In-hospital management of elderly patients undergoing myocardial perfusion scintigraphy.

OBJECTIVE: To investigate the impact of myocardial perfusion scintigraphy results on the decision for invasive coronary angiography in elderly patients (≥75 years) with suspected coronary artery disease hospitalized in a single tertiary medical center. SUBJECTS AND METHODS: In the retrospective study, data of 276 (136 elderly) consecutive hospitalized patients referred to myocardial perfusion imaging were analyzed. The clinical characteristics, myocardial perfusion scintigraphy results, invasive coronary angiography and revascularization rates and in-hospital adverse events were identified by manually reviewing the patients' records. RESULTS: Ischemia was found in 40.2% of patients. There was no significant difference in the proportion of ischemia between elderly and younger patients (38.2% vs. 42.1%, P=0.508). Invasive coronary angiography was performed in 64.0% of patients with ischemia and in 6.8% of patients with normal myocardial perfusion imaging (P<0.001). The referral rate for invasive coronary angiography was not different between elderly and younger patients with ischemia (63.5% vs. 64.4%, P=0.848). Ischemia on myocardial perfusion imaging was the most predictive variable for a referral to invasive coronary angiography (odds ratio 31.8, 95% confidence interval 14.6-69.5, P<0.001). There was no significant difference between the younger and elderly patients in revascularization rate and adverse events until discharge (39% vs. 40%, P=0.99 and 7.1% vs. 8.8%, P=0.6, respectively). CONCLUSION: Ischemia on myocardial perfusion scintigraphy is a powerful predictor for in-hospital invasive coronary angiography independent of the patient's age. Elderly patients with ischemia received invasive coronary angiography equally as their younger counterparts and have similar rates of adverse events until discharge.

Differential effects of dopamine D-1 and D-2 receptor antagonist antipsychotics on sleep-wake patterns in the rat.

A series of antipsychotics having different selectivity for dopamine (DA) D-1 and D-2 receptors were studied for their effects on sleep stages in the rat. Electroencephalographic activity was recorded and classified according to the stages of wakefulness, rapid eye movement (REM) sleep and non-REM sleep. Total sleep duration, non-REM and REM latencies, number and duration of REM episodes were calculated. The DA D-1 antagonists, SCH 23390 (0.001-0.1 mg/kg s.c.), SCH 39166 (0.01-0.3 mg/kg s.c.) and NNC-756 (0.003-0.1 mg/kg s.c.), enhanced markedly the time spent in sleep through a significant increase of both non-REM and REM. Enhancement of REM was due to an increase in the number of episodes. The selective DA D-2 antagonists, raclopride (0.03-1 mg/kg s.c.) and remoxipride (1-10 mg/kg s.c.), did not affect sleep stages. Haloperidol (0.1-3 mg/kg p.o.) increased the duration of total sleep through an increase of non-REM, leaving REM unmodified. The nonselective DA antagonists, chlorpromazine (0.3-3 mg/kg s.c.) and clozapine (0.3-3 mg/kg s.c.) produced either no effect or slightly increased non-REM, respectively. Both drugs reduced REM duration by lowering the number and duration of episodes. The data show that there are differences between DA D-1 and D-2 antagonists with regard to their effects on sleep and wakefulness. Concomitant enhancement of both total sleep and REM appears to be a peculiar feature which clearly distinguishes DA D-1 antagonists from the other DA receptor blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

The dopamine D1 receptor agonists, A68930 and SKF 38393, induce arousal and suppress REM sleep in the rat.

The effects of the dopamine D1 receptor full agonist, A68930, on sleep-wake patterns and grooming behaviour were studied in the rat. The partial dopamine D1 receptor agonist, SKF 38393, was used for comparison. A68930 (0.003-0.3 mg/kg s.c.) increased waking time, reduced the amount of rapid eye movement (REM) sleep and enhanced spontaneous grooming dose dependently. The ED50 were 0.06, 0.02 and 0.05 mg/kg, respectively. The D1 antagonist, SCH 23390 (0.003 mg/kg s.c.), blocked the effects of A68930 on wakefulness and grooming but not those on REM sleep. SKF 38393 (0.1-10 mg/kg s.c.) increased grooming with an ED50 of 1.4 mg/kg and a dose-response relationship similar to that of A68930 (potency ratio 28). Conversely, the increase of wakefulness and reduction of REM sleep caused by SKF 38393 had dose-response curves different from those of A68930. The results support the view that D1 receptors may have a physiological function in producing arousal.

Effects of remoxipride, a dopamine D-2 antagonist antipsychotic, on sleep-waking patterns and EEG activity in rats and rabbits.

The antipsychotic remoxipride, a selective dopamine D-2 receptor antagonist, was studied for its effects on sleep-waking patterns in the rat and electroencephalographic (EEG) activity in the rabbit. Haloperidol, which has lesser selectivity for D-2 receptors, was used for comparison. In the rat, remoxipride (1-10 mg/kg SC) did not affect either total sleep or non-rapid eye movement (non-REM) sleep. Only REM was slightly reduced by the high dose of 10 mg/kg. Haloperidol (0.1-1 mg/kg PO) enhanced duration of both total sleep and non-REM sleep. In the rabbit, remoxipride (3 and 10 mg/kg IV) induced no significant changes of the EEG power spectrum over 0.1-38.5 Hz or individual frequency bands. In both cortex and hippocampus the drug did not alter the arousal response to acoustic sensory stimuli. Plasma concentration of remoxipride 10 mg/kg IV in rabbits declined biexponentially and was 4 and 2 mumol/l at 30 min and 1 h, respectively. Haloperidol (0.3 and 1 mg/kg) slowed down the EEG activity, enhanced the power spectrum of the cortical and hippocampal activity, and significantly reduced the duration of arousal induced by sensory stimuli. The results indicate that, unlike haloperidol, remoxipride has weak or no sedative effects. The data also provide support to the notion that D-2 receptors are not involved in the regulation of states of sleep and sedation.

Modulation of sleep and waking states by D-1 receptors.

This review describes pharmacological studies showing that the dopamine D-1 receptor subtype is involved in the modulation of states of sleep and wakefulness. Stimulation of D-1 receptors by SKF 38393 produces electro encephalographic (EEG) arousal, enhances duration of wakefulness and markedly reduces the stage of rapid eye movement sleep (REM). Importantly, all these effects occur in the absence of the most typical dopamine- mediated behaviours such as stereotyped movements or hyperactivity. On the contrary, studies with the selective D-1 receptor antagonists, especially with the drug SCH 23390, have shown that these compounds increase duration of total sleep including both components, non-REM and REM. Likewise, they produce sedation in different animal species. An important distinguishing feature of the action of D-1 antagonists, compared with non-selective or D-2-selective antagonists, is their ability to enhance the amount of REM. The effect appears to be specifically mediated by D-1 receptors, whereas the interaction of SCH 23390 or its derivatives with the serotonin receptor subtype 5-HT(2) may contribute to an increase of total sleep, but does not seem to influence REM changes. The overall findings indicate that D-1 receptors are involved in mediating the sedation-arousal continuum and the states of sleep-wakefulness. The REM-enhancing action of D-1 antagonists appears to be a unique response, which, considering that sleep disorder is a prominent feature in psychiatric illness, may have clinical relevance. The involvement of D-1 receptors in the modulation of REM stimulates further research aimed at gaining insights into both the complex process of sleep and the function of the D-1 receptor within the central nervous system.

An in vitro study on the hippocampal electrophysiological properties of enkephalinase inhibitors in rats.

The effects of two enkephalinase inhibitors were studied on the CA1 and dentate hippocampal extracellular field potentials (FPs). The enkephalinase inhibitors thiorphan and SCH 32615, at a concentration of 1-500 microM, failed to significantly affect CA1 and dentate FPs. Thiorphan and SCH 32615, at a concentration of 150 microM, were able to potentiate the enkephalin-induced epileptiform bursting, inducing an increase in the bursting duration and in the number of spikes per burst due to 3.5 microM DAEAM or 0.20 microM DAGO. The results suggest: 1) the potentiation of an electrophysiological opiate receptor-mediated response by enkephalinase inhibitors; 2) the inability to show a direct effect on the basal CA1FP as a result of the inhibition of the endogenous enkephalinase.

The neutral endopeptidase-24.11 (enkephalinase) inhibitor, SCH 32615, increases dopamine metabolism in the nucleus accumbens of the rat.

SCH 32615 is a novel inhibitor of the enzyme, neutral endopeptidase (NEP, E.C. 3.4.24.11), the so called 'enkephalinase', which plays a functional role in the degradation of [Met5]- and [Leu5]enkephalin. The present study was designed to assess whether SCH 32615 is able to modify the activity of dopaminergic neurons as reflected by changes in the content of the major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), in three different areas of the rat brain: the nucleus accumbens, the striatum, and the prefrontal cortex. When administered at analgesically active doses (1-100 mg/kg s.c., 60 min before killing), SCH 32615 induced a dose-dependent increase in dopamine metabolism in the nucleus accumbens but was ineffective in the striatum and in the prefrontal cortex. This effect appears to be mediated via opioid receptors, since it was completely prevented by naloxone (5 mg/kg s.c.). The increase in DOPAC content in the prefrontal cortex elicited by foot-shock was unaffected by pretreatment with SCH 32615. In the nucleus accumbens, dopamine metabolism was increased to the same extent by foot-shock and SCH 32615 administered separately, but these effects were not additive, suggesting that SCH 32615 and foot-shock act via a common mechanism. Taken together, these results support the hypothesis that inhibition of the in vivo degradation of enkephalins induced by the systemic administration of SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.

Effects of selected beta-adrenergic blocking agents on sleep stages in spontaneously hypertensive rats.

The effects on sleep of six beta-adrenergic blockers (propranolol, dilevalol, pindolol, metoprolol, celiprolol and atenolol) which differ in their pharmacological characteristics were studied in spontaneously hypertensive rats. Electroencephalographic activity was recorded for 6 hr after p.o. administration of drugs or vehicle, and the stages of wakefulness, rapid eye movements (REM) sleep and non-REM sleep (non-REM) were classified thereafter. In separate experiments antihypertensive activity of each drug was assessed by the tail-cuff technique. The most common effect of the beta-blockers examined was a decrease of the duration of REM. The effect was marked for propranolol (10-100 mg/kg), celiprolol (10-100 mg/kg) and pindolol (1-10 mg/kg), whereas it occurred at low doses, but not at high doses for metoprolol (10 mg/kg) and atenolol (3 and 10 mg/kg). Dilevalol induced a moderate REM decrease at 30 mg/kg only. For the beta-1 antagonists, the dose reducing REM substantially (ED30) was slightly above (1.4- to 3.7-fold) that effective on blood pressure (ED10), whereas the separation was high for pindolol (17.4-fold) and dilevalol (22.4-fold). Conversely, propranolol displayed a weak antihypertensive activity in this model and was more potent on REM than in reducing blood pressure. Propranolol, celiprolol and atenolol also increased duration of wakefulness. Considering the pharmacological characteristics of the beta-blockers examined, it is suggested that selective beta-1 antagonism and interaction with other neurotransmitters, such as serotonin, are relevant to the potential effects of this class of antihypertensive drugs on sleep function.(ABSTRACT TRUNCATED AT 250 WORDS)

The dopamine D1 receptor is involved in the regulation of REM sleep in the rat.

The dopamine D1 receptor agonist, SKF 38393, and the D1 antagonist, SCH 23390, were studied for their effects on sleep in the rat. Over 6 h, SKF 38393 (0.1-10 mg/kg s.c.) dose dependently reduced the amount of rapid eye movement (REM) sleep and enhanced the duration of wakefulness. The drug affected REM at low doses (ED50 = 0.4 mg/kg) at which wakefulness was unchanged and the characteristic grooming behavior was not apparent. REM changes were characterized by a decrease in the number of episodes with no alteration of latency to the first episode. Over a very low dose range (0.003-0.3 mg/kg s.c.), SCH 23390 enhanced the amount of REM by increasing both number and average duration of episodes. There was also a moderate increase of non-REM sleep but the percent change was less marked than that occurring for REM. Given at 0.003 mg/kg, SCH 23390 prevented the REM changes induced by SKF 38393 (0.3-3 mg/kg). It is suggested that D1 receptors are involved in the regulation of the REM sleep process.

The neutral endopeptidase-24.11 inhibitor SCH 34826 does not change opioid binding but reduces D1 dopamine receptors in rat brain.

The effect of repeated administration of the neutral endopeptidase-24.11 (NEP) inhibitor SCH 34826 on the kinetic properties of opioid and dopamine binding in the rat cerebral cortex and striatum was investigated. SCH 34826, given at 100 and 300 mg/kg orally twice a day for 14 days, did not alter either Bmax or Kd for the mu, delta, or kappa opioid receptor type in the cortex, as measured by studying binding parameters for the mu-selective ligand [3H][D-Ala2, Me-Phe4,Gly(ol)5]enkephalin (DAGO), the delta-selective ligand [3H][D-Pen2,D-Pen5]enkephalin (DPDPE) and the kappa ligand [3H]ethylketazocine (EKC). SCH 34826 reduced significantly the number of D1 dopamine receptors labeled with [3H]SCH 23390 in the striatum (Bmax was 90 and 84% of controls at 100 and 300 mg/kg, respectively). The number of D2 receptors, measured by [3H]spiperone binding was unaltered. The Kd values for both receptor types were not affected. The data demonstrate that chronic inhibition of enkephalin degradation by SCH 34826 does not alter opioid receptors, whereas it reduces the number of D1 receptors. These findings provide further support for the role of opioids in modulating central dopaminergic systems. As a reduction in the number of D1 receptors is an effect common to antidepressant treatments, the antidepressant potential of NEP inhibitors should be investigated.

An in vitro study on the hippocampal epileptogenic properties of enkephalins and enkephalinase inhibitors in rats.

1. The effects of enkephalins and enkephalinase inhibitors were studied in CA1 area in rat hippocampal slices. 2. The data demonstrate a prevalent involvement of mu opiate receptors in the epileptogenic properties of enkephalins. 3. A potentiation of the mu opiate receptor-mediated epileptogenic response by enkephalinase inhibitors has been shown. 4. The results also show an inability to affect basal CA1 field potentials by inhibition of endogenous endopeptidase.

The D1 dopamine receptor antagonist SCH 23390 enhances REM sleep in the rat.

The effect of the D1 dopamine receptor antagonist SCH 23390 on sleep patterns was studied in rats by means of the electroencephalographic (EEG) technique. Haloperidol, an established D2 antagonist neuroleptic, was used for comparison. Over a very small dose range (0.003-0.03 mg/kg, subcutaneously), SCH 23390 significantly increased the time spent in total sleep, including rapid eye movement (REM) and non-REM sleep. The magnitude of the overall change of REM sleep was considerably greater than that of non-REM sleep. Enhancement of the amount of REM was characterized by increase in number of episodes but no change of latency to the first period of REM. Haloperidol increased non-REM sleep at 0.3-3 mg/kg, orally, but did not affect other measures of REM. Considering the small dose range at which SCH 23390 was effective, and the fact that REM and non-REM sleep may be unrelated events, it is suggested that promotion of REM sleep is a specific effect induced by selective blockade of D1 receptors.

Effects of the enkephalinase inhibitor SCH 34826 on the sleep-waking cycle and EEG activity in the rat.

The sedative effect of SCH 34826, an enkephalinase inhibitor, was evaluated by studying electroencephalographic (EEG) activity, behaviour and the sleep-waking cycle in the rat. The reference opioid, morphine, was used for comparison. After administration of morphine (10 mg/kg s.c.) the rats were motionless and stuporous at first and then hyperactive. An increase of slow wave sleep, at the expense of both wakefulness and REM sleep was recorded, with high-amplitude slow wave bursts appearing in the EEG tracings during the waking, albeit stuporous, phase. Relative spectral power in the 1-4 and 12-16 Hz bands was increased and there was a shift of the dominant frequency to a lower frequency. The specific opioid antagonist, naltrexone, readily reversed most of these effects. The drug SCH 34826 (10-100 mg/kg p.o.) had no effect on the parameters examined; large doses (300 and 1000 mg/kg p.o.) induced restlessness in some animals, resulting in increased waking. This effect was antagonized by naltrexone. The data indicate that SCH 34826, at doses far greater than those proposed for clinical use, is devoid of sedative liability and does not induce any of the behavioural or EEG effects typical of morphine.

Effects of nonsedating histamine H1-antagonists on EEG activity and behavior in the cat.

The central effects of the newly-developed antihistamines (H1-receptor antagonists) loratadine, astemizole, mequitazine and terfenadine were evaluated by studying brain electrical activity (EEG), sleep-waking patterns and behavior in the cat. The different stages of the sleep-waking cycle, i.e., wakefulness (W), spindle sleep (SS), slow wave sleep (SWS) and REM sleep (REM) were evaluated. The power spectrum analysis of the EEG was obtained by a computerized technique. For comparison, the sedating agent diphenhydramine was examined. Given at 3 mg/kg orally, a dose slightly above that effective therapeutically, diphenhydramine markedly affected behavior and all sleep stages. In particular, it depressed REM and increased SS (drowsiness). The EEG showed occasional spikes typical of subconvulsive states. Loratadine did not modify either sleep patterns or behavior over the 3-30 mg/kg dose range orally, which is far above that used clinically. The EEG, evaluated either visually or by spectral power analysis, was unaffected. Astemizole at 10 and 30 mg/kg PO reduced REM, markedly altered behavior at 30 mg/kg, but did not modify EEG activity. Mequitazine, at low doses (1-10 mg/kg PO), enhanced SS and decreased SWS and REM. Like diphenhydramine, mequitazine induced EEG changes typical of subconvulsive states and affected EEG power over the frequency range of 0.1-15.0 Hz. Terfenadine did not change sleep patterns and slightly affected behavior only at the high dose of 30 mg/kg orally; EEG activity was not influenced. These data show that: a) diphenhydramine and mequitazine appear to produce CNS effects by altering basic processes within the brain; b) astemizole and terfenadine seem to cross the blood-brain barrier at high doses only; c) loratadine has the lowest liability to produce central side effects. Of the sleep features examined, REM appeared to be the most sensitive stage to blockade of central H1-receptor pathways.