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Disturbances of the autonomic nervous system are common in right hemisphere stroke patients, including a marked decline in male sexual functions. There is a lack of information on the influence of stroke on male secondary sex organs such as the vas deferens. This study investigates the effect of right brain focal ischaemia on the adrenergic and purinergic responses in isolated epididymal and prostatic portions of rat vas deferens. In both epididymal and prostatic portions the concentration-response curves to noradrenaline are flattened resulting in a reduction (up to 67 – 76%) of the maximum contractile response in the tissue from ischaemic rats compared to the controls. In the prostatic portion from ischaemic rats the concentration-response curve to α,β-methylene ATP was also depressed. The first purinergic and the second delayed adrenergic phase to single pulse was not modified by brain ischaemia. In contrast both phasic and tonic components of the electrically induced contractions by trains of stimuli at high frequencies (2 – 30 Hz) were significantly depressed in the epididymal and prostatic portions from ischaemic rats. These results demonstrate an autonomic imbalance at the level of male sexual secondary organs which may contribute to sexual impairment after stroke. British Journal of Pharmacology (2002) 135, 1723–1732; doi:10.1038/sj.bjp.0704628

We used different anaesthetic procedures to study the possible effects of anaesthesia on extracellular aminoacid concentration in rat brain. Glutamate, aspartate and glycine concentrations were determined by HPLC in samples collected from the right fronto-parietal region of the rat brain cortex by transcerebral microdialysis before and up to 2 h following anaesthesia induction. Anaesthesia induced by ketamine, alone or in association with xylazine, caused a significant decrease in the levels of glutamate, aspartate and glycine, compared to before anaesthesia values (range: 27–72% according to the time of sampling and to the anaesthetic used). Inhalation anaesthesia with halothane (3%) in N2O/O2 mixture produced no significant effects on aminoacid levels. Equitensine (pentobarbital in association with chloral hydrate and ethanol) and pentobarbital also had no significant effect on glutamate, aspartate and glycine levels during anaesthesia. This demonstrates that some anaesthetics alter excitatory aminoacid release and suggests that Equitensine may represent an easy and reliable method to induce a long lasting anaesthesia associated without changes in excitatory aminoacid extracellular concentration.

A photochemical method using the Rose Bengal dye as thrombogenic agent was employed to induce focal cerebral ischemia in frontoparietal cortex of rats. A transcerebral microdialysis probe was used to collect samples from ischemic cortical area. An increase in glutamate (6-fold) and in taurine (4-fold) within the first hour occurred. Neuropathological investigations demonstrate a reproducible damaged area surrounded by a thin peripheral area showing neuronal apoptotic phenomena. The method represents a reproducible model of focal cerebral ischemia with neuropathological aspects superimposable to those characteristic of thrombogenic stroke in man. This method could also be relevant in the study of neurotransmitters during the evolution of ischemia. Furthermore, the presence of apoptotic phenomena in the perilesional halo confirms an ischemic penumbra suggesting the significance of preclinical pharmacological trials.

Summary The calcium antagonist flunarizine (FLN) was tested for its ability to prevent dixorubicin (DXR)-induced cardiotoxicity in the rat. A cumulative dose of 9.0 mg/kg of DXR was administered i.v. over a period of 1 week. FLN (10 mg/kg/day i.p., 6 days/week) was administered according to two different time schedules, covering respectively the first and last 4 weeks after the beginning of DXR treatment. The two schedules were adopted to assess whether early and/or delayed DXR-induced cardiotoxic effects were affected by FLN. The development of cardiac toxicity was monitored by ECG recordings. The animals were sacrificed 8 weeks after the beginning of DXR treatment. The contractile performance of isolated atria and the morphological pattern of left ventricular fragments were subsequently evaluated. The early administration schedule of FLN was shown to be ineffective in preventing DXR-induced cardiotoxicity and in some cases was actually found to potentiate the effects of DXR. In contrast, the histological evaluation of ventricular preparations from rats treated with DXR and FLN according to the delayed time schedule showed a significant improvement with respect to hearts from animals treated with DXR alone. An inhibition of the delayed calcium overload occurring after DXR administration has been proposed as a possible mechanism for this protective action.

The effects of two sulfhydryl compounds, glutathione (GSH) and N-acetylcysteine (NAC), on the cardiotoxicity of doxorubicin (DXR) were tested on in vitro and in vivo models. DXR was administered to rats as 4 weekly i.v. doses of 3 mg/kg. GSH (1.5 mmoles/kg), given i.v. 10 min before and 1 hr after DXR, was found to prevent the development of the delayed cardiotoxic effects of DXR, as assessed by electrocardiographic and mechanical parameters, as well as by histological examination of left ventricular preparations. In contrast, equimolar oral doses of NAC (1 hr before and 2 hrs after DXR) were found to be ineffective. Both GSH and NAC prevented the negative inotropic effect produced by DXR on isolated rat atria. A good correlation exists between the cardioprotective effects of the two agents and their ability to enhance the non-protein sulfhydryl group content of the myocardium. Differences observed in vivo between GSH and NAC might be accounted for by pharmacokinetic factors.

The aim of this research was to evaluate the safety and reliability of an anaesthetic mixture (Equitensine: pentobarbital, chloral hydrate, dihydroxypropane, ethanol) which, unlike other 'classic' anaesthetics, such as ketamine [The Electroencephalogram in Anaesthesia, Springer, Berlin, 1984], has been demonstrated not to induce alterations in the extracellular concentrations of cerebral excitatory amino acids. Quantified EEG analysis monitoring and behavioural observation were used to quantify the degree and the time course of the changes in cerebral electrical activity, analgesia and sedation induced, in rats, by the compound under investigation. Equitensine (0.33 ml/100 g), administered intraperitoneally, induced analgesia (monitored by the tail flick method) for 60-70 min and a pattern of behavioural sedation (loss of the righting reflex) lasting, on average, 130-150 min. The EEG monitoring revealed a pattern typical of burst suppression which lasted 15-20 min, followed by another, lasting 270-300 min, characterized by slow waves of high amplitude. The quantified EEG analysis demonstrated that the changes in cerebral electrical activity lasted longer than behavioural observation suggested. The compound under examination was found to be safe, reliable and non-invasive to administer and sustain in all the animals, and quantified EEG analysis proved to be a very sensitive method for highlighting the functional changes in the central nervous system.

High doses of ethanol increase stroke risk: in this context, a role for excitatory amino acids has been proposed. The present results show that, in frontoparietal cerebral cortex, chronic ethanol treatment (10% v/v in drinking water for 28 days) was able to slightly reduce glutamate release (evaluated through transdialysis coupled with high-pressure liquid chromatography) following focal ischemia as regards non-treated ischemic rats. This reduction was, however, not associated with decreased cerebral damage. In 24-h withdrawing rats, histological and morphometric analyzes showed an exacerbated cerebral damage coupled with higher glutamate and aspartate release compared to controls. These results suggest that adaptive changes following chronic ethanol consumption lead to an increased excitotoxicity that is particularly evident during the withdrawal condition.

Focal ischemia was induced in the fronto-parietal region of rat brain, by injection of Rose Bengal, followed by light activation. Focal ischemia was accompanied by formation of PGD 2 peaking 60–90 min post irradiation and declining thereafter. Increased Cycloxygenase-2 (COX-2) expression was also observed. Control ischemic rats showed distinct morphological alterations with necrosis of neurons, glial cells and blood vessels, surrounded by a halo with pyknotic cells with cytoplasm swelling and vacuolization. Compound SC58236, a selective COX-2 inhibitor, dose-dependently prevented, ischemia-induced eicosanoid formation (area under the curve (AUC) of controls: 3.11±0.87; AUC of 20 mg/kg SC58236: 0.39±0.24), and caused significant reduction of damaged area (30.7 and 18.9% at SC58236 20 and 6.6 mg/kg), suggesting that selective inhibitors of COX-2 are neuroprotective.

Epidemiological studies show that chronic ethanol consumption at high doses enhances the risk of cerebral stroke. The mechanisms responsible for the greater vulnerability of alcoholics' brains to stroke have to be completely understood, but a role for excitatory amino acids has been suggested. In order to study the interaction between alcohol and ischemia, we investigated the effect of acute alcohol administration in a model of focal cerebral ischemia. In particular, we evaluated the release of glutamate and aspartate from the cerebral frontal cortex by a transdialysis technique. Alcohol was acutely administered at 1.5 and 3.0 g/kg ip. During the period of maximal alcoholemia, ethanol almost abolished the ischemia-induced release of glutamate leading to glutamate values around or below the basal. Aspartate levels were unaltered both following ischemia and alcohol+ischemia. The decrease in glutamate release, however, was not accompanied by a significant reduction of the extension of the damaged area assessed by histological analysis.

Changes in prostanoids concentration and effects of the non-specific COX inhibitor indomethacin on prostanoids levels and extension of tissue damage were studied following focal ischemia induction in the fronto-parietal region of rat brain. Ischemia was induced in animals bearing a transcerebral microdialysis probe by injection of Rose Bengal, a photosensitive dye, followed by light activation. Prostanoid levels were determined in the dialysate using immunoenzymatic techniques. PGD2 levels rose significantly up to 237+/-22 pg/ml compared to a basal level measured before ischemia induction which was below the detection limit. TXB2 changes were smaller and had a different time course. Treatment with indomethacin abolished the ischemia-induced PGD2 release and reduced the extent of injury to the area by 43+/-3.7%. These results suggest that prostanoid release may play an important role in neurodegenerative processes and that cyclooxygenase inhibitors may contribute to protect against cerebral tissue damage.

The effect of idebenone on the serotonergic system was evaluated in the aging rat by measuring the kinetic constants of 3 H-5HT and 3 H-ketanserin binding sites in the cerebral cortex of rats at 3, 15 and 24 months of age following acute and subchronic administration of the drug. Idebenone displayed no in vitro affinity toward any population of serotonin receptors and did not modify their kinetic parameters after a single dose of 100 mg/kg at any age tested. A subchronic treatment with the drug for 21 days at the dose of 30 mg/kg did not induce any relevant change in 3- and 15-month-old rats, whereas it significantly increased the density of both 3 H-5HT and 3 H-ketanserin binding sites in 24-month-old rats, where a lower number of receptors is detected as a consequence of aging. This effect was rather specific, since under the same experimental conditions no changes were detected in the density of cortical β-adrenergic receptors in aged animals. In microdialysis studies, acute administration with idebenone did not affect 5HT and 5HIAA release at any age. Conversely, the pattern of serotonin metabolism was significantly modified in aged rats following repeated treatment with idebenone and was partially restored to a value similar to the one observed in young animals. These results suggest that idebenone, a putative neuroprotective agent which has been shown to improve brain metabolism in ischemic conditions, might also attenuate age-associated neuronal damage, acting probably on several neurotransmitter systems which undergo selective modification during aging.

We have studied the kinetic constants of β;-adrenergic receptors in lymphocytes and of serotonin uptake sites in platelets from adult and elderly volunteers and from aged patients with a diagnosis of multi-infarct dementia (MID) or senile dementia of Alzheimer's type (SDAT). The results showed that in the physiological aging process, β;-adrenergic receptor density is reduced and 5HT transport system is enhanced. MID is associated to a loss of β;-adrenoceptor affinity and a slight increase in the capacity of 5HT uptake. The kinetic constants of both β;-adrenergic receptors in lymphocytes and 5HT uptake sites in platelets from SDAT patients were comparable to those observed in the adult population, being thus different from those found in the aged matched volunteers. These changes could be interpreted as resulting from compensatory mechanisms that replaced altered plasma monoamine concentrations. The apparent absence of such changes in SDAT patients could suggest the lack of these compensatory effects.

Thromboembolic phenomena and transient ischaemic attacks (TIA) are considered the basis of ischaemic pathologies. The aim of the present research is to investigate the involvement of k-opioid receptors in cerebral blood flow (CBF) impairment which results in experimental stroke or dietary atherosclerosis in rabbits. CBF measurement showed a significant decrease in rabbits submitted to embolization and/or atherosclerosis. Binding studies showed that massive cerebral ischaemia and atherosclerosis produced a significant increase in the number of k-opioid receptors (Bmax), without changing (KD) affinity values. In conclusion, the results obtained seem to indicate that the increase in k-opioid receptors might play a crucial role in a common cerebral biochemical mechanism both in ischaemic and atherosclerotic pathologies.

Doxorubicin (DXR), administered iv in rats at the weekly dose of 3 mg/kg for 5 weeks, significantly impaired body weight gain and induced irreversible ECG alterations, mainly consisting of a progressive prolongation of ST and QT intervals. Five weeks after the last DXR administration, the contractile performance of atria isolated from treated animals was significantly reduced. At the same time, relevant morphologic lesions, consisting of myocyte vacuolization and myofibrillar loss, were also present in the myocardium of the same rats. The study showed that ICRF-187, administered ip at a dose of 125 mg/kg, significantly prevented body weight loss, QT and ST prolongation, and the decreased contractile force induced by DXR. In addition, ICRF-187 caused a significant reduction in incidence and severity of myocardial lesions. The cardioprotective effect of ICRF-187 is not mediated by a modification in DXR pharmacokinetics in heart, since the drug was actually found to increase DXR uptake in myocardial cells.

Two new anthracycline analogs, 4'-epi-doxorubicin and 4'-deoxydoxorubicin, were tested for their cardiotoxicity and their activity on calcium turnover in guinea pig heart. The df/dt was used as an index of contractile force; calcium turnover was studied by means of a radioisotopic technique. 4'-Epi-doxorubicin was found less cardiotoxic than doxorubicin, whereas 4'-deoxydoxorubicin was found almost completely devoid of cardiotoxicity. The different cardiotoxic activity was found to be linearly correlated with the relative capacity to inhibit the fast-exchanging calcium compartment in cardiac muscle: doxorubicin greater than 4'-epi-doxorubicin greater than 4'-deoxydoxorubicin. This result supports that the inhibition of calcium exchange is involved in development of the early cardiotoxicity of anthracyclines.

In the present investigation, the cardiotoxic effects of three anthracycline analogs (doxorubicin, 4′-epi-doxorubicin and 4′-deoxy-doxorubicin) were compared. For this purpose, 9.0 mg/kg of doxorubicin, divided into three closely spaced sub-doses, were injected intravenously in rats. The two derivatives were administered according to the same time schedule and their doses were chosen on the basis of the clinically adopted ratio, doxorubicin : 4′-epidoxorubicin : 4′-deoxy-doxorubicin = 1:1: 0.5. The degree of cardiomyopathy induced by the three anthracyclines was evaluated by ECG changes and morphological alterations. Doxorubicin was found to produce a significant degree of cardiotoxicity, thus confirming the validity of the experimental model adopted. Both 4′-substituted derivatives proved to be less cardiotoxic than the parent compound, although not completely devoid of this side effect.

Doxorubicin and 4'-epi-doxorubicin, two anthracycline derivatives with different cardiotoxic effects in experimental models, were found to decrease myocardial contractility in isolated guinea pig atria by significantly modifying calcium turnover. This effect seems to be mainly localized on the fast exchanging membrane-bound calcium, while these drugs do not significantly influence the intracellular stores of calcium. 4'-epi-doxorubicin, which induces a less negative inotropic effect than doxorubicin, produces a smaller inhibition of calcium turnover. This supports the hypothesis that the inhibition of calcium turnover and particularly of the fast exchanging calcium compartment is a general mechanism involved in the early anthracycline-induced cardiotoxicity.

Previous investigations suggest that lanthanum might enter uterine smooth muscle cells and work as intracellular calcium displacing agent. The present investigation had been carried out in order to confirm if lanthanum develops an intracellular effect. Experiments show that lanthanum brings about a marked increase of the intracellular calcium; the comparison of the uptake and of the wash-out curve of 45Ca shows that lanthanum induces a lowering of the rapid phase of 45Ca release from rat uterus, while the uptake of the labelled ion is not modified or is even enhanced. The present data demonstrate that the action of lanthanum in rat uterus is limited to the cell membrane, whose calcium extruding properties are inhibited.

The present investigation of the cellular distribution of lanthanum was undertaken in order to control the validity of the "Lanthanum method" used for the study of the cell calcium compartments. The presence of lanthanum was evaluated in the isolated guinea-pig heart and its subcellular fractions perfused with a lanthanum-containing Tyrode solution. Lanthanum was determined by instrumental neutron activation analysis. Under the adopted experimental conditions (30-min incubation in the presence of 12.5 microM lanthanum), lanthanum is carried across the cell membrane and is taken up by subcellular organelles. These results confirm the limited validity of investigations based on of the "Lanthanum method".

A single administration of adriamycin (DXR) 6.0 mg/kg i. v. to rats brings about a biphasic impairment of the maximal myocardial contractile performance, measured as dF/dt of ex vivo isolated atria incubated in the presence of calcium concentrations varying up to 12 mM. The initial impairment of the contractile performance peaks 1 week after DXR administration and recovers within 3 weeks (acute phase of cardiotoxicity). After this time and up to the end of the observation period (8 weeks after treatment), delayed cardiotoxicity occurs, showing a progressive and irreversible impairment of the contractile performance of the atria. This behaviour parallels the previously shown ECG and morphological abnormalities. Tissue determinations of DXR showed that the drug is present in myocardium during the acute phase of cardiotoxicity, while the metabolite adriamycinol is not detectable 1 week after DXR administration. These data show that the presence of DXR and/or metabolites in heart muscle is not necessary for the delayed form of cardiotoxicity to become apparent and suggest that this form of cardiotoxicity is related to a mechanism different from that involved in acute cardiotoxicity.

The aim of the present study was to evaluate the dose- and time-dependence of the effect displayed by doxorubicin (DXR) on the electrocardiogram (ECG) and to establish the relationship between structural alterations of the myocardium and ECG changes in rats administered DXR, at a dose of 1.5 or 3.0 mg/kg, every 3 days for a total of three administrations. The most interesting findings consisted of a dose-dependent, but reversible prolongation of the QRS complex, and in a dose-dependent and progressive irreversible increase in QaT and, in particular, in SaT duration. Furthermore, animals treated with the higher DXR dose showed a slight increase in serum K+ concentration and a significant decrease in serum Ca2+ levels. A good correlation was found between the morphologic score indicating the degree of observed tissue damage and SaT prolongation. These results therefore support the usefulness of measuring this ECG parameter for monitoring the development of DXR-induced cardiotoxicity in rats.

The present study in rats was performed to evaluate the cardiotoxic activity of 4′ -deoxy-4′ -iodo-doxorubicin (4′-deoxy-4′-I-DXR), a new anthracycline derivative with interesting antineoplastic properties and possible lower cardiotoxicity than doxorubicin (DXR). DXR produced ECG alterations consisting of a progressive and irreversible prolongation of SaT and QaT. In contrast, in 4′-deoxy-4′-I-DXR-treated rats the increase in SaT and QaT duration was significantly lower than that observed in DXR-treated rats and slightly increased over controls. DXR produced significant histologic changes in myocardium consisting of myocyte vacuolization and myofibrillar loss. No significant modifications were observed in mitochondria. In contrast, no significant cardiac lesions were observed in 4′-deoxy-4′-I-DXR-treated rats. These results suggest that this new anthracycline derivative has a significantly lower degree of cardiotoxic activity than DXR.

Previous observations suggested that the turnover of tissue calcium might be involved in the mechanism of smooth muscle contraction induced by lead. In the present investigations, the effect of lead on calcium exchangeability has been studied in the isolated rat tail artery. Experimental results suggest that the mechanism of lead action might be identified with a tissue calcium accumulation and with a lead-to-calcium competition. Evidence exists that the site of action is located in the cell membrane, where lead inhibits the processes of calcium extrusion, and in the intracellular calcium stores, whose calcium binding capacity is lowered; both processes induce an increase of the cellular exchangeable calcium available for contraction.

Summary When the Lanthanum method is used for the study of the action mechanism of drugs interfering with calcium transport, a physiological solution of different composition is usually employed in order to avoid interactions between Lanthanum and the anions of the standard Krebs-Ringer solution. The modified medium is buffered with Tris-HCl and contains chloride as the only anion. The pharmacological behaviour of the isolated artery has been studied in normal Krebs solution and in the modified solution. Both the contractile properties and the tissue calcium content decrease when the organ is bathed in the modified solution, thus suggesting that a medium of this composition is not indicated for experiments concerning the turnover of calcium in arterial smooth muscle.

Ten μg/ml of adriamycin produces a significant decrease in peak tension of isolated guinea pig atria without modification of cellular Ca content. The analysis of the curve of Ca exchanges shows that adriamycin significantly reduces the calcium exchangeable fraction, whereby the Ca fast exchanging compartment is suppressed and the slow exchanging one is slightly increased. Ouabain prevents the negative inotropic effect of adriamycin and restores the rapid Ca compartment without significantly modifying either the cellular Ca content or the amount of calcium exchangeable fraction. These results demonstrate that calcium plays a role in the negative inotropic effect of adriamycin in cardiac muscle and confirm the importance of the fast exchanging fraction in regulating the contractile force of the heart.

The present investigations were carried out in guinea pig to ascertain whether mitomycin C has a direct cardiotoxic effect or interacts with doxorubicin-induced cardiotoxicity. I.p. administration of mitomycin C did not modify the survival rate up to 30 days, whereas the combined administration of doxorubicin and mitomycin C significantly decreased the survival time in comparison to the doxorubicin-treated group. On isolated atria, mitomycin C did not cause significant inhibition of the contractile force or an enhancement of the doxorubicin-induced negative inotropic effect. These results do not support the possibility that mitomycin C potentiates the acute cardiotoxic effects produced by doxorubicin.

It has been mainly reported that drugs are transported into the cell by simple or facilitated diffusion and generally not by active transport (1). Since biological membranes can be seen as a protein-coated lipidic bilayer, it has been assumed that the most important property which enables molecules to be transferred across the membrane is their lipophylic character. As far as antibiotics are concerned, it has been postulated that the same property is also requested for bacterial cell permeation. On the basis of this assumption, it has been suggested that a relationship exists between the water-to-oil partition coefficient and the antibacterial activity (2–3), although the chemical composition of the mammalian cell membrane is different from that of bacterial cells.

Summary Investigations have been undertaken in order to study the possibility that Lanthanum could differently affect the different calcium binding sites. Experiments have been carried out in normal and in K + -depolarized rat uterus. A biphasic action (inhibition of the concentration which wears off at higher doses) is shown by Lanthanum. The suggestion that this dual effect could correspond to a dual site of action (cell membrane and intracellular calcium stores) seems to be confirmed by the enhancement of contraction occurring at high Lanthanum concentrations in depolarized preparations. Finally, the contractions elicited by Lanthanum in Ca-free, K + -depolarized preparations suggest that Lanthanum can penetrate into the cells and bind to the contractile elements, acting as a calcium substitute. The activation of the contractile elements in smooth as well as in skeletal muscles involves the increase of calcium concentration in cytoplasm ( Hurwitz, 1971 ) above 10 −7 M ( Bianchi, 1969 ). Activator calcium may come from intracellular storage sites ( Carsten, 1969 ; Peachey et al., 1959 ), or from extracellular sources; the last process could become more evident when the cell permeability is enhanced, like during the depolarization of the cell membrane ( Hurwitz, 1971 ). A direct proof of the involvement of one or both mechanisms is difficult to obtain, since a small increase in tissue calcium content is needed for maximal activation of contractile elements; to this purpose a new method has been recently proposed. The method is based on the use of Lanthanum, making the assumption that this element, whose affinity for negative groups is higher than that of calcium, can displace calcium from the membrane-located binding sites; because of the apparent ability to limit its action at the level of the membrane, Lanthanum could effectively “lock in” the intracellular calcium and block the calcium movements across the membrane ( Marschall, 1973 ). Since all conclusions drawn by the Lanthanum method are based on the assumption that the activity of this element is limited to a calcium displacement from the cell membrane, further investigations are needed in order to check if Lanthanum can penetrate into the cell and in this case which effect it brings about. In fact, some observations ( Goodman et al., 1971 ) let suggest that Lanthanum could differently affect the different calcium sites or stores. In these experiments, the action of Lanthanum on smooth muscles has been studied in control conditions and after depolarization, i.e. by normal and by enhanced membrane permeability. Rat uterus has been choosen as the target organ since it develops spontaneous contractions which can be used for evaluating the action of an inhibiting agent.

A procedure for the determination of cerebral blood flow by the local clearance method after intracarotid injection of 133 Xe in the conscious rabbit is described. The inert radioactive indicator is injected into a permanent nylon catheter equipped with a two-way Gordth's needle inserted into the common carotid artery and filled with heparin, emerging behind the shoulders of the animals. All branches of the homolateral common carotid artery except the internal carotid artery were ligated. Studies of the distribution of colored tracers (dark blue ink) and radioactive tracers ( 99m Tc albumin microspheres) show that the main localization of the injected indicator is within the homolateral hemisphere. Brain to blood partition coefficients of 133 Xe are worked out for rabbit's gray matter (0.576 ± 0.048) and white matter (0.808 ± 0.023). The slope method for first and second component of the wash-out Xenon curve is used for CBF calculations. CBF determinations in 9 normal rabbits result in 84.27 ± 5.59 and 16.69 ± 2.44 ml/min × 100 g tissue, respectively, for the fast and slow component. Significant changes do not occur in serial determinations within 2 hr.

Allylisopropylacetamide (AIA) administered to rats, increases the liver δ-aminolevulinic acid (ALA) synthetase activity and porphyrin values elevate plasma triglyceride levels and decreases plasma-free fatty acids. 3,5-Dimethylisooxazole (3,5-DMl) markedly lowers the liver ALA synthetase activity, porphyrin levels and also decreases plasma triglyceride levels in AIA-treated rats. 3,5-DMI exerts its antiporphyric activity probably by increasing the protein catabolism.