Hypovolemic shock in acute lethal T-2 mycotoxicosis.

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.

Early toxicity of recombinant interleukin-2 in cats.

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.

Neural factors in acute emetic, cardiovascular, and respiratory effects of T-2 toxin in cats.

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.

Central respiratory inhibition by angiotensin II in anesthetized cats.

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.

Radioemetic protection at 24 h after 60Co irradiation in both normal and postremectomized cats.

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.

High dorsal column cordotomy plus subdiaphragmatic vagotomy prevents acute ionizing radiation sickness in cats.

Our purpose was to determine the effects on acute radiation sickness of interrupting afferent neural pathways that converge upon the medullary vomiting center but which bypass the emetic chemoreceptor trigger zone in the area postrema. A comparison was made of the vomiting response and other signs of sickness in three groups of chronic cats surgically prepared as follows: high spinal cord section of the dorsal columns, subdiaphragmatic vagotomy, and the combination of procedures. Every cat was exposed over the whole body to 45 Gy 60Co gamma-radiation which was effective in evoking emesis in 11 of 12 normal cats. Neither cordotomy alone (8 cats) nor vagotomy alone (2 cats) reliably blocked the vomiting response but they separately delayed its onset. On the other hand, the cordotomy prevented the loss of appetite and behavioral malaise that was invariably caused by the irradiation in normal cats. Finally, the combination of cordotomy and vagotomy protected all of 3 cats against the entire radiation syndrome. These cats then vomited appropriately in response to the injection of deslanoside which induces emesis through an action on the area postrema. Histological examination of the lower medulla revealed no damage of the area postrema resulting from the cordotomies. We conclude that acute radiation sickness in the cat is signaled through afferent neural pathways originating in the abdomen and that the area postrema does not participate in the causation of this syndrome.

Acute radiation-induced vomiting in area postrema-ablated 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.

Motion sickness reflex arc bypasses the area postrema in cats.

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.

Neurological analysis of respiratory, cardiovascular and neuromuscular effects of brevetoxin in cats.

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.

A misconception of motion sickness leads to false therapeutic expectations.

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.

Role of the area postrema in vomiting and related functions.

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.

History and status of the area postrema.

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.

Peripheral and central actions of sodium azide on circulatory and respiratory homeostasis in anesthesized cats.

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.

Lack of protection against ouabain cardiotoxicity after chronic ablation of the area postrema in cats.

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.

Cisplatin-induced vomiting eliminated by ablation of the area postrema in cats.

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.

Respiratory and cardiovascular depressant effects of nabilone, N-methyllevonantradol and delta 9-tetrahydrocannabinol in anesthetized cats.

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.