for inhalation. Bolus i.v. injection of angiotensin II (AII), 0.6 to 6.0 micrograms/kg, evoked a prompt shortlasting suppression of breathing, manifested mainly as a reduction in tidal volume susceptible to the development of tachyphylaxis if injections were spaced more closely than 30 min apart. Ablation of the area postrema failed to eliminate the respiratory effect of All. The response also persisted after midbrain transection, spinal cord transection at C8, dorsal rhizotomy of spinal segments C1 to C8 and interruption of cranial nerves V, VII, VIII, IX, X, XI and XII. No influence of All was evident on indirectly evoked tibialis muscle contractions and on pulmonary compliance. A reduction in phrenic nerve impulse traffic coincided with the respiratory response to All. Cranial i.a. injection of All initiated the respiratory effect in its first pass through the brain, before any change occurred in the blood pressure. The degree of All-induced respiratory inhibition was relatively constant at different magnitudes of breathing produced by CO2 inhalation or by electrical stimulation of the respiratory center in the medulla oblongata. It is concluded that All given by bolus intravascular injection causes respiratory inhibition through a direct central action at the final processing step in the CO2-tidal volume controller.

The emetic chemoreceptor trigger zone (CTZ), located in the area postrema of the medulla oblongata, is generally believed to be indispensable for the vomiting in motion sickness and, by extrapolation, also in space sickness. Accordingly, it has been postulated that a "motion vomiting substance" is secreted into the cerebrospinal fluid in the emetic process. Furthermore, certain therapeutic measures against motion sickness are aimed at preventing the presumed chemical stimulation of the CTZ. This concept originated from laboratory experiments in which ablation of the area postrema protected some dogs and monkeys against motion-induced vomiting. More recent experiments, however, showed that verified lesions of the area postrema were not effective in preventing motion sickness in cats. It appears that an indispensable unidentified element close to but separate from the area postrema was fortuitously destroyed in the earlier experiments. The overall evidence leads to the conclusion that the area postrema is not essential for motion-induced vomiting. Therefore, no functional basis exists for the postulation of a motion vomiting substance, and it is irrational for the treatment of motion sickness to seek pharmacologic blocking agents that act at the CTZ.

In pentobarbital-anesthesized cats, bolus i.v. injections of sodium azide produced dose-dependent transient hypotension accompanied by a modest tachycardia and a brief hyperpnea. Intracerebroventricular injections of azide elicited graded effects similar to the i.v. doses, but the responses were slower in onset and could be delayed by occluding the cranial blood supply. This is interpreted to mean that intracerebroventricular azide acts systematically after escaping from the cerebrospinal fluid into the bloodstream. The hypotensive response to i.v. azide was not affected by cholinergic or adrenergic blockade or buffer nerve section. The tachycardia was blocked by sympathetic neural blockade or buffer nerve section indicating that it is a baroreflex response to the vasodepressor effect. Respiratory effects of bolus i.v. azide occurred independently of the hypotensive response and were abolished by peripheral chemodenervation. Infusion of azide facilitated CO2-tidal volume responsiveness in the steady state, an effect that was essentially eliminated by carotid sinus neurotomy. The azide did not affect the tidal volume-respiratory frequency relationship mediated by the pulmonary stretch receptors. Thus, the respiratory stimulant effect of azide in subtoxic doses is attributable to an excitatory action on the arterial chemoreceptors. Toxic doses of azide resulted in centrally mediated hypertension, tachycardia, cardiac arrhythmia, respiratory depression, seizures and death.

1 In cats anaesthetized with pentobarbitone and vagotomized, observations were made on the phrenic nerve action potential and the diaphragm electromyogram (EMG) at constant end-tidal Pco(2). Arterial blood pressure was stabilized by intravenous infusions of noradrenaline.2 Intravenous administration of saxitoxin (STX) initially abolished respiratory activity in the EMG and caused a slowing of oscillation in the central phrenic neurogram. Additional STX produced apneustic phrenic discharges followed by a progressive loss of nerve action potentials.3 The inspiratory centre in the medulla oblongata was stimulated electrically to evoke a sustained phrenic nerve discharge. STX, given intravenously, resulted in the elimination of spontaneous nerve activity without interfering with the evoked response.4 The cephalic intravascular infusion of STX into a carotid or vertebral artery depressed spontaneous respiratory activity while sparing EMG activity evoked by electrical stimulation of the intact phrenic nerve.5 Spontaneous respiratory discharge in the phrenic nerve was eliminated by smaller doses of STX administered intra-arterially than were required intravenously. In addition, onset of and recovery from neural silence occurred faster following intra-arterial injection of STX.6 Depressant effects on arterial blood pressure coincided with those on respiration when STX was given intra-arterially.7 An electrophysiological assay on frog sartorius muscle was used to measure STX in the cerebrospinal fluid. Levels of STX detected were proportional to amounts of the toxin infused intra-arterially.8 It is concluded that STX exchanges rapidly between blood and brain to bring about central depression and this adds to its peripheral paralytic actions.

Motion-induced vomiting was studied in cats exposed to vertical sinusoidal oscillation on a spring-suspended platform. Two groups of five cats each, namely, motion-untested and motion sickness-susceptible, were subjected to chronic ablation of the area postrema. Motion sickness occurred postoperatively in all the previously untested cats, and in four of the five previously susceptible cats. Statistical comparison with normal cats indicated that the operated cats were significantly more susceptible to motion sickness. The manifest loss of susceptibility in one cat with a lesion is attributed to excessive peripostremal damage. It is concluded from these results that the area postrema is not an essential link in the reflex arc of motion-induced vomiting.

Arterial blood hydrogen ion concentration (Ha+) was altered over the range of 25 to 110 nM (pH 7.60 to 6.96) by slow intravenous infusion of 1.0 N NaHCO3 or 0.5 N HC1 at controlled levels of Paco2in unanesthetized decerebrate cats. Respiratory f varied as a single function of Vt irrespective of a lterations in Paco2 and Ha+ even after interruption of the carotid sinus nerves. The dependence of f upon Vt was abolished by vagotomy. However, Vt continued to respond to changes in Ha+ over its entire range after combined section of the vagus and carotid sinus nerves. In all statxceeded by 5 to 10 times the delta Vt/delta Ha+ response to acid or bicarbonate infused under isocapnic control. Increases and decreases of ha+ caused downward and upward shifts, respectively, in the operating setpoint of the CO2 regulation system.

The comprehensive emetic response to xenobiotics can be quantified by monitoring the physiological forces which effectuate vomiting. A unique sequence of thoracic pressure pulses, generated by the somatic muscles of ventilation, can be measured by means of a central venous catheter. This unambiguous emetic endpoint is used to record emetic latency, repetitions and duration of action, all on an established time base and dependent of stomach content. Deslanoside (160 micrograms/kg) produced emesis in 15 cats beginning in 4.4 +/- 1.9 min (mean +/- S.D.). Subsequent emetic episodes were related in time in a log-linear but biphasic manner. Cisplatin (7.5 mg/kg) had an emetic latency of 71 +/- 18 mn in 7 cats. Additional events also had a long-linear temporal relationship for up to 400 min. This quantified emetic profile of cisplatin served as a measure for assessing antiemetic activity of N-metyllevonantradol (Pfizer), nabilone (Lilly) and prochlorperazine. The cannabinoids all evinced dose dependent antiemetic activity in terms of either complete protection, or increased latency to the first emetic episode and reduced number of episodes in those animals not completely protected. By comparison prochlorperazine afforded only minimal protection.

Xylazine is an effective sedative analgesic that induces vomiting in the cat. A consistently effective intramuscular emetic dose of xylazine was established in normal cats in this laboratory. Animals in which the area postrema of the medulla oblongata had been chronically destroyed did not exhibit emesis in response to the standard test dose of xylazine but continued to show sedation. By contrast, sham-operated cats responded normally. Refractoriness to deslanoside, a known specific emetic drug, was used as functional proof for successful ablation of area postrema, and the lesions were also validated histologically. We conclude that xylazine exerts its emetic action on the chemoreceptor trigger zone of the area postrema. It is suggested that this action may be mediated by an opiate type of molecular receptors.

Cats were anesthetized with a mixture of pentobarbital and barbital given intraperitoneally and vagotomized. All animals were pretreated with atropine i.v. which blocked conventional muscarinic receptors and at the same time revealed atropine-insensitive sites whose stimulation by the cholinergic drug, bethanechol, was earlier found to produce respiratory analepsis. Respiration was recorded by pneumotachograph and intrapleural cannula. Apneustic breathing was produced by placing electrolytic lesions in the pneumotaxic area or by injecting a local anesthetic agent into the cerebrospinal fluid. Experiments were performed under isocapnic conditions. Bethanechol, administered intracerebro-ventricularly, restored regular breathing and increased the tidal volume in a dose-related manner within minutes of its injection. In cats with lesions, the expiratory pause generally decreased first and was followed by shortening of the inspiratory plateau. In cats made apneustic by intracerebro-ventricular injection of procaine, bethanechol acted competitively to normalize the distorted waveshape. The central excitant drug pentylenetetrazol was given intravenously for comparison with bethanechol. Apneustic breathing was partially corrected by pentylenetetrazol through a facilitatory influence on the brain stem interpreted to be independent of its convulsant action. These experiments demonstrate correction of pathological breathing by two chemically unrelated agents which share the ability to increase central excitatory state.

Cisplatin-induced emesis was characterized using the cat as an experimental model. The incidence, latency, and number of vomiting episodes which occurred over an 8-hour period were determined for iv doses ranging from 3 to 10 mg/kg. Oscillographic recording of physiologic pressures which produce vomiting served to document the observation that 7.5 mg/kg iv was the most effective dose. This dose produced vomiting in seven animals with a latency of 71 +/- 7.04 minutes (mean +/- SE) and subsequent emetic episodes (averaging 3.86/animal) followed a linear relationship with respect to the logarithm of time. The larger dose of 10 mg/kg appeared to be less effective, because not all animals responded. Those animals that vomited in response to this dose did so only after a significantly increased latency. Four animals with longstanding lesions of area postrema were tested with cisplatin (7.5 mg/kg); all four failed to vomit during a 6-hour observation period. In addition, none of the animals exhibited the sustained malaise associated with cisplatin administration to intact animals and only one displayed any prodromal emetic signs. These findings demonstrate that the area postrema, the anatomic site of the chemoreceptor trigger zone for emesis, is essential for cisplatin-induced vomiting. Elucidation of this action suggests a possible mechanism for other emetogenic anticancer agents.

The radioemetic dose-response relationships were established in 46 unanesthetized cats for each of two whole-body exposures, 24 h apart, to 60Co radiation at selected doses between 7.5 and 60 Gy. Individual episodes of vomiting were recorded for a period of 48 h as distinctive intrathoracic pressure deflections signaled through a catheter placed in the superior vena cava. Five cats with chronic lesions of the area postrema were included in the group exposed to 45 Gy. The lesioned animals were not detectably different in their radiation response behavior from the intact cats. Initial exposure in the entire cat series produced an increasing incidence of radioemesis from 25 to 80% over the specified dose range for the first observation period of 24 h. By contrast, the second exposure produced an inverse dose-related incidence of emesis varying from 63% to zero with an apparent crossover of radioemetic susceptibility for the two exposures at about 15 Gy. Complete protection during 12 h after the second exposure was obtained at 30, 45, and 60 Gy, and for all of 24 h at 45 and 60 Gy. In a separate group of 11 normal cats, the emetic drug xylazine invariably evoked vomiting when radioemetic protection was otherwise manifest after initial irradiation at 45 Gy. We conclude that the temporary recovery of well-being following acute lethal irradiation results selectively through increased radioemetic resistance, and it does not depend on the integrity of the area postrema.

Arterial blood pH (pHa) was continuously monitored in decerebrate or pentobarbital-anesthetized cats with a rapidly responding hydrogen ion sensor inserted into the aorta. Alveolar carbon dioxide partial pressure and pHa were controlled independently during infusions of 1 N NaHCO3 or 0.5 N HCl into the inferior vena cava. Shifts in pHa up to 0.3 unit were effected isocapnically within 2.5-20 s over a working pHa range of 6.9-7.7. Before carotid sinus neurotomy, average onset latency of the tidal volume (VT) response to acid and alkaline pHa shifts was less than 5 S and the average VT response half time was less than 8.5 s regardless of whether the vagus nerves had been interrupted. After carotid sinus neurotomy, the deltaVT onset latency was approximately doubled, whereas the response half time was prolonged about eightfold on the average. Subsequent vagotomy tended further to increase the responding time lag. Nevertheless, the minimum response latency after peripheral chemodenervation was less than the deltapHa forcing rise time. It is concluded that the central chemoreceptors promptly sense pH change in the arterial blood and that neural processes adjust the time course of the respiratory response through the VT controller.

A direct stimulating action of oxygen on the CO2 respiratory control system was determined from steady-state and dynamic observations in unanesthetized decerebrate cats. In peripheral nerve-intact animals, inhalation of oxygen (1 atm) produced a small but significant shift to the left as well as a decrease in slope in the steady-state VT vs. log PACO2 relationship. Carotid sinus neurotomy more than doubled the shift, to the extent that the mean PACO2 apneic point was lowered by 6.5 mmHg. Neither vagotomy nor chronic ablation of the area postrema had any detectable influence on the stimulating effect of oxygen on CO2 responsiveness. The arterial-alveolar PCO2 difference, prior to and following carotid chemo-denervation, remained unchanged or was increased by a negligible amount during oxygen inhalation. The oxygen threshold for respiratory stimulation, obtained isocapnically, occurred between 115 and 200 mmHg; VT then increased exponentially tending to level off as PAO2 approached 1 atm. The dynamic response to sudden presentation of oxygen after carotid chemodenervation consisted of a monotonic rise in VT, starting after 20-30 s with a t 1/2 of about 75 s.

1 In cats anaesthetized with pentobarbitone, saxitoxin and, on a few occasions, tetrodotoxin were injected into a lateral cerebral ventricle or into the subarachnoid space of the lower brain stem. Observations were made on frequency and tidal volume of breathing, on CO(2) responsiveness and on electrical responsiveness of the respiratory centre. Effects on the blood pressure were observed simultaneously.2 A single large dose of toxin, e.g., 250 ng, produced within minutes apneustic breathing and a rise in blood pressure which were converted rapidly to respiratory failure and hypotension. In contrast, repeated small doses, e.g., 25 ng, yielded only progressive slowing of the respiration together with circulatory hypotension. Bulbar depression was produced as effectively by subarachnoid injection as by intraventricular injection of the toxins. Onset of action was detectable within seconds.3 Slowing of the respiration occurred independently of change in tidal volume and whether or not the vagus nerves were cut. The reduction in breathing frequency is attributed to direct toxin-induced depression of the central respiratory oscillator.4 Steady-state measurements of tidal volume at controlled levels of alveolar CO(2) pressure in intermediate stages of respiratory depression showed that the toxins produced an increase in CO(2) stimulation threshold as well as a reduction in gain of CO(2) responsiveness, whether or not the vagus nerves were cut. Carotid arterial chemoreceptor reactivity to O(2) was demonstrable when central sensitivity to CO(2) was depressed. These effects are attributed to a direct influence of the toxins upon the brainstem CO(2)-tidal volume controller.5 Responsiveness of the medullary inspiratory centre to electrical stimulation persisted after the failure of spontaneous breathing was caused by the toxins. Conversely, restitution of electrical responsiveness preceded the reappearance of spontaneous respiratory activity in the recovery phase of toxic depression. Circulatory effects paralleled the changes in respiratory behaviour.6 On the basis of the relatively prompt and discrete alterations in the central respiratory and circulatory control mechanisms produced by saxitoxin and tetrodotoxin placed in the cerebrospinal fluid, it is concluded that the agents rapidly penetrated to deep target loci in the lower brain stem.

Effects of brevetoxin were evaluated in cats anesthetized with pentobarbital under conditions of controlled end-expiratory pCO2 and constant body temperature. Recordings were made of arterial blood pressure, heart rate, respiratory pattern, diaphragm EMG, evoked tibialis muscle twitch and evoked contraction of the nictitating membrane. Electrical stimulation was employed for periodic excitation of the medullary respiratory center, the phrenic nerve, the peroneal nerve and the cervical sympathetic nerve. Brevetoxin was prepared at a concentration of 1.0 mg/ml in an aqueous medium of 2.5% ethanol plus 2.5% Emulphor 620 (General Aniline and Film Corp., New York). Small i.v. bolus injections of the toxin (40 micrograms/kg) evoked, without tachyphylaxis, the Bezold-Jarisch reflex triad of bradycardia, hypotension and bradypnea. This effect was essentially abolished by vagotomy. Continued injections then resulted in pressor reactions and tachycardia, along with the development of respiratory dysrhythmia. Large doses of brevetoxin (160 micrograms/kg i.v.) caused somatomotor seizures accompanied by severe hypertension, that occurred even after decerebration and cervical spinal cord transection. Cranial intra-arterial and intra-cerebroventricular injections of brevetoxin produced hypertension and respiratory depression more effectively than did i.v. injections. Systemic cumulation of the toxin, with the respiration supported artificially, caused death from cardiovascular collapse, without significant blockade of neuromuscular and ganglionic transmission. It is concluded that brevetoxin exerts its major toxic effects on the circulation and respiration through reflex and central actions, largely sparing peripheral motor mechanisms.

We evaluated the hypothesis that the area postrema facilitates the cardiac arrhythmias caused by toxic doses of digitalis. The arrhythmic dose of ouabain was determined in four cats with chronic selective destruction of the area postrema, and in a control group of two sham-operated cats and three normal unoperated cats. The cats were anesthetized with pentobarbital, and polygraph records were made of end-tidal Pco2, arterial blood pressure, heart rate, and the electrocardiogram (lead II and a bipolar lead in the superior vena cava). The vagosympathetic trunks were cut bilaterally, and 1 h later an i.v. infusion of [3H]ouabain was begun at the rate of 1.71 nmol/kg/min. This was continued until ventricular tachycardia appeared, as determined electrocardiographically. The total ouabain dosage required for ventricular tachycardia was recorded, and the ouabain concentrations in the arterial plasma and in the myocardium were determined by liquid scintillation counting. No statistically significant difference was found between the chronically postremectomized cats and the controls in any of these measures of ouabain cardiotoxicity. These results indicate that the area postrema plays no important role in the cardiotoxic action of ouabain in pentobarbital-anesthetized, vagotomized cats.

A dose-response relationship was established in normal unanesthetized cats for emetic incidence, latency to onset of vomiting, and duration of emetic activity over a period of 24 h after whole-body exposure to 60Co radiation at selected doses between 7.5 and 90 Gy. Each episode of vomiting, i.e., retching and expulsion, was recorded oscillographically as its characteristic intrathoracic pressure waveform by means of a catheter inserted some days before into the superior vena cava. The gamma-radiation dose of 45 Gy evoked vomiting optimally with an incidence of 92% and an average onset time of 98 min. When administered to animals prepared chronically with surgical ablation of the area postrema, the same dose of radiation evoked vomiting in four of five test cases and with an average time to onset that was not by either measure significantly different from normal. Vomiting was also elicited in all of six normal cats exposed to an intestinal dose of 45 Gy X radiation with the head shielded. The same form of irradiation evoked vomiting in two of three chronically postremectomized cats. Successful ablation of the area postrema was determined functionally by emetic refractoriness to an injection of digitalis and confirmed for completeness by histological examination. It is concluded that the area postrema is not an essential element in the reflex mechanism of radiation-induced vomiting and, therefore, no physiological basis exists for dependence on a centrally acting chemogenic factor in radioemesis.

Chest and abdominal wall movements were assessed as objective indicators of emesis. Thirty-six vomiting episodes in one intact and four decerebrate cats were monitored either by an inductive plethysmograph or by magnetometers applied to the chest and abdomen. The plethysmographic method was found to be the more suitable of these two monitoring techniques because it produced stable, artifact-free recordings with excellent signal differentiation. The occurrence of emesis was validated by simultaneously recording thoracic central venous pressure. Unlike the intrathoracic pressure measurement, spasmodic movements of chest and abdomen did not differentiate retching from expulsion. However, rhythmic abdominal excursions recorded during vomiting were several times greater than those occurring during any other activity. Surprisingly, these movements indicated an increase in abdominal dimensions during vomiting in contrast to the reduction in size observed during sneezing and coughing. We believe that recording of abdominal movements that accompany vomiting might potentially serve as a noninvasive research tool for the study of emesis in cancer chemotherapy.

The history of morphological and functional studies on the area postrema (AP) is traced for significant landmarks from 1896, when its name was conferred by Retzius, to 1960 when the foundation of inquiry had become firmly set. A comparative anatomical survey of the medulla oblongata identifies the AP in mammals and birds but not in amphibians and lower phyla even though other members of the so-called circumventricular organ system are represented in the more ancient creatures. Existence of the AP in reptiles is insufficiently documented. The transition from water- to land-dwelling animal life affords propitious neural remodeling for the emergence of the AP in evolving species. No vital role is known to be served by the AP. Nonetheless, its physical interposition between the blood and cerebrospinal fluid and its shared functions with the nucleus tractus solitarii indicate a capability for widespread somatovisceral influence in response to particular perturbations. It is suggested that the diverse systemic expressions of postremal activation are encompassed in the general syndrome of nausea and vomiting.

Drug effects were examined in cats anesthetized with a mixture of pentobarbital and barbital injected i.p. Respiratory observations were analyzed according to effects produced on 1) chemoregulatory responsiveness determined by changes in tidal volume resulting from CO2 inhalation or measured during isocapnic stabilization, and on 2) mechanoreflex control of respiratory frequency through the vagus nerves. Blood pressure and heart rate were recorded concomitantly. Cardiovascular effects were manifested as dose-related hypotension and bradycardia that were generally response-limited by contrast with the respiratory depressant effects which progressed ultimately to failure. Relative potency of the three agents to produce an elevation of 4% in resting alveolar CO2 fraction was 100 times for N-methyllevonantradol and 10 times for nabilone by comparison with delta 9-tetrahydrocannabinol. Marked slowing of respiratory frequency occurred in vagotomized as well as in nerve-intact cats. Apneustic respiration was not observed in any case. It is concluded that the effects of the cannabinoids resulted from 1) an upward shift in CO2 setpoint of the central chemorespiratory "detector"; 2) decreased gain of the CO2-tidal volume "controller"; 3) depression of the respiratory "oscillator" in the lower medulla; 4) depression of the vasomotor center; and 5) a central vagotonic action in addition to a direct cardiodecelerator action on the heart.