Characterization of radiation-induced emesis in the ferret

Forty-eight ferrets (Mustela putorius furo) were individually head-shielded and radiated with bilateral 60Co gamma radiation at 100 cGy min-1 at doses ranging between 49 and 601 cGy. The emetic threshold was observed at 69 cGy, the ED50 was calculated at 77 cGy, and 100% incidence of emesis occurred at 201 cGy. With increasing doses of radiation, the latency to first emesis after radiation decreased dramatically, whereas the duration of the prodromal period increased. Two other sets of experiments suggest that dopaminergic mechanisms play a minor role in radiation-induced emesis in the ferret. Twenty-two animals were injected either intravenously or subcutaneously with 30 to 300 micrograms/kg of apomorphine. Fewer than 50% of the animals vomited to 300 micrograms/kg apomorphine; central dopaminergic receptor activation was apparent at all doses. Another eight animals received 1 mg/kg domperidone prior to either 201 (n = 4) or 401 (n = 4) cGy radiation and their emetic responses were compared with NaCl-injected-irradiated controls (n = 8). At 201 cGy, domperidone significantly reduced only the total time in emetic behavior. At 401 cGy, domperidone had no salutary effect on radiation-induced emesis. The emetic responses of the ferret to radiation and apomorphine are compared with these responses in other vomiting species.     

The abdominal visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity

In recent years the role of the area postrema in the emetic reflex has been predominant and the involvement of the abdominal visceral innervation has tended to be overlooked. This paper attempts to redress the balance reflex by reviewing aspects of the existing literature and complementing this with original studies from the ferret. In view of the widespread use of the ferret in studies of emesis and particularly in the characterization of the antiemetic actions of 5-HT3 receptor antagonist, the opportunity is taken to assess the suitability of this species for studies of emesis. It is concluded that the ferret is sensitive to a wide range of emetic stimuli including intragastric irritants, opiate and dopamine receptor agonists, many cytotoxic drugs, and radiation. For several stimuli it is more sensitive than other species and for radiation on the basis of its ED100 it appears to be the most sensitive of the laboratory animals studied. Using electrical stimulation of the central end of the dorsal vagal trunk in the abdomen in conscious and anaesthetized animals, the vagal afferents were shown to be capable of eliciting emesis. Using lesioning studies an involvement of the vagus in the emetic response to a number of cytotoxic drugs (e.g., cisplatinum, cyclophosphamide, mustine) and radiation was demonstrated, although the magnitude of the effect varied with the different stimuli. An attempt is made to reconcile these observations with previous studies of area postrema ablation. The problems of interpreting the effects of nerve lesions are critically discussed in light of preliminary evidence presented here that there may be a degree of plasticity in the emetic pathway following such lesions. The range of antiemetic effects of 5-HT3 receptor antagonists is reviewed and an attempt is made to identify the site(s) at which these agents act. Results are presented that suggest a link between the vagus and 5-HT3 receptor antagonism. These studies are discussed together with others and lead us to propose that (in the ferret) 5-HT3 receptor antagonists have their main antiemetic effect by acting on vagal afferent terminals in the wall of the upper gut with an additional minor site either in the nucleus tractus solitarius or presynaptically on the vagal afferent terminals in the medulla where binding sites for 5-HT3 receptor ligands have recently been demonstrated in this species.     

Local cerebral blood flow following the intrastriatal administration of vasoactive intestinal peptide or peptide histidine isoleucine in the rat

The effect of the intrastriatal microinjection of either vasoactive intestinal peptide (VIP) or a related peptide-peptide histidine isoleucine (PHI)-on local cerebral blood flow in the striatum was examined using iodo[14C]antipyrine quantitative autoradiography. In 37 rats, an injection needle was inserted into a chronically implanted guide cannula and 1 microliter of vehicle, VIP or PHI was injected into the striatum. Blood flow in sham controls was reduced by 15% in proximity to the injection site, when compared with blood flow in the contralateral uninjected control side (P less than 0.01). Similarly, following PHI administration (20 pmol), blood flow in the striatum was reduced by 14% when compared to that contralaterally (P less than 0.02). In contrast, following VIP administration (20 pmol), blood flow in proximity to the injection site was increased compared to flow in the contralateral striatum in 4/8 animals with the mean flow being elevated by 10% (n.s.) compared to blood flow contralaterally. VIP and PHI had similar effects on local cerebral glucose utilization in the caudate nucleus, their response being equivalent to that of sham animals. These experiments suggest that VIP and PHI have a differential influence on the microvasculature of the caudate nucleus, with VIP but not PHI mediating cerebrovascular dilation.     

Marked depression of radiation-induced emesis in frogs following prior exposure to a brief dose of X-rays

Acute emesis response to harmful doses of X-rays on frogs (Rana porosa porosa) was examined. Results showed that the number of radioemesis events following exposure to 0.85 Gy was slightly higher than in the sham control animals. The increase in emesis action became more pronounced when the total dose of radiation was raised to 2.5 Gy. Only 1 frog out of a total of 12 did not show vomiting following radiation, while no response was observed in sham control animals. Note that animals in which the low dose rate of radiation was applied to whole body did not display any changes in the emesis response relative to control animals. The present studies, and those by others, showed that a brief dose of X-rays prior to a second exposure to a sub-lethal dose might induce a tolerance to radiation. An additional experiment was conducted to examine whether a small conditioning dose could induce a depression of radioemesis (tolerance) following an exposure to high dose X-ray. With prior exposure to 0.3 Gy, only 1 frog out of a total of 5 frogs vomited as a result of radiation exposure. Suppression of the emetic response became significant when the pre-radiation dose was decreased to 0.1 Gy. On the contrary, increasing the small conditioning dose to 0.5 Gy resulted in a remarkable rise of radiation-induced emesis. This results indicate that exposure to the smaller dose of X-rays elicits a tolerance effect to toxic dose level of radiation.     

Effect of angiotensin II and peptide YY on cerebral and circumventricular blood flow

Angiotensin II and peptide YY (PYY) are putative neuro/humoral agents acting at several circumventricular regions. These peptides also constrict cerebral vessels. We examined the effect of acute intravenous infusion of saline, angiotensin II and peptide YY on local cerebral blood flow (14C-iodoantipyrine autoradiography) in the circumventricular and non-circumventricular brain regions of 17 conscious rats. No reductions in brain blood flow (28 regions) were observed although angiotensin II and PYY infusion elevated arterial blood pressure 15-25% without influencing heart rate, suggesting an increase in peripheral resistance. However, local blood flow was dependent on the peptide infused. During PYY infusion, blood flow was rather constant in the 20 non-circumventricular regions examined whereas an increase in blood flow and a slight decrease in cerebrovascular resistance occurred in the circumventricular regions. The area postrema exhibited the most pronounced changes--an elevation in blood flow of 44 +/- 11% and a reduction in resistance of 20 +/- 5% in comparison to that in control animals. During angiotensin II infusion, local cerebral blood flow was similar to that in controls and local cerebrovascular resistance was elevated. Thus, the local cerebral circulatory response to peptide administration was dependent on the location of the region examined (circumventricular or non-circumventricular) and on the vasoactive peptide infused.     

The inhibitory effect of halothane on the emetic response in the ferret

Emesis and nausea are often associated with anaesthesia and continue to be a common clinical problem. Past clinical studies have demonstrated that halothane produces a higher incidence of vomiting compared with other anaesthetics, but some investigators have described an antiemetic effect. The purpose of this study was to investigate the effects of various doses of halothane on the emetic response in the decerebrate ferret. Following a control emetic response, a maximum of six increasing cumulative concentrations of halothane were delivered. At the end of each delivery period, the supradiaphragmatic vagal communicating branch, which has been shown to reproducibly elicit vomiting, was electrically stimulated and the emetic response was monitored. An increase in halothane concentration produced a marked depression of tongue, abdominal muscle, and diaphragm EMG activity as well as a decrease in central venous pressure. Licking, a prodromal response comparable to nausea in the human, appeared to be most sensitive. An increase in latency of the emetic response occurred as the concentration of halothane was increased. All phases of the response were observed at concentrations below 0.6 vol% halothane. At 0.6 vol% halothane, 75% of the animals vomited. At higher concentrations, the emetic response was completely abolished. One hour post-halothane, all latencies had returned to near control values. The methods utilized in this study provided a model that was not complicated by a large number of variables usually present in clinical studies. These data demonstrate that halothane exerts an inhibitory, concentration-dependent, and reversible effect on the emetic response in the ferret and provide further support that halothane alone does not possess emetic properties at clinical properties at clinical concentrations.     

Animal models in the study of vomiting

The emetic responses to various pharmacological agents, cytotoxins, and radiation are compared among animal species. The species included for comparison are the human, nonhuman primate, dog, cat, and ferret. The categories of pharmacologic compounds include both those compounds that act on identified membrane receptors (e.g., cholinergic agonists, catecholamines, and neuroactive peptides) and those that act on unidentified receptors (e.g., cardiac glycosides and Veratrum alkaloids, among others). Emphasis is placed on emetic dose-response relations and threshold ED50 and ED100 values calculated from these relations, as indices of species sensitivity to emetic stimuli. For the more noxious emetics, the cytotoxins and radiation, the latency to the first emetic episode and duration of emesis are also compared across species. The effect that peripheral and central nerve lesions have on species differences in emetic responses to stimuli is also discussed.     

Effect of 4-hydroxypyrazolo (3,4-d) pyrimidine (allopurinol) on postirradiation cerebral blood flow: implications of free radical involvement

In an attempt to elucidate mechanisms underlying the irradiation-induced decrease in regional cerebral blood flow (rCBF) in primates, hippocampal and hypothalamic blood flows of rhesus monkeys were measured by hydrogen clearance, before and after exposure to 100 Gy, whole body, gamma irradiation. Systemic blood pressures were monitored simultaneously. Compared to control animals, the irradiated monkeys exhibited an abrupt decline in systemic blood pressure to 35% of the preirradiation level within 10 min postirradiation, falling to 12% by 60 min. A decrease in hippocampal blood flow to 32% of the preirradiation level was noted at 10 min postirradiation, followed by a slight recovery to 43% at 30 min and a decline to 23% by 60 min. The hypothalamic blood flow of the same animals showed a steady decrease to 43% of the preirradiation levels by 60 min postirradiation. The postradiation systemic blood pressure of the allopurinol treated monkeys was not statistically different from the untreated, irradiated monkeys and was statistically different from the control monkeys. However, the treated, irradiated monkeys displayed rCBF values that were not significantly different from the nonirradiated controls. These findings suggest the involvement of free radicals in the postirradiation decrease in regional cerebral blood flow but not necessarily in the postirradiation hypotension seen in the primate.     

The emetic reflex in African walking catfish develops with age

This opportunistic observational study showed that following feeding, subadult catfish, Clorias gariepinus (>3 months old; n=37) were sensitive to the disturbance caused by removing two fish for weighing. This initiated intense and prolonged vomiting (oral expulsion of upper gut contents). The main emetic response occurred within a few minutes after fish removal, although commercial grade food pellets were still being vomited 50 to 100 min later. The magnitude of the vomiting response was relatively greater after consumption of larger meals, however, nothan 44% of a meal was ever vomited. Juvenile catfish (<3 months; n=8) were also sensitive to disturbance as indicated by vomiting. The emetic response in these younger fish wasas pronounced as that of the subadults even when given meals of similar relative size (approx. 2.4% wet body weight). No emesis was observed in post-hatching catfish (<3 weeksd; n=7) after feeding and following a similar disturbance. This suggests the emetic reflex may not operate in post-hatching catfish in reaction to a stimulus that in subadults and juveniles produced a graded, weight-dependent vomiting response. This raises the question of whether this difference represents neuronal pathway development or learning of the reflex.     

Nitric oxide and carbon dioxide in neurotoxicity induced by oxygen under pressure

Hyperbaric oxygen (HBO2) causes CO2 retention in the brain that leads to the increase in cerebral blood flow (CBF) by poorly understood mechanisms. We have tested the hypothesis that NO is implicated in CBF-responses to hypercapnia under hyperoxic conditions. Alert rats were exposed to HBO2 at 5 ata and blood flow in the striatum measured by H2 clearance every 10 min. Acetazolamide, the inhibitor of carbonic anhydrase, was used to increase brain PCO2. CBF responses to acetazolamide administration (30 mg/kg, i.p.) were assessed in rats breathing air at 1 ata or oxygen at 5 ata with and without NOS inhibition (L-NAME, 30 mg/kg, i.p.). In rats breathing air, acetazolamide increased CBF by 34 +/- 7.4% over 30 min and by 28 +/- 12% over 3 hours while NOS inhibition with L-NAME attenuated acetazolamide-induced cerebral vasodilatation. HBO2 at 5 ata reduced CBF during the first 30 min hyperoxia, after that CBF increased by 55 +/- 19% above pre-exposure levels. In acetazolamide-treated animals, no HBO, induced vasoconstricton was observed and striatal blood flow increased by 53 +/- 18% within 10 min of hyperbaric exposure. After NOS inhibition, cerebral vasodilatation in response to acetazolamide during HBO2 exposure was significantly attenuated. The study demonstrates that NO is implicated in acetazolamide (CO2)-induced cerebral hyperemia under hyperbaric oxygen exposure.     

Functional, Metabolic, and Circulatory Changes Associated with Seizure Activity in the Postischemic Brain

Abstract: The present study was undertaken to explore how transient ischemia in rats alters cerebral metabolic capacity and how postischemic metabolism and blood flow are coupled during intense activation. After 6 h of recovery following transient forebrain ischemia 15 min in duration, bicuculline seizures were induced, and brains were frozen in situ after 0.5 or 5 min of seizure discharge. At these times, levels of labile tissue metabolites were measured, whereas the cerebral metabolic rate for oxygen (CMRO₂) and cerebral blood flow (CBF) were measured after 5 min of seizure activity. After 6 h of recovery, and before seizures, animals had a 40–50% reduction in CMRO₂, and CBF. However, because CMRO₂ rose threefold and CBF fivefold during seizures, CMRO₂ and CBF during seizures were similar in control and postischemic rats. Changes in labile metabolites due to the preceding ischemia encompassed an increased phosphocreatine/ creatine ratio, as well as raised glucose and glycogen concentrations. Seizures gave rise to minimal metabolic perturbation, essentially comprising reduced glucose and glycogen contents and raised lactate concentrations. It is concluded that although transient ischemia leads to metabolic depression and a fall in CBF, the metabolic capacity of the tissue is retained, and drug-induced seizures lead to a coupled rise in metabolic rate and blood flow.     

Cannabinoid modulation of electrically evoked pH and oxygen transients in the nucleus accumbens of awake rats

Cannabinoid receptors have been implicated in the regulation of blood flow in the cerebral vasculature. Because the nucleus accumbens (NAc) shows high levels of central cannabinoid receptor 1 (CB1) expression we examined the effects of cannabinoids on the local transient alkaline shifts and increases in extracellular oxygen induced by electrical stimulation of the medial forebrain bundle (MFB) in conscious animals. These changes result from increases in cerebral blood flow (CBF) and metabolism in the NAc that are evoked by the stimulation. Oxygen and pH changes were monitored using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in the NAc of freely moving rats. Administration of the cannabinoid receptor agonist WIN55,212-2 potently inhibited extracellular oxygen and pH changes, an effect that was reversed and prevented by pre-treatment with the CB1 receptor antagonists SR141716A and AM251. The effects on pH following WIN55,212-2 were similar to those following nimodipine, a recognized vasodilator. When AM251 was injected alone, the amplitude of electrically evoked pH shifts was unaffected. Administration of AM404 and VDM11, endocannabinoid transport inhibitors, partially inhibited pH transients in a CB1 receptor-dependent manner. The present findings suggest that CB1 receptor activation modulates changes in two well-established indices of local blood flow and metabolism resulting from electrically evoked activation of ascending fibers. Although endogenous cannabinoid tone alone is not sufficient to modify these responses, uptake blockade demonstrates that the system has the potential to exert CB1-specific effects similar to those of full agonists.     

WISE-2005: reduced cerebral blood flow velocity with nitroglycerin--comparison with common carotid artery blood flow

During the WISE-2005 study of 24 women, we observed a reduction (21.6 +/- 0.89%, mean +/- SEM) in cerebral blood flow velocity (CBV) measured by transcranial Doppler ultrasound, following 0.3 mg sublingual nitroglycerin (NG). In parallel, we observed quantitative reductions in leg blood flow (47.3 +/- 7.0%) and corresponding reductions in calculated conductance (Conductance = Femoral Flow / Mean Arterial Pressure; 45.7 +/- 7.2%). To determine if the reduction in CBV was the result of reduced cerebral blood flow or dilation of the middle cerebral artery (MCA), the change in CBV in the MCA was compared with changes in quantitative flow measured in the common carotid artery (CCA). The relationship between CBV and CCA blood flow was tested in five men and four women using hyper- and hypo-ventilation to manipulate arterial PCO2. Changes in CCA blood flow were positively correlated with changes in CBV (p<0.001). We then investigated the CBV and CCA flow responses to sublingual NG in an additional two men and six women. Concurrent with the reduction in CBV there was no change in blood flow through the CCA (p>0.05). These results indicate that the decrease in CBV observed in response to NG was probably the result of dilation of the MCA and that total cerebral blood flow was similar after administration of NG. These results suggest regional differences in the vascular responses to NG during the WISE bed rest. Conduit vessels of both the peripheral and cerebral vasculature dilated; however, the resistance vessels in skeletal muscle constricted causing a reduction in blood flow, while the resistance vessels of the brain appeared to be unaffected by NG so that cerebral blood flow remained constant. These results highlight the need to obtain quantitative measures of cerebral blood flow if there is reason to suspect that the diameter of the MCA might not remain constant.     

Chronic CO exposure stimulates erythropoiesis but not glomus cell growth

The effect of chronic CO exposure, which stimulates erythropoietin production and erythropoiesis, was studied on carotid body cells in the rat. The hypothesis to be tested was that chronic CO inhalation would stimulate cellular hypertrophy and hyperplasia of carotid body if it caused local tissue hypoxia as in chronic hypoxia. The failure of an appropriate response would indicate a lack of a specific local effect on carotid body tissue PO2 presumably because of its unusually high tissue blood flow. Six young male rats were exposed to 0.4-0.5 Torr (0.05-0.07%) inspired PCO in air for 22 days. Control rats (n = 6) were maintained under similar conditions except for CO exposure. After the exposure period the rats were anesthetized, blood was collected for hematocrit, and the carotid bodies were surgically exposed and fixed for electron microscopy and morphometry of type I and type II cells and capillary endothelium. Hematocrit was significantly greater in the CO-exposed group (75 vs. 48%), whereas no significant difference was found in the carotid body parenchyma between the control and CO-exposed groups. We conclude that the lack of an effect of chronic CO exposure on the carotid bodies in contrast to the strong erythropoietic response indicates a relatively high tissue blood flow rate in the carotid body and that CO did not exert a direct cellular effect. The results also suggest that the hypertrophic response of carotid body glomus cells to chronic hypoxic hypoxia is the result of a local direct effect of low PO2 rather than secondary to systemic effects.     

Chronic exposure to ionizing radiation as a tumor promoter in mouse skin.

We have tested chronic exposure to 90Y beta radiation for its action as a complete tumor promoter, a stage I tumor promoter, or a stage II tumor promoter in SENCAR mouse skin. In skin initiated with a single application of 7,12,dimethylbenz[a]anthracene (DMBA, 10 nmol), chronic exposure to beta radiation as a complete promoter (0.5 Gy, twice/week, 13 weeks) produced no tumors and, when added to a complete chemical promoter (TPA), reduced tumor frequency about 30%. A similar result was observed when beta radiation was tested as a stage II promoter. DMBA-initiated mice that received chemical (12-O-tetradecanoylphorbol-13-acetate, TPA) stage I promotion followed by 13 weeks of beta-radiation exposure (0.5 Gy, twice/week) as stage II promotion produced essentially no tumors, and combining the same chronic beta-radiation exposure with chemical (mezerein) stage II promotion reduced tumor frequency about 20% when compared to a similar group that was not irradiated. Chronic beta-radiation exposure was tested two ways as a stage I tumor promoter in initiated skin that was subsequently treated with mezerein as a stage II promoter. Stage I promotion was shown to proceed with the passage of time, indicating this process occurs naturally in the absence of chemical or physical stimulation. Hyperthermia, previously shown to be a potent inhibitor of chemically stimulated stage I promotion, had no effect on the natural process, indicating at least some differences in mechanism between the two processes. The natural process was, in fact, inhibited by chemical tumor promoters, but not by radiation. In addition to the increase resulting from this natural process, tumor frequency was further increased slightly but significantly (12-15%, P less than or equal to 0.05) when chronic radiation exposure was given as a stage I promoter (0.5 Gy, twice/week, 13 weeks) subsequent to initiation, in spite of the expected 20% reduction resulting from this dose. Exposure of initiated animals to radiation (0.5 or 1.0 Gy, twice/week, 2 weeks) in addition to TPA as stage I promotion produced a similar increase in tumor frequency (P less than 0.02). At higher radiation doses, however, tumor frequency was reduced compared to unirradiated controls. In a third test as a stage I promoter, beta radiation (0.5 Gy twice/week, 4 weeks) was given prior to initiation with N-methyl-N'-nitro-N-nitrosoguanidine in animals subsequently promoted by TPA (twice/week, 13 weeks), and again the radiation slightly but significantly (P less than 0.03) increased tumor frequency compared to the unirradiated control group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Continuous measurement of cerebral blood volume in rats with the photoelectric technique: effect of morphine and naloxone

The validity of a photoelectric method for continuous cerebral blood volume (CBV) measurement was tested and modified for the rat's brain. A new way of introducing a miniature light source between the two hemispheres and fixing a light sensitive silicone blue cell to the outer surface of the parietal bone was developed. Light extinction factor of the rat's blood was determined experimentally (Eb rat = 1.38 +/- 0.15) in order to calculate absolute CBV value in this species, resulting in a 4.77 +/- 0.13 vol % absolute CBV value. Data obtained in anesthetized, artificially ventilated rats by simultaneous recording of CBV and local cerebral blood flow (H2-gas clearance technique) show that local hypothalamic blood flow decreased significantly after morphine (1.0 mg/kg s.c.), while total CBV remained unchanged. Opiate receptor blockade with naloxone (1.0 mg/kg s.c.) on the contrary, as well as naloxone and morphine administration, caused no change in local hypothalamic blood flow, but resulted in a significant increase of total cerebral blood volume.     

Local exposure of the rat cortex to radiofrequency electromagnetic fields increases local cerebral blood flow along with temperature

Few studies have shown that local exposure to radiofrequency electromagnetic fields (RF) induces intensity-dependent physiological changes, especially in the brain. The aim of the present study was to detect reproducible responses to local RF exposure in the parietal cortex of anesthetized rats and to determine their dependence on RF intensity. The target cortex tissue was locally exposed to 2-GHz RF using a figure-eight loop antenna within a range of averaged specific absorption rates (10.5, 40.3, 130, and 263 W/kg averaged over 4.04 mg) in the target area. Local cerebral blood flow (CBF) and temperatures in three regions (target area, rectum, and calf hypodermis) were measured using optical fiber blood flow meters and thermometers during RF exposure. All parameters except for the calf hypodermis temperature increased significantly in exposed animals compared with sham-exposed ones during 18-min exposures. Dependence of parameter values on exposure intensity was analyzed using linear regression models. The elevation of local CBF was correlated with temperature rise in both target and rectum at the end of RF exposure. However, the local CBF elevation seemed to be elevated by the rise in target temperature, but not by that of the rectal temperature, in the early part of RF exposure or at low-intensity RF exposure. These findings suggest that local RF exposure of the rat cortex drives a regulation of CBF accompanied by a local temperature rise, and our findings may be helpful for discussing physiological changes in the local cortex region, which is locally exposed to RF.     

Effects of combination alfaxalone and alfadolone, anesthetic derivatives of pregnanedione, on cerebral hemodynamics in cats]

Intravenous injection of CT 1341 (a mixture of alphaxalone and alphadolone dissolved in cremophor el) induced a decrease in cerebral blood flow (CBF) measured by 133Xe clearance in cats with artificial respiration (the mean reduction in CBF was 2 ml/100 g/mn for 1,2 mg/kg or CT 1341. So, CBF was decreased by 22% when CT 1341 (7,2 mg/kg) was intravenously injected, (mean Pa CO2 equals 30 mm Hg). Changes in CBF following CT 1341 intravenous injection seems to be caused by cerebral vascular constriction evidenced by the direct observation of pial vessels. Following intravenous injection of CT 1341 (from 7, 2 mg/kg to 19,2 mg/kg), the cerebrovascular reactivity to hypercapnia or hypocapnia was not affected, but autoregulation of cerebral blood flow was transiently abolished. In animals with free respiration, CBF was increased in relation with the elevation in Pa CO2 caused by the depression of respiration.     

Effects of an analogue of thyrotrophin-releasing hormone, RX77368, on infarct size and cerebral blood flow in focal cerebral ischaemia in the rat

Effects of a stable analogue of thyrotrophin-releasing hormone, RX77368, on cerebral blood flow and infarct size have been studied in an acute model of cerebral ischaemia in the rat. Two hours after electrocoagulation of the left middle cerebral artery (MCA), the mean area of ischaemia (+/- SEM), determined histochemically, was 11.5 +/- 2.2% of a single hemisphere and blood flow, determined using radiolabelled microspheres, was reduced by 40% in the left forebrain (p less than 0.001 compared with sham-operated animals). Administration of RX77368 (50 micrograms/kg, intracerebroventricularly) within 10 min of arterial occlusion caused a significant (p less than 0.01) reduction in mean lesion size to 3.7 +/- 1.8% and stimulation of blood flow to the left ischaemic forebrain (60% above saline treated). Peripheral administration of RX77368 (1 mg/kg intraperitoneally) also significantly stimulated blood flow to the ischaemic forebrain and caused an apparent decrease in frequency of large infarcted areas of brain tissue, although mean lesion size was not significantly affected. These findings indicate that RX77368 ameliorates tissue damage in acute focal cerebral ischaemia. Such effects may be related to stimulation of cerebral blood flow.     

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.