Management of heart disease in the elderly in the Plymouth Health District.

In the light of a report from the Royal College of Physicians, the management of heart disease in the elderly (> 70 years) was studied in the Plymouth Health District in 1992. A survey of general practitioners was undertaken to assess how they would handle particular aspects of heart disease in their elderly patients. The admissions of older patients to the coronary care unit following an acute myocardial infarction and their outcome were detailed. The numbers of non-invasive cardiological investigations undertaken in the elderly were monitored, as were the referral rates to a cardiology outpatient clinic. The overall conclusion is that physicians and general practitioners alike view coronary artery disease as a medical condition with little consideration of the surgical option, despite good evidence that elderly patients often do very well following coronary artery bypass grafting. Future resource planning should address the problem of an overburdened cardiac surgery service.

Phaeochromocytoma presenting as acute circulatory collapse and abdominal pain.

Phaeochromocytomas may present as an acute emergency with a perplexing variety of symptoms. We report a case which presented with abdominal pain and severe respiratory distress due to a ruptured haemorrhagic phaeochromocytoma. The severe cardiorespiratory collapse which precipitated admission to the intensive care unit was managed with high doses of dobutamine and noradrenaline and the patient was stable during the operative resection. The management of this previously undiagnosed phaeochromocytoma and its atypical presentation are discussed.

The pharmacokinetics and sputum penetration of ampicillin and amoxycillin following simultaneous i.v. administration.

Five patients with exacerbation of chronic bronchitis received as a single iv injection 500 mg of ampicillin and 500 mg of amoxycillin. Blood and sputum samples were collected at timed intervals following dosing and the concentrations of the two antibiotics present in the samples were determined by HPLC analysis. No statistically significant differences were observed between the serum concentrations of ampicillin and amoxycillin, and the pharmacokinetics of the two drugs were almost identical, with half lives of 93 min (amoxycillin) and 103 min (ampicillin). Sputum amoxycillin concentrations were significantly higher (Student's paired t-test; P less than 0.001) than those of ampicillin, with mean levels two hours after dosing of 2.9 mg/l (range 1.9-4.0) for amoxycillin and 1.4 mg/l (range 0.8-2.4) for ampicillin.

Thalamic control of dopaminergic functions in the caudate-putamen of the rat--III. The effects of lesions in the parafascicular-intralaminar nuclei on D2 dopamine receptors and high affinity dopamine uptake.

Dopamine receptor binding in the caudate-putamen was studied following bilateral lesions of the thalamostriatal pathway. Receptor binding was assayed using [3H]spiperone and defined with both (+)-butaclamol and S(-)-sulpiride. Radiofrequency lesions resulted in an increase in the Bmax of [3H]spiperone binding defined with both (+)-butaclamol and S(-)-sulpiride between 7 and 14 days following surgery. At longer survival times a fluctuating response was seen in which a decrease in receptor binding was observed at 28 days following lesion and a further rise again at 70 days. At no time point was significant change in Kd recorded. Further experiments were carried out to control for the possible effects of damage to fibres of passage and for inadvertent damage to habenula, as well as to define the receptor subtype involved. Ibotenic acid lesions resulted in similar effects to those reported with the radiofrequency method. Thus, 7 days following lesion, Bmax for (+)-butaclamol-defined [3H]spiperone binding increased by approximately 14-20% over that recorded in sham-lesioned animals. Using S(-)-sulpiride to define binding, Bmax was found to increase 13-17% in the same membrane preparations. Similar results were obtained in experiments at 14 days following ibotenic acid induced lesions. Again, no change in Kd was recorded. When radiofrequency lesions were made, which were largely restricted to habenula and associated fibres of passage, only small [(+)-butaclamol defined] or insignificant [S(-)-sulpiride defined] changes in Bmax were recorded. Combined radiofrequency lesions of habenula and ibotenic acid lesions of the thalamus resulted in a larger increase in Bmax for (+)-butaclamol defined binding than with S(-)-sulpiride defined binding. Our interpretation of these findings, in the light of the histology of the lesions, is that the predominant effect of removing thalamic input to the caudate-putamen is an increase in the number of D2 receptors, but without any change of affinity. A small component of the change in Bmax defined with (+)-butaclamol found with radiofrequency lesions may be due to a response at non-dopamine sites (possibly a 5-hydroxytryptamine receptor subtype) following damage to other caudate-putamen afferents which pass near the habenula or fasciculus retroflexus. Following unilateral ibotenic acid lesions of the thalamus, the number of high affinity uptake sites for dopamine was increased at long survival times.(ABSTRACT TRUNCATED AT 400 WORDS)

Retinal neurotransmission.

The mammalian retina is classically divided into ten layers which contain the neuronal elements identified as photoreceptors, horizontal cells, bipolar cells, amacrine cells and ganglion cells. Using various neuroscientific techniques possible neurotransmitter substances have been assigned to each of these cell types. Thus the localization of transmitter synthesizing enzymes and storage vesicles, the demonstration of release of transmitter in response to specific stimuli, the observation of post-synaptic events mimicked or blocked by the iontophoretic application of exogenous transmitter/agonist or antagonist drug respectively, and the identification of efficient transmitter inactivation mechanisms synaptically add evidence for the association of certain proposed transmitter substances with specific neuronal elements. The evidence for the proposal that the excitatory amino acids glutamate and aspartate are transmitters of photoreceptors, that gamma-aminobutyric acid (GABA) is the inhibitory transmitter of horizontal and amacrine cells, that acetylcholine is associated with the functioning of bipolar cells, and that taurine, glycine and dopamine may all also play neurotransmitter or neuromodulatory roles at amacrine cell synapses is discussed.

Evidence that thalamic efferent neurones are non-cholinergic: a study in the rat with special reference to the thalamostriatal pathway.

Controversy surrounds the question as to whether some fibres of the thalamostriatal projection, are cholinergic. The present experiments show that lesions of the parafascicular-intralaminar thalamus produced no reductions in choline acetyltransferase (ChAT) activities in any area of microdissected rat caudate-putamen complex or dorsolateral frontal cortex. We conclude that thalamostriatal projections are entirely non-cholinergic. Furthermore, lesions of the mediodorsal or periventricular thalamus resulted in no change in ChAT activities in their terminal projection areas (medio-/orbitofrontal cortices and nucleus accumbens, respectively). The probability that all thalamic outputs are non-cholinergic is discussed.

Tyramine-induced noradrenaline release from rat brain slices: prevention by (-)-deprenyl.

Clorgyline (1 and 10 microM) and (+)-deprenyl (10 microM) both significantly potentiated the tyramine (100 microM)-induced release of [3H]-noradrenaline from rat cerebral cortex slices. (-)-Deprenyl (50 microM) significantly reduced it, while lower concentrations had no effect on noradrenaline release. However, in combination, 1 microM (-)-deprenyl blocked the release-facilitating action of 1 microM clorgyline, and 10 microM (-)-deprenyl that of 10 microM (+)-deprenyl. Low concentrations of (+)- and (-)-deprenyl (1 and 10 microM), both selectively inhibited phenylethylamine oxidation by monoamine oxidase B. Higher concentrations of (-)-deprenyl (20 and 50 microM) also inhibited 5-hydroxytryptamine oxidation by monoamine oxidase A. Clorgyline (1 and 10 microM) inhibited both enzymes. Thus, the effects of these drugs on noradrenaline-release cannot be explained solely in terms of irreversible inhibition of monoamine oxidase A and B, and other possible mechanisms are discussed. If the brain-slice model faithfully mirrors the sequence of events manifesting peripherally as the tyramine hypertensive response ('cheese effect'), then it is possible that low doses of (-)-deprenyl, administered with antidepressant monoamine oxidase inhibitors, can prevent this adverse reaction.

Studies on the interaction between cerebral 5-hydroxytryptamine and gamma-aminobutyric acid in the mode of action of diazepam in the rat.

The effect of the benzodiazepine, diazepam, administered for 7 days in doses between 1.25 and 5 mg kg-1 was studied on the turnover of 5-hydroxytryptamine (5-HT) in rat cerebral cortex. 5-HT turnover was assessed by calculating the ratio of the concentration of the major metabolite 5-hydroxyindoleacetic acid (5-HIAA) to that of 5-HT (i.e., 5-HIAA:5-HT). Diazepam (2.5 and 5 mg kg-1 i.p. daily for 7 days) significantly reduced cerebral cortical 5-HT turnover. The effect of manipulating cerebral gamma-aminobutyric acid (GABA) mechanisms on this action of diazepam was studied. Treatment of animals with a subconvulsive dose of picrotoxin (3 mg kg-1 i.p.) reversed the fall in cortical 5-HT turnover seen following diazepam. In contrast, however, treatment with the GABA transaminase inhibitors, amino-oxyacetic acid (25 mg kg-1) or ethanolamine-O-sulphate (250 mg kg-1, 7 days) which elevated cerebral GABA concentrations, enhanced the reduction in cortical 5-HT turnover following diazepam. Focal injection of picrotoxin (0.1 micrograms) into the region of the dorsal raphé nucleus reversed the decrease in cortical 5-HT turnover caused by diazepam. The hypothesis that doses of diazepam which result in total plasma concentrations comparable to those observed in man produce a reduction in 5-HT turnover mediated via GABA neurones is discussed.

Interactions of dopamine and the release of [3H]-taurine and [3H]-glycine from the isolated retina of the rat.

1 The dose-related, calcium-dependent, potassium-stimulated release of preloaded [(3)H]-dopamine from the superfused rat retina has been demonstrated.2 A high-affinity uptake system for dopamine exists in rat retina in vitro; K(m) value was calculated as 1.89 muM, V(max) value as 1.4 nmol g(-1) tissue h(-1).3 Dopamine (0.8 and 4 mM) inhibited the spontaneous release of [(3)H]-glycine from retina, and in the case of 0.8 mM dopamine this inhibitory effect was antagonized by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.4 The potassium-evoked (25 mM) release of [(3)H]-glycine from rat retina was similarly inhibited by dopamine (0.4-4 mM) in a dose-related manner when added to the superfusate with the potassium. The effect of 0.8 mM dopamine was antagonized by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.5 Dopamine (4 mM) significantly reduced the spontaneous release of [(3)H]-taurine from rat retina.6 The potassium-stimulated (25 mM) release of [(3)H]-taurine occurred after the cessation of the depolarizing stimulus. This delayed release of [(3)H]-taurine was unaffected if dopamine was applied to the superfusate at the same time as the potassium, but it was significantly reduced if dopamine (0.8 and 4 mM) was applied after the depolarizing stimulus had been removed and during the actual amino acid release phase.7 The inhibition of K(+)-stimulated (25 mM) delayed release of [(3)H]-taurine by applying dopamine (0.8 mM) after the depolarizing stimulus was blocked by 10 muM (+)-butaclamol but not by 10 muM (-)-butaclamol.8 The results are discussed with respect to the possible neurotransmitter role for dopamine within the rat retina, and its possible interaction with glycine and taurine.

An investigation into the interaction between ethanol at low doses and the benzodiazepines nitrazepam and temazepam on psychomotor performance in normal subjects.

Ten healthy male volunteers received, in randomized order, temazepam 20 mg, nitrazepam 5 mg or placebo in combination with ethanol 0.1, 0.2 or 0.4 g/kg. Psychomotor tests were performed at regular intervals over 8 h. Ethanol alone at 0.4 g/kg significantly showed simple reaction time for between 30 and 60 min, whereas nitrazepam (5 mg) or temazepam (20 mg) plus the placebo alcohol dose (0.1 g/g) had no significant effect. The benzodiazepines and ethanol (0.2 and 0.4 g/kg) in combination showed no potentiation or prolongation of action. Both ethanol and the two benzodiazepines significantly reduced critical flicker detection in themselves and, in combination, had additive effects. Only nitrazepam and temazepam produced decreases in performance in the code substitution (DSST) test, and the time course of action of nitrazepam was markedly longer than that of temazepam. Ethanol alone had no detectable effect on immediate recall, prompted recall, learning, or word recognition tests. Both benzodiazepines reduced immediate and prompted recall and nitrazepam, in addition, reduced word recognition ability. It is concluded that the spectrum of CNS depressant actions of ethanol and the benzodiazepines are different and that there is no evidence of a potentiation or prolongation of their effects by concomitant administration of the doses used in the present study.

Differential actions of diazepam on the release of [3H]5-hydroxytryptamine from cortical and midbrain raphe slices in the rat.

The possible interaction of the benzodiazepine diazepam with synaptic mechanisms of the central neurotransmitter 5-hydroxytryptamine (5-HT) has been studied in the rat using the superfusion in vitro release technique. The effect of diazepam (1-100 microM) on the spontaneous and potassium-induced release of radioactivity from superfused slices preloaded with [3H]5-HT prepared from cerebral cortex (fronto-parietal) and midbrain raphe region was monitored and compared. The results demonstrate a differential action of diazepam on the release of cortical and raphe 5-HT. In cerebral cortex diazepam significantly reduces both spontaneous and potassium-evoked release of [3H]5-HT. Conversely in raphe slices diazepam significantly enhances both spontaneous and potassium-evoked release of [3H]5-HT. In both tissues the effect of diazepam on K+-stimulated neurotransmitter release was abolished in the presence of picrotoxin. The experiments suggest that the effects of benzodiazepines on 5-HT mechanisms may be manifested at least in part through gamma-aminobutyric acid receptors.

Potassium-stimulated release of radiolabelled taurine and glycine from the isolated rat retina.

The release of preloaded [3H]glycine and [3H]taurine in response to a depolarising stimulus (12.5-50 mM KCl) has been studied in the superfused rat retina. High external potassium concentration immediately increased the spontaneous efflux of [3H]glycine, the effect of 50 mM K+ apparently being abolished by omitting calcium from the superfusing medium. In contrast, although high potassium concentrations increased the spontaneous efflux of [3H]taurine from the superfused rat retina, this release was not evident until the depolarising stimulus was removed from the superfusing medium. The magnitude of this "late" release of [3H]taurine was dependent on external K+ concentrations, and appeared immediately after cessation of the stimulus irrespective of whether it was applied for 4, 8, or 12 min. Potassium (50 mM)-induced release of taurine appeared partially calcium-dependent, being significantly reduced (p less than 0.01) but not abolished by replacing calcium with 1 mM EDTA in the superfusate. High-affinity uptake systems for both [3H]glycine and [3H]taurine were demonstrated in the rat retina in vitro (Km values, 1.67 microM and 2.97 microM; Vmax values, 19.3 and 23.1 nmol/g wet weight tissue/h, respectively). The results are discussed with respect to the possible neurotransmitter roles of both amino acids in the rat retina.

Behavioural and biochemical changes following chronic administration of L-dopa to rats.

Rats were given powdered diet containing L-DOPA (together with the peripheral decarboxylase inhibitor carbidopa) for a period of 6 months. The estimated daily intake was in the range 20-30 mg/kg. Initially, at 1 week and 1 month, L-DOPA-fed rats exhibited enhanced spontaneous locomotor activity, but this fell to within the control range by 3 and 6 months, although (+)-amphetamine-induced hyperactivity was greater at 6 months in L-DOPA-treated animals than in control rats. Six months after receiving L-DOPA in their diet rats showed enhanced stereotypy scores to a series of dopamine agonists administered acutely including (+)-amphetamine, nomifensine, L-DOPA, apomorphine and piribedil compared with the control animals. In another behaviour test L-DOPA administration reduced the cataleptic potency of both fluphenazine and haloperidol was increased. Biochemically 6 months treatment of rats with L-DOPA was associated with significantly increased plasma concentrations of L-DOPA, enhanced striatal levels of L-DOPA, dopamine and dopamine metabolites, enhanced specific binding (as indicated by increased Bmax values) of [3H] spiroperidol, [3H] ADTN and [3H] 5-HT to striatal membranes, and increased basal and dopamine-stimulated striatal adenylate cyclase activity. The results are discussed in the light of changes of sensitivity of cerebral dopamine receptors, an increase in receptor numbers, and the tolerance to L-DOPA which often develop in the treatment of Parkinson's disease.

Lesions of the superior colliculus in the rat differentiate between nigrostriatal and mesolimbic dopamine systems.

Bilateral electrolytic lesions of the superior colliculus in rats increased spontaneous locomotor activity, enhanced amphetamine-induced hyperactivity and attenuated apomorphine-induced biting. These lesions were associated with an increased rate of turnover of dopamine in the nucleus accumbens, but not in the striatum. Similarly concentrations of the dopamine metabolites homovanillic acid and 3,4-dihydroxyphenylacetic acid were elevated in accumbens tissue but not in striatum in rats with bilateral collicular lesions. The results indicate that lesions of the superior colliculus cause differentiation between hyperactivity and stereotypy, and that this may be related to blockade of a nigrostriatal outflow, and relief of inhibition on mesolimbic systems.

Dopamine neurones of the ventral tegmentum project to both medial and lateral habenula. Some implications for habenular function.

Using the techniques of microdissection and microradiochemical assay for catecholamines, it has been shown that a specific subgroup of ventral tegmental area (VTA) dopamine neurones project to the medial sector of lateral habenula. In addition a new dopamine pathway, arising from midline VTA neurons, has been shown to project to the medial sector of medial habenular. These findings are discussed and some implications for habenular functions are stated.

Motor effects following application of putative excitatory amino acid antagonists to the region of the mesencephalic dopamine cell bodies in the rat.

The excitatory amino acid antagonists 2-amino-5-phosphonovalerate and gamma-D-glutamylglycine have been applied focally to the ventral tegmental area and both the pars compacta and pars reticulata of the substantia nigra of the rat. The injections were performed under halothane anaesthesia so that behavioural effects could be observed 5 min afterwards. Bilateral application of either antagonist to the ventral tegmental area and the pars compacta of the substantia nigra induced enhanced locomotor activity in an open field. This effect was blocked by pretreatment of the animals with a low dose of the dopamine receptor antagonist fluphenazine. Bilateral application of either antagonist to the pars reticulata of the substantia nigra produced sedation and a reduction in locomotor activity. Unilateral injection of either of the excitatory amino acid antagonists into the pars reticulata or pars compacta of the substantia nigra both resulted in contraversive circling behaviour. The effect of intranigral (both pars compacta and reticulata) 2-APV and gamma-DGG was accompanied by a significant increase in concentrations of both 3,4-dihydroxyphenylacetic acid (to 158-160% of control following injection into pars compacta, and 134-146% of control injected into pars reticulata) and homovanillic acid (to 161-166% of control following injection into pars compacta, and 186-210% of control injected into pars reticulata) in the ipsilateral striatum. Pretreatment of these animals with fluphenazine (0.3 mg/kg) antagonized this circling behaviour. These results indicate that antagonism of excitatory amino acid receptors in the region of the midbrain of the rat leads to specific behavioural effects which may in part be mediated through the ascending dopaminergic projections.

Increased central 5-hydroxytryptamine receptor mechanisms in rats after chronic neuroleptic treatment.

1 The behavioural responses of drugs known to act through central 5-hydroxytryptamine (5-HT) mechanisms have been investigated in rats receiving a neuroleptic (trifluoperazine) in their drinking water for 4 to 6 months.2 5-Hydroxytryptophan (5-HTP) induced 5-HT-dependent behaviours including head bobbing and lateral head weaving, reciprocal forepaw treading, tremor, backward walking, body writhing and ;wet-dog' shakes. In doses of 50 to 150 mg/kg, 5-HTP induced more intense behavioural effects in neuroleptic-treated rats than in the control animals.3 Similarly the putative 5-HT agonist, quipazine (1 to 20 mg/kg) and the 5-HT releasing drug, fenfluramine (5 to 20 mg/kg), both induced significantly greater motor responses in the chronically neuroleptic-treated rats.4 A 5-HT uptake inhibitor (femoxetine, 2.5 to 10 mg/kg) had little behavioural effect in either control or trifluoperazine-treated rats.5 Total specific high-affinity binding of radiolabelled 5-HT was significantly increased in crude membrane fractions prepared from the cortex, striatum and substantia nigra of neuroleptic-treated rats compared to control animals.6 High-affinity uptake of radiolabelled 5-HT into striatal slices was similar in experimental and control animals.7 Behavioural and biochemical data would indicate that postsynaptic 5-HT mechanisms are enhanced in rats treated chronically with trifluoperazine. Chronic neuroleptic therapy may thereby induce cerebral 5-HT receptor supersensitivity in addition to the well-documented cerebral dopamine receptor supersensitivity.