Biomedical subjects

M Radulovacki

Publications and source records attributed to M Radulovacki.

At least 19 recordsLinked to original sources

PubMed1996

Effect of REM sleep deprivation on sleep apneas in rats.

We studied the effects of 48 h of REM sleep deprivation on spontaneous and post-sigh central apneas in Sprague-Dawley rates by simultaneously monitoring sleep by the EEG and respiration for 6 h. During the recovery sleep following REM deprivation a decrease in post-sigh apneas occurred in total sleep. There was no change in spontaneous apneas. The results suggest the existence of partially distinct mechanisms for the two types of apneas.

Animals↗

PubMed1996

p-SPA, a peripheral adenosine A1 analogue, reduces sleep apneas in rats.

The actions of N6-p-sulfophenyladenosine (p-SPA), a novel peripherally selective adenosine A1 agonist, were assessed on spontaneous and postsigh central sleep apneas in freely moving, unanesthetized rats by simultaneously monitoring sleep and respiration. Intraperitoneal administration of 0.1, 0.3, and 1.0 mg/kg of the drug significantly decreased postsigh and spontaneous sleep apnea index (AI). This effect persisted throughout the 6-h recording period. Doses of 0.1 and 0.3 mg/kg did not affect sleep efficiency, whereas 1.0 mg/kg of p-SPA reduced it to 60% of baseline value.

Adenosine↗

PubMed1996

Hydralazine reduces elevated sleep apnea index in spontaneously hypertensive (SHR) rats to equivalence with normotensive Wistar-Kyoto rats.

The effects of lowering blood pressure (BP) by hydralazine (HY) (2 mg/kg) on spontaneous (SA) and post-sigh (PSA) sleep apneas have been studied in spontaneously hypertensive (SHR) rats by monitoring their respiration and sleep by the EEG for 6 hours. Normotensive Wistar-Kyoto (WKY) rats, from which the SHR rat strain was derived, were used as an appropriate control. The SHR rats had more SA (p < 0.02) and PSA (p < 0.0001) apneas/hour than WKY rats during nonrapid eye movement sleep and their mean BP was higher by 40 mm Hg (p < 0.0001) than WKY rats. Administration of HY to SHR rats equalized their BP with the arterial pressure of WKY rats and reduced the SA and the PSA apneas/hour to equivalence with WKY normotensive rats. These results demonstrate that even in the context of lifelong hypertension, acute normalization of BP significantly reduces sleep apneas in rats. They further suggest that improved management of BP may be clinical benefit to patients with apnea who have long-standing hypertension.

Animals↗

PubMed1996

Effects of inspired gas on sleep-related apnea in the rat.

Central apneas have been reported to occur in the rat during all stages of sleep. Two types of apnea have been described: spontaneous and postsigh, which are immediately preceded by an augmented breath. We studied the effect of inspired gas on the number and type of apneas in nine adult male Sprague-Dawley rats that were surgically prepared with cortical electroencephalogram and nuchal electromyogram electrodes. In addition to the electroencephalogram and electromyogram, we recorded respiration by the barometric method by using a single-chamber plethysmograph. Each rat was recorded from 1000 until 1600 on 4 separate days by using different inspired gases: room air, 100% O2, 15% O2, and 5% CO2. We found that the sleep-related apnea index was significantly higher during 100% O2 compared with room air (P < 0.05) and was significantly lower during 15% O2 and 5% CO2 compared with room air (P < 0.05). Postsigh apneas occurred more frequently than did spontaneous apneas (P < 0.0001). The coupling between sighs and apneas was strengthened by hyperoxia and weakened by hypoxia and hypercapnia (P < 0.05 for each). We conclude that stimulation of chemoreceptors acts to oppose apnea in the rat.

Animals↗

PubMed1995

Adenosine analogues modulate the incidence of sleep apneas in rats.

The effects of adenosine A1 and A2 agonists on spontaneous central sleep apneas in rats have been examined by simultaneously monitoring sleep and respiration in freely moving unanesthetized animals. Intraperitoneal administration of 1.0 mg/kg of the A1 receptor agonist R(-)N6-L-(2-phenyl-isopropyl)adenosine (L-PIA) and 150 and 300 micrograms/kg of 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido-adenosine hydrochloride (CGS 21680), a selective A2 agonist, decreased the apnea index (AI) during sleep. Within a sleep period, AI increased over time in both control and drug-treated animals. For both agonists, doses effective in reducing AI also significantly reduced sleep efficiency.

Adenosine↗

PubMed1991

The effect of soluflazine on adenosine receptors in the rat brain.

Soluflazine, a potent adenosine transport inhibitor, was intracerebroventricularly administered to rats via ALZET mini osmotic pumps (4nmole, 0.5 L/hr) for 14 days and the effect on adenosine receptors was determined in specific brain areas. Soluflazine decreased adenosine A1 radioligand binding in the hippocampus as measured by [3H]R-PIA, and lowered adenosine A2 binding sites in the striatum, as estimated by the "NECA minus R-PIA" assay. Previous work from our lab has shown the ability of diazepam and triazolam to decrease adenosine binding in the same brain areas. The data show that a specific adenosine transport inhibitor produces the same effect on adenosine receptors as benzodiazepines, and suggest a role for adenosine in the CNS effects of benzodiazepines.

Adenosine↗

PubMed1991

The effect of soluflazine on sleep in rats.

Soluflazine, a specific adenosine transport inhibitor, was intracerebroventricularly administered to rats in a dose range of 10, 25, and 50 nmoles. At a dose of 50 nmoles, soluflazine decreased waking and increased sleep during the first hour of EEG recording. Our previous work has shown that chronic intracerebroventricular administration of soluflazine to rats decreased radioligand binding to adenosine A1 and A2 receptors in specific brain regions. The present data show that administration of an adenosine transport inhibitor to rats produces a transient hypnotic effect presumably through increases in synaptic adenosine levels.

Animals↗

PubMed1991

Role of adenosine in sleep and temperature regulation in the preoptic area of rats.

We have examined the effects on sleep and brain temperature of bilateral microinjections of adenosine and adenosine analogs to the preoptic area (PO) of rats. Administration of adenosine (12.5 nmoles), a nonselective adenosine A1/A2 receptor agonist NECA (N-ethyl-carboxamido-adenosine, 1.0 nmole), and the selective adenosine A1 receptor agonist CPA (cyclopentyladenosine, 0.25, 0.5 nmoles) increased total sleep primarily through an enhancement in deep slow-wave sleep (SWS2), while adenosine also increased REM sleep. Administration of 12.5 nmoles adenosine and 0.25 nmoles CPA did not affect brain temperature, while 1.0 nmole NECA and 0.5 nmoles CPA caused a transient and prolonged hypothermia, respectively. Administration of the selective adenosine A2 receptor agonist CV-1808 (2-phenylaminoadenosine, 5, 10 nmoles) had no effect on sleep or brain temperature. The present results demonstrate a site for the central hypnotic action of adenosine, and a functional role for adenosine A1 receptors in the hypothalamus.

Adenosine↗

PubMed1991

Radioligand binding to adenosine receptors and adenosine uptake sites in different brain regions of normal and narcoleptic dogs.

The present study compares the characteristics of radioligand binding to adenosine receptors and adenosine uptake sites in 100- and 50-day-old normal and narcoleptic dogs. Binding to A1 receptors was quantified using a selective A1 agonist ([3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, [3H]R-PIA) and an antagonist ([3H]dipropyl-8-cyclopentyl-xanthine, [3H]CPX). Differences in the binding of [3H]R-PIA and that of [3H]5'-ethylcarboxamide adenosine ([3H]NECA), which binds to both A1 and A2 receptors with similar affinities, were used to quantify A2 receptors. Nucleoside transport sites were labeled with [3H]nitrobenzylthioinosine ([3H]NBTI), a potent inhibitor of nucleoside transport systems. The present study offered no evidence that either adenosine A1 receptors and adenosine uptake sites in the frontal cortex or adenosine A2 receptors in the putamen were altered in narcoleptic dogs. However, we found that adenosine A1 receptors in the dog exist in different affinity states and that the affinity state in which the receptor is found depends on the brain region examined. A characterization of these low- and high-affinity sites was performed and results indicated that these sites cannot be explained by a single interaction of the A1 receptor with a single G-protein population.

Adenosine↗

PubMed1991

Chronic Ro 15-1788 treatment increases REM sleep in rats.

Administration of Ro 15-1788, a benzodiazepine antagonist (3.6 mg/kg/day in drinking water for 14 days), increased total sleep and rapid eye movement (REM) sleep in rats. Standard six-hour EEG recording periods were obtained on day 0, 1, 3, 7, 10, 14, as well as 24 and 72 hours following withdrawal. Enhanced REM sleep reached significance on day 7 of continuous drug treatment and remained significantly increased on day 10 and 14, as well as at 24 and 72 hours following drug withdrawal. The present data show that chronic administration of Ro 15-1788 increases total sleep time due to increases in REM sleep. The actions of Ro 15-1788 presumably occur through either adenosinergic or cholinergic mechanisms.

Analysis of Variance↗

PubMed1990

A comparison of the effects of caffeine, 8-cyclopentyltheophylline, and alloxazine on sleep in rats. Possible roles of central nervous system adenosine receptors.

The dose-response effects of administration of 8-cyclopentyltheophylline (CPT) (10, 20, and 40 mg/kg intraperitoneally [IP]) and alloxazine (ALX) (12.5, 25, and 50 mg/kg, IP) on sleep and wakefulness in rats were examined and compared to those of caffeine (12.5 mg/kg IP). Both CPT and ALX injected individually produced sleep suppression qualitatively similar to that produced by caffeine, but of a lower magnitude. However, when 20 mg/kg CPT and 50 mg/kg ALX were injected together, their sleep suppressant effect was of the same magnitude as that of 12.5 mg/kg caffeine. These results support the hypothesized involvement of adenosine receptor blockade in the effects of caffeine on sleep in rats. They further suggest that A1 adenosine receptor blockade may be more important than A2 receptor blockade, since behavioral effects of the selective in vitro A1 antagonist CPT were generally similar to those of nonselective in vitro adenosine receptor antagonists caffeine and ALX.

Animals↗

PubMed1989

Effects of prolonged administration of triazolam on adenosine A1 and A2 receptors in the brain of rats.

Continuous subcutaneous administration of triazolam, a benzodiazepine with short plasma half-life, for 10 days either decreased (31%, 2 mg/day) or increased (15%, 0.5 mg/day) radioligand binding to adenosine A2 receptors in the rat striatum. In a similar manner, we have shown previously that diazepam (5-10 mg/day), a benzodiazepine with a long plasma half-life attenuated radioligand binding to adenosine A2 receptors in the rat striatum by 45-25%.

Animals↗

PubMed1988

Dose-response effects of 8-cyclopropyltheophylline on sleep and wakefulness in rats.

The dose-response effects of the substituted xanthine 8-cyclopropyltheophylline (CPRT) on sleep and wakefulness (W) after intraperitoneal administration to rats were examined by means of simultaneous electroencephalographic (EEG) and electromyographic (EMG) recordings. Doses of 20 and 40 mg/kg CPRT increased W and decreased slow wave sleep (SWS) in rats, indicating CNS stimulant effects. The greatest CNS stimulation was produced by the lowest (20 mg/kg) dose of CPRT examined, which also increased the latency to SWS. In addition, the 20 mg/kg dose of CPRT also significantly decreased the amount of total sleep (TS), as compared to the vehicle group, during all time periods examined. In contrast, the 80 mg/kg dose of CPRT decreased W and increased both SWS and TS. However, this apparent hypnotic effect of the 80 mg/kg CPRT may be due to toxicity, since 80% of rats treated with this dose of the drug died within 48 h of injection.

Animals↗

PubMed1988

Desensitization of adenosine A2 receptors in the striatum of the rat following chronic treatment with diazepam.

Following prolonged treatment (7 days) with diazepam (10 mg/kg/day, using ALZET mini-osmotic pumps) in rats, the function of adenosine receptors was assessed in specific structures of the brain, using both agonist ligand binding and adenylate cyclase assays. Binding to A1 receptors was quantified using [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine, a selective ligand at A1 receptors. Differences in the binding of this ligand and that of [3H]5'-N-ethylcarboxamide adenosine, which binds to both A1 and A2 subtypes of receptors with similar affinities, were used to quantify A2 receptors. Treatment with diazepam failed to alter the binding of [3H]N6-[(R)-1-methyl-2-phenylethyl] adenosine in all areas of the brain studied. However, the binding of A2 receptors and A2 receptor-mediated stimulation of adenylate-cyclase were significantly attenuated in striatal membranes from diazepam-treated rats. Thus, the present study indicated that functional adenosine A2 receptors were desensitized after prolonged treatment with diazepam, since decreased agonist binding to A2 receptors paralleled an attenuation in the stimulation by adenosine of the activity of adenylate cyclase, an effect mediated by the A2 receptor. These results further indicate that the changes in adenosine A2 receptors correlated with significant short-lasting alterations in the sleep-wake cycle during the withdrawal of diazepam. The alterations in sleep-wakefulness did not correlate with the effect of diazepam on benzodiazepine receptors since no changes were observed in the binding of benzodiazepine receptors.

Adenylyl Cyclases↗

PubMed1988

An inexpensive sleep-wake state analyzer for the rat.

Manual classification of sleep stages is a tedious and time consuming task. We describe an inexpensive system for sleep-wake state classification for as many as eight rats at a time. It is based on determining threshold values for each parameter of each rat, then finding the natural transitions from one sleep state to another and finally classifying these states utilizing the cortical EEG and EMG signals.

Animals↗

PubMed1988

Chronic administration of diazepam downregulates adenosine receptors in the rat brain.

Following chronic administration (10 or 20 days) of diazepam (5 mg/kg/day, subcutaneous pellets) or RO 15-1788 (5 mg/kg/day, intraperitoneally), adenosine and benzodiazepine receptors in different rat brain areas were assessed by radioligand binding studies using [3H]R-PIA for A1 receptors, [3H]NECA and [3H]R-PIA for A2 receptors and [3H]FNZ for benzodiazepine receptors. Chronic administration of diazepam for 10, but not for 20 days, decreased A2 receptors in the striatum by 46% (p less than 0.05) and A1 receptors in the hippocampus by 13% (p less than 0.05). Administration of diazepam for 10 days and 20 days failed to alter [3H]FNZ binding in all brain areas studied. However, 20 days of diazepam administration decreased the magnitude of GABA enhancement of [3H]FNZ binding in the cortex by 25% (p less than 0.05). In contrast, chronic administration of RO 15-1788 failed to alter [3H]R-PIA, [3H]NECA and [3H]FNZ binding in all brain areas. These results suggest that adenosine receptors may play a role in the CNS actions of benzodiazepines.

Animals↗

PubMed1988

Effects of chronic administration of caffeine on adenosine A1 and A2 receptors in rat brain.

Chronic administration of caffeine (75 mg/kg/day) to rats for 12 days increased [3H]R-PIA binding in the cerebral cortex and cerebellum and [3H]NECA binding to high affinity receptor sites in the striatum. The results indicate that both adenosine A1 and A2 receptor subtypes possess mechanisms of adaptation to chronic caffeine treatment. In addition, adenosine A1 receptor binding shows heterogenous neuroanatomical pattern indicating that the A1 response to caffeine treatment presents regional variation in the rat brain.

Adenosine↗

PubMed1988

Low-frequency oscillations of cortical oxidative metabolism in waking and sleep.

To study the changes in cortical oxidative metabolism and blood volume during behavioral state transitions, we employed reflectance spectrophotometry of the cortical cytochrome c oxidase (cyt aa3) redox state and blood volume in unanesthetized cats implanted with bilateral cortical windows and EEG electrodes. Continuous oscillations in the redox state and blood volume (approximately 9/min) were observed during waking and sleep. These primarily metabolic oscillations of relatively high amplitude were usually synchronous in homotopic cortical areas, and persisted during barbiturate-induced electrocortical silence. Their mean amplitude and frequency did not vary across different behavioral/EEG states, although the mean levels of cyt aa3 oxidation and blood volume during rapid eye movement (REM) sleep significantly exceeded those during waking and slow-wave sleep. These data suggest the existence of a spontaneously oscillating metabolic phenomenon in cortex that is not directly related to neuroelectric activity. A superimposed increase in cortical oxidative metabolism and blood volume occurs during REM sleep. Experimental data concerning cerebral metabolism and blood flow that are obtained by clinical methods that employ relatively long sample acquisition times should therefore be interpreted with caution.

Animals↗