Behavioural effects mediated by unilateral nigral dopamine receptor stimulation in the rat

Summary Unilateral intranigral injections of dopamine in conscious rats pretreated with nialamide resulted in either ipsiversive or contraversive rotation depending upon the site of injection. Injection of dopamine (50 g) into the zona compacta of the substantia nigra induced weak ipsiversive or mixed ipsiversive and contraversive rotation. Injection of dopamine (12.5–50.0 g) into zona reticulata of substantia nigra induced only contraversive circling. Destruction of the ipsilateral medial forebrain bundle (MFB) using 6-hydroxydopamine (6-OHDA) abolished ipsiversive circling but enhanced contraversive circling produced by dopamine or apomorphine. The combination of a unilateral 6-OHDA lesion of MFB with a kainic acid or electrolesion of the ipsilateral strio-nigral and pallido-nigral pathways reduced contraversive circling to intranigral apomorphine (10 g). Ipsiversive circling produced following intranigral injection of dopamine is dependent upon the integrity of ascending dopamine neurones. Contraversive rotation is independent of ascending dopamine pathways but is reliant upon afferent input to the substantia nigra from the striatum and/or globus pallidus.     

Evidence for a GABAergic nigrothalamic pathway in the rat

Summary Unilateral stereotaxic microinjection of muscimol into the caudal region of the substantia nigra (SN) evoked tight, dose-related contralateral locomotor asymmetry and stereotypy. These behaviours were partially attenuated by various pre-treatments, including 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway, intraperitoneal (i.p.) haloperidol, and inhibition of thalamic GABA-transaminase activity by local intrathalamic injection of ethanolamine-O-sulphate. Electrolytic or kainic acid lesions of the medial thalamic nuclei (MTN) partially reduced the contraversive rotation to intranigral muscimol, and completely abolished the similar behaviour elicited by apomorphine (25 g) injected into the ipsilateral caudate nucleus. Contraversive turning to intranigral muscimol was completely inhibited by kainic acid lesions of the ipsilateral SN, but potentiated by intrathalamic injection of picrotoxin. Muscimol (40 ng-4 g) administered to the MTN complex in one hemisphere stimulated rats to move in ipsilateral circles that were unaffected by haloperidol. The results of these behavioural experiments suggest that the nigrostriatal dopamine pathway, the nigrothalamic projection and possibly other non-dopaminergic SN efferents all play important roles in mediating the influences of the SN on motor and stereotyped behaviours. Disruption of the nigrothalamic pathway following electrical or chemical injury to the SN was accompanied by falls in GABA and its synthesising enzyme in the corresponding MTN. These data, together with the findings of our electrophysiological study presented in the following paper, are consistent with the nigrothalamic system having a GABAergic inhibitory function.This work was partly supported by an M.R.C. programme grant awarded to Prof. D.W. StraughanI.C. Kilpatrick and A. Fletcher are respectively M.R.C. and S.R.C. scholars     

Cholinergic stimulation of substantia nigra: abolition of carbachol-induced eating by unilateral 6-hydroxydopamine lesion of nigrostriatal dopamine neurones

Summary Microinjection of cholinergic agonists into the substantia nigra is known to elicit increases in eating, drinking and sexual behaviour under appropriate circumstances. It has been suggested that these effects are dependent on stimulation of nigrostriatal dopamine-containing neurones in the substantia nigra pars compacta, but no direct evidence has confirmed this. The present experiment was therefore undertaken to determine whether unilateral lesions of nigrostriatal dopamine neurones made by 6-hydroxydopamine would attenuate or abolish eating in satiated rats elicited by intranigral microinjection of the muscarinic agonist carbachol. Two groups of rats were tested: a 6-hydroxydopamine- and a sham-lesion group. Before lesions were made intranigral microinjection of 0.5 g/0.5 l carbachol stimulated significantly more eating than control microinjections in both groups. After 6-hydroxydopamine lesions, microinjection of carbachol elicited no more eating than vehicle alone. Rats given sham lesions (ascorbate-saline vehicle only) showed increased feeding to intra-nigral carbachol before and after sham-lesioning. Post-mortem analysis by HPLC was used to determine the concentration of dopamine, DOPAC, HVA, serotonin and 5-HIAA in the lesioned and nonlesioned hemispheres of both 6-hydroxydopamine- and sham-lesioned rats. In caudate-putamen there were significant reductions in the concentration of DA (to 50.03% of the level in control sides), DOPAC (to 49.34%) and HVA (to 63.98%) in the 6-hydroxydopamine-lesioned but not sham-lesioned rats. The concentration of dopamine, DOPAC and HVA were not affected in the nucleus accumbens. The turnover of dopamine (assessed by calculating the ratio of dopamine to DOPAC) in the caudateputamen but not nucleus accumbens was also altered by the 6-hydroxydopamine lesions. The concentration and turnover of serotonin was not affected in either the caudate-putamen or nucleus accumbens in either group of rats. These data show that loss of dopamine from the caudate-putamen but not nucleus accumbens is sufficient to abolish completely the eating stimulated by intranigral carbachol.     

Facilitation by 5-hydroxytryptamine of ATP-activated current in rat pheochromocytoma cells

The effects of 5-hydroxytryptamine (5-HT) on an inward current activated by extracellular ATP were investigated in rat pheochromocytoma PC12 cells. Under whole-cell voltage-clamp conditions 5-HT (10 M) reversibly enhanced the amplitude of the current activated by 30 M ATP. The enhancement may not be due to an increase in the number of functional channels because the current activated by 300 M ATP was not remarkably augmented compared with the current activated by 30 M ATP. The current enhancement by 100 M 5-HT was less obvious than that by 10 M 5-HT. When the current kinetics were compared, activation of the ATP-evoked current was accelerated to the same extent by either 10 or 100 M 5-HT, whereas deactivation was largely more accelerated by 100 M 5-HT. Propranolol (10 M), a 5-HT₁ receptor antagonist, or LY53857 (10 M), a 5-HT₂ receptor antagonist, exerted an agonistic effect: the ATP-activated current was facilitated by these compounds. Metoclopramide (10 M), a 5-HT₃ receptor antagonist, neither facilitated the ATP-activated current, nor blocked the current facilitation by 5-HT. Guanosine 5-O-(2-thiodiphosphate) (GDP[S]) (2 mM), the non-hydrolysable analog of guanosine 5-triphosphate (GTP), or K-252a (2 M), a protein kinase inhibitor, did not affect the facilitation by 5-HT of the ATP-activated current when they were included in the intracellular solution. The ATP-activated current pre-facilitated by 10 M dopamine was not enhanced by 10 M 5-HT. Similarly, the pre-facilitation by 5-HT attenuated the current enhancement by dopamine. The results suggest that 5-HT facilitates the ATP-activated channels through receptors that are not readily classified into conventional subclasses of 5-HT receptors. The reciprocal masking between the current facilitation by 5-HT and that by dopamine, combined with their sensitivities to the compounds involved in the intracellular solution, indicates that the facilitation by 5-HT may share not all, but some, common cellular mechanism with that by dopamine.     

Regulatory aspects of nigrostriatal dopaminergic neurons

Summary In the urethane-anesthetized rat, electrical stimulation (10 Hz, 30 s, 250 A) of the medial forebrain bundle (MFB), at 20-min intervals over an 8-h period, combined with intracerebral microdialysis in the striatum caused: an undiminished increase in the release of dopamine (DA) with each stimulation episode; a decreased efflux of 3,4-dihydroxyphenylacetic acid (DO-PAC) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) after the first stimulation only; a delayed increased efflux of DOPAC with no change in HVA; and a poststimulation depression of firing of dopaminergic neurons in the substantia nigra (before, 3.1±0.7 Hz; after, 1.9±1.0 Hz; P<0.05). After the last stimulation episode, the release of DA declined to prestimulation values, while the increased efflux of DOPAC persisted for three more hours. After the infusion of tetrodotoxin (4.0×10^-7 M, 1.5 l, 1.0 l/min) into the MFB, the basal release of DA was reduced (P<0.05), while the efflux of DOPAC and HVA was increased (P<0.05). A model is proposed suggesting that: (1) during increased release of DA in the striatum, the metabolism of DA is decreased; (2) inhibition of nigrostriatal dopaminergic neurons is the usual cause of increased synthesis and metabolism of DA in the striatum; and (3) increased release of DA, and increased synthesis and metabolism of DA in the striatum are not causally linked and are noncoupled processes.     

Calmodulin content in specific brain areas

Summary A radioimmunoassay was used to measure the calmodulin content in eleven brain areas of the rat. Calmodulin showed an uneven distribution. Various cortical regions, striatum, hippocampus, amygdala and substantia grisea were highest in calmodulin content (15 g/mg protein). Locus coeruleus, nucleus tractus solitarii (+A2 region) and A1 region, contained 7 g calmodulin per mg protein and the cerebellum 4 g/mg.     

Neuronal responses to iontophoretically applied dopamine,glutamate, and GABA of identified dopaminergic cells in the rat substantia nigra after kainic acid-induced destruction of the striatum

Summary Kainic acid (KA 1.2–1.5 g) was injected unilaterally into the rat striatum (ST). Fifteen to 30 days later neurons of the substantia nigra (SN) were identified by antidromic stimulation from the ST or medial forebrain bundle (MFB). The projecting axons had conduction velocity similar to that recorded in unlesioned animals.Responses to iontophoretically applied dopamine (DA), glutamate (GLU), and GABA (5–100 nA) were recorded from neurons of the dopaminergic pars compacta-striatal projection. Control experiments were performed in intact rats. GABA and DA inhibited neurons tested in controls while GLU had an excitatory effect. Changes in firing rate induced by GABA and GLU developed 1–5 s after the beginning of their ejection while the action of DA appeared after a delay of 20–40 s.Neurons in lesioned animals showed a net decrease in sensitivity to all three neurotransmitters. The highest current tested gave responses 50–70% lower than in controls.The data suggest that destruction of striatal efferents with KA does not induce hypersensitivity in the pars compacta of the SN.     

Opioid peptides inhibit the release of noradrenaline from slices of rat medial preoptic area

Summary Previous circumstantial evidence suggested that endogenous opioid peptides inhibit an excitatory noradrenergic projection to the medial preoptic area (MPOA), and thereby suppress the activity of neurones containing luteinising hormone-releasing hormone and thus systemic concentrations of luteinising hormone (LH) itself. In this paper, we report that electrically stimulated release of ³H-Noradrenaline (³H-NA) from perifused slices of rat MPOA is diminished when opioid agonists are added to the incubation medium. Thus, morphine (10 M), beta-Endorphin (1 M) and met-Enkephalin (1 M), but not Dynorphin A (1–8) (1 M), caused a significant decrease in electrically stimulated ³H-NA release. The inhibition was reversed by addition of naloxone (10 M) to the perifusion medium but ³H-NA release was unaffected by dopamine or acetylcholine (or their antagonists sulpiride and atropine, respectively), or serotonin, neurotensin, muscimol or bicuculline (the latter two being agonist and antagonist respectively for the GABA A receptor). Therefore, the experiments provide direct evidence that brain opioids modulate the noradrenergic input to MPOA neurones and support the hypothesis that this may be one mechanism for the regulation of LH secretion.     

Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues

Summary A series of experiments have been conducted to assess the specificity of recovery from motor asymmetries that is provided by dopamine-rich grafts in the neostriatum of rats with unilateral dopamine-depleting lesions produced by injection of 6-hydroxydopamine into the ascending nigrostriatal pathway. Grafts of embryonic tissue taken from the substantia nigra (rich in dopamine neurons) could provide a complete recovery of methamphetamine-induced rotation and a partial recovery of apomorphine-induced rotation, whereas no recovery was seen in rats with grafts of tissue rich in another monoamine (serotonin, dissected from the mesencephalic raphe) or of tissue appropriate to the target (dissected from the striatal eminence). 6-Hydroxydopamine lesions of dopamine cells in the grafts of recovered animals reinstated the initial lesion-induced asymmetry. Dopamine-rich grafts implanted into the intact neostriatum did not induce any supernormal asymmetry in the rats, but did provide a prophylactic protection against subsequent lesions of the intrinsic ipsilateral dopamine nigrostriatal system. Post-mortem biochemical assays indicated that the extent of dopamine depletion in the neostriatum of lesioned rats correlated highly with both methamphetamine and apomorphine turning rates. Similarly, both drug rotation tests correlated significantly with the extent of dopamine restoration in the dorsal striatum of rats with dopamine-rich grafts, the correlation being significantly higher for the methamphetamine than for the apomorphine test.     

Involvement of the Rat Caudate Nucleus in the Immunostimulatory Effect of Dago

The involvement of the caudate nucleus, i.e., the terminal zone of the nigrostriatal dopaminergic system, in neuroimmunostimulation during the activation of opioid receptors by the highly specific agonist DAGO. Single doses of DAGO (100 g/kg) in sham-operated control Wistar rats induced significant increases in the numbers of direct IgM-antibody-forming and total rosette-forming cells at the peak of the immune response after immunization with sheet red blood cells. The experiments showed that bilateral electrolytic lesioning of the caudate nucleus in rats suppressed the immune response, demonstrating its involvement in neuroimmunomodulation. Since the effect of immunostimulation induced by DAGO disappeared when given to animals with caudate nucleus lesions, it was concluded that this structure is involved in activatory immunogenesis via opioid mechanisms.     

Comparison of disk diffusion,the E test,and detection ofmecA for determination of methicillin resistance in coagulase-negative staphylococci

The aim of this study was to find a reliable, fast, and simple alternative to the methicillin disk method for determination of methicillin resistance in coagulase-negative staphylococci, since results of this method are often difficult to read due to growth within the zone of inhibition. The sensitivity of 319 strains of coagulase-negative Staphylococci to a 5 g methicillin disk on Mueller-Hinton agar using an incubation period of 48 h was compared with that of 1 (1 g and 5 g oxacillin disks on Mueller-Hinton agar with or without 2% NaCl, using an incubation period of 24 h. The detection ofmecA (MecAgen) by the polymerase chain reaction was used as a standard. Minimum inhibitory concentrations were determined by means of the E test. Of the 225mecA-positive strains, 190, 215, and 193 were resistant to 5 g methicillin, 1 g oxacillin and 5 g oxacillin disks on Mueller-Hinton agar, respectively, and 216, 218, and 223 were resistant on Mueller-Hinton agar with 2% NaCl. Of the 94mecA-negative strains, 89, 93, and 94 were susceptible to 5 g methicillin, 1 g oxacillin, and 5 g oxacillin disks on Mueller-Hinton agar, respectively, and 92, 93, and 94 were susceptible on Mueller-Hinton agar with 2% NaCl. Using breakpoints of 2 g/ml for oxacillin resistance and 8 g/ml for methicillin resistance, the E test yielded sensitivities of 99.6 and 99.1% and specificities of 97.9 and 98.9% after 48 h of incubation. The 5 g oxacillin disk was faster and easier to read than the methicillin disk and correlated better with detection ofmecA than the methicillin disk or the 1 g oxacillin disk.     

Cutaneous mechanoreceptors influencing impulse discharges in cerebellar cortex. II. In Purkyně cells by mossy fiber input

Summary This paper gives an account of single Purkyn cell responses when three types of mechanical stimulation, as in the previous paper, are applied to the forefoot and hindfoot of the decerebrate unanesthetized cat. Attention was concentrated on the effects of brief mechanical pulses to the footpad. Recording was extracellular by glass microelectrodes and special precautions were taken in identifying the spike responses as being due to a single Purkyn cell and in securing its effective isolation for our computer averaging techniques, as described in the previous papers. All Purkyn cells were in the ipsilateral anterior lobe in the lateral vermis or pars intermedia of lobules III, IV, V, except for a few recordings in the extreme rostral zone of lobule VI.Mechanical pulses or taps evoked responses from many Purkyn cells which were pure excitatory, pure inhibitory or admixtures thereof. The latencies of onset were usually in the range of 12–20 msec from the onset of the tap, which tends to be a little longer than the observed latencies for mossy fiber responses described in the preceding paper. There was often a considerable difference in the sizes of the responses evoked from different pads of the same foot, and the usual threshold for response was below 0.2 mm amplitude. Durations of responses were usually 10–20 msec for excitation and 50–100 msec for inhibition.Pressure pulses to the central foot pads of 2 sec duration evoked a wide variety of responses: brief phasic at on and off that could be admixtures of excitation and inhibition; almost pure tonic excitations or inhibitions that were well maintained during the 2 sec; phasic-tonic responses in various relative degrees. Usually 500 g was maximally effective and the threshold was below 100 g.Hair receptors were stimulated preferentially by brief air jets, there being brief excitatory or inhibitory responses much as with taps, but with rather longer latency. The effective area was usually fairly extensive over the hairy skin of the foot.In general the effects on Purkyn cells by cutaneous mechanoreceptors acting via mossy fibers were in accord with the mossy fiber responses reported in the preceding paper and with the well-known excitatory and inhibitory effects that are exerted by mossy fiber inputs on Purkyn cells.     

The influence of chronic activation and blockade of the dopamine- and enkephalinergic systems of the neostriatum on conditioned reflex behavior and dopamine metabolism in the rat nigrostriatal system

The effects of daily injections, over the course of 14 days, of 45 g of phenamine, 5 g of haloperidol and naloxone, 15 g of leuenkephalin and its analog, a tetrapeptide, into the rostral neostriatum have been studied. The chronic stimulation of the dopaminergic system of the striatum induced facilitation of the realization of an active avoidance conditioned reflex, and stimulated exploratory stereotypy, while its blockade led to suppression of conditioned reflex activity against the background of a clearcut rigid akinetic syndrome. The microinjections of leu-enkephalin and naloxone did not substantially alter the behavior, but the injection of the tetrapeptide was accompanied by changes in behavior, with symptoms of catalepsy and hyperkinesia. Injections of phenamine and haloperidol were accompanied by a decrease in the content of dopamine in the striatum and an increase in the level of DOPAC; the injections of enkephalin and naloxone induced changes of the reverse order. The possible causes of the noncorrespondence of the behavioral and neurochemical shifts in the presence of a direct chronic pharmacological action on the mediator of the neostriatum.Translated from Zhurnal Vysshei Nervnoi Deyatel'nosti imeni I. P. Pavlova, Vol. 42, No. 5, pp. 930–935, September–October, 1992.     

Efficient selection of μ m − mutants from μm-expressing myeloma cells by treatment with ricin A-conjugated anti-μ antibody

We have developed an efficient system for obtaining myeloma mutants defective intrans-acting factors required for immunoglobulin (Ig) gene expression. The system consists of a myeloma cell line designed for this purpose and an efficient method for selecting mutants from it. The cell line is X63.653 transfected with the gene, whose tailpiece sequence was replaced with the transmembrane sequence of human EGF receptor to hold on the cell surface and whose CH1 sequence was removed to prevent from being retained in the endoplasmic reticulum. It efficiently and stably expressed chains of IgM on the cell surface ( _m ⁺ ) without light chains. To obtain mutants lacking _m ( _m ^– ) from the _m ⁺ cell line by selectively killing _m ⁺ cells, a method with ricin A-conjugated anti- antibody was more reliable than complement lysis mediated by anti- antibody. Applying the system, we obtained a variety of _m ^– mutants.     

The pattern of ocular dominance columns in flat-mounts of the cat visual cortex

Summary Ocular dominance (OD) columns in the cat visual cortex were visualized with autoradiography after intravitreal injection of (³H)proline. Extending previous studies, a flat-mount technique was applied that enabled the analysis of the distribution of label throughout extensive regions of the visual cortex without requiring reconstructions from serial sections. OD-columns were confined to layer IV and consisted of isolated patches and short bands. The latter were parallel to each other and regularly spaced, the main trajectory being orthogonal to the 17/18 border. This pattern of the geniculo-cortical terminals was similar in the hemispheres ipsi- and contralateral to the injected eye. The mean periodicities of the OD-bands were virtually identical in the two hemispheres of the same animal: 850 m and 830 m in cat D1 and 770 m and 800 m in cat D2. However, the ipsilateral OD-columns appeared smaller, more heavily labeled and more sharply delineated than the contralateral columns.     

Effects of PAF and PAF antagonists on the shape of venous endothelial cellsin vitro

Three platelet-activating factor (PAF) antagonists were tested for their ability to prevent or reduce PAF-induced shape changes of large vein endothelial cellsin vitro. BN52021 had a significant protective action at concentrations of 1 M and 0.1 M, but at 100 M had a damaging effect of its own. CV3988 (0.1 M and 1 M) and L652, 731 (20 M) did not reduce the responses to PAF, and at higher concentrations (CV3988 10 M and 100 M, L652, 731 100 M) both compounds alone caused significant changes of shape. BN52021 (0.1 M) was also effective against leukotriene (LT) C₄, at 1 M against bradykinin and LTE₄, and at 10 M against LTD₄ and the calcium ionophore A23187. BN52021 (10 M) was ineffective against shape changes induced by histamine, prostaglandin (PG) E₂ and lysophosphatidylcholine (LPC). Neither indomethacin (100 M) nor verapamil (20 M) altered the response to PAF.Using electron spin resonance (ESR) spectrometry it was shown that the damaging effects of LPC and CV3988 may be due partly to their detergent properties. It is suggested that the mechanism by which PAF alters the shape of large vein endothelial cells is primarily receptor mediated.     

Effects of dipyridamole on adenosine concentration,insulin sensitivity and glucose utilisation in soleus muscle of the rat

Adenosine has been shown to modulate the sensitivity of skeletal muscle to insulin (Budohoski et al. 1984). In an attempt to further characterize the modulatory action of adenosine on insulin sensitivity inskeletal muscle we have investigated the effect of the nucleoside transport inhibitor dipyridamole in isolated incubated soleus muscle strips. At a concentration of 50 M, dipyridamole increased the concentration of adenosine in the soleus muscle by 36% and in the incubation medium by 32%. At this concentration of dipyridamole, the basal rates (in the presence of 1 unit of insulin/ml) of lactate formation, 2-deoxy [2,6-³H]glucose phosphorylation and glucose oxidation were decreased by 48%, 43% and 47% respectively, whilst the rate of glycogen synthesis was unaffected. Insulin-stimulated rates (in the presence of 10000 unit of insulin/ml) of lactate formation, 2-deoxy [2,6-³H] glucose phosphorylation, glycogen synthesis and glucose oxidation were decreased by 70%, 30%, 26% and 20% respectively in the presence of 50 M dipyridamole. Although 50 M dipyridamole was required to exert a significant effect on medium and soleus muscle adenosine concentrations, statistically significant effects on glycolytic rate were observed at concentrations as low as 2 M dipyridamole.It is concluded that the results are not consistent with dipyridamole exerting an effect on skeletal muscle carbohydrate metabolism solely through elevation of the intracellular or interstial adenosine concentration, but strongly suggest that dipyridamole inhibits glucose transport and/or phosphorylation in skeletal muscle.     

The distribution of single P2x1-receptor clusters on smooth muscle cells in relation to nerve varicosities in the rat urinary bladder

The distribution of purinergic (P2x1) receptors on smooth muscle cells in relation to autonomic nerve varicosities in the rat urinary bladder has been determined using immunofluorescence and confocal microscopy. P2x1 receptors were visualized using rabbit polyclonal antibodies against the extracellular domain of the P2x1 receptor, and varicosities were visualized using a mouse monoclonal antibody against the ubiquitous synaptic vesicle proteoglycan SV2. Two size classes of P2x1 receptor clusters were observed on the smooth muscle cells of the detrusor, namely, a large ellipse of mean long axis 1.23 ± 0.21 m and short axis 0.92 ± 0.17 m and a smaller spherical cluster with a mean diameter of 0.40 ± 0.04 m. The latter occured in much greater numbers than the former in selected areas, with a density as high as 0.8 per m2 or two orders of magnitude more than the larger-sized clusters. The large clusters are in general located beneath varicosities, with only 4.5% of P2x1 clusters not possessing an overlying varicosity. None of the small clusters was associated with varicosities. Three-dimensional reconstruction of the P2x1 and SV2 labelling at individual varicosities showed that the varicosities were immediately apposed to the P2x1 receptor clusters. On occasions, two or more small SV2-labelled varicosities about 0.7 m in diameter each with a receptor patch were found juxtaposed to each other; these might represent the splitting up of a single large varicosity. These observations are discussed in relation to the identity of the autonomic neuromuscular junction.     

Differential effects of malotilate on 5-, 12- and 15-lipoxygenase in human ascites cells

Conclusions These effects of malotilate on eicosanoid formation differ from those of known lipoxygenase inhibitors such as BW 755C (IC₅₀ of 5-lipoxygenase 35 M, 12-lipoxygenase >100 M and 15-lipoxygenase 1.2 M), nordihydroguiaretic acid (IC₅₀ of 5-lipoxygenase 1.4 M, 12-lipoxygenase 26 M and 15-lipoxygenase 1 M) and ketoconazole (5-lipoxygenase 28 M, 12-lipoxygenase not affected and 15-lipoxygenase increased) [5]. The differential effects of malotilate on the 5-, 12- and 15-lipoxygenases and also on the generation of the compounds of the cyclooxygenase, have not previously been reported. The suppression of leukotriene productionin vitro occurred at concentrations found following normal therapeutic dosesin vivo. Inhibition of the production of the chemotactic substance LTB₄ and the vasoconstrictive TxA₂ provide a possible explanation for the useful effects of this drug on liver necrosis and liver fibrosis.     

A diffractometer using a lateral effect photodiode for the rapid determination of sarcomere length changes in cross-striated muscle

A simple method is devised to record rapid sarcomere length changes of muscle fibres using a lateral effect diode. In the standard position the diffractometer records length changes between 1.65 and 3.8 m, the output being linear 1 V/m with a frequency response of –3 dB at 1.2 kHz. The absolute error is<0.05 m between 1.65 and 2.80 m and <0.1 m between 2.81 and 3.30 m. The resolution of length changes is<0.005 m over the whole range. By varying the detector position the length range can be extended to either side, and spatial resolution can be improved at the expense of length range.