Respiratory Rate Depression Research Articles

The use of etorphine/methotrimeprazine and midazolam as an anaesthetic technique in laboratory rats and mice.

The results of a preliminary evaluation of etorphine/methotrimeprazine ('Small Animal Immobilon') and midazolam in rats and mice are reported, and this regimen is compared to fentanyl/fluanisone/midazolam in mice. In rats, a surgical plane of anaesthesia with good muscle relaxation was produced, but blood gas analysis showed the presence of severe hypoxia, hypercapnia and acidosis. In mice etorphine/methotrimeprazine/midazolam and fentanyl/fluanisone/midazolam produced adequate anaesthesia, but blood gas analysis showed severe respiratory depression with both regimens. Since etorphine/methotrimeprazine/midazolam produced severe respiratory depression in rats and mice it is suggested that this regimen is used with caution. Administration of supplemental oxygen would seem advisable when using either etorphine/methotrimeprazine/midazolam or fentanyl/fluanisone/midazolam in rats and mice.

Pedunculopontine stimulation alters respiration and increases ACh release in the pontine reticular formation.

The present study examined the hypothesis that cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) can cause the release of acetylcholine (ACh) in the pontine reticular formation and contribute to respiratory depression. In vivo microdialysis of the gigantocellular tegmental field (FTG) was performed in 10 adult male cats while respiration was being measured. In four intact, unanesthetized cats these measurements were obtained during states of quiet wakefulness and during the rapid eye movement (REM) sleeplike state caused by FTG microinjections of carbachol. The results demonstrate a simultaneous time course of enhanced ACh release in the FTG and respiratory rate depression. In six barbiturate-anesthetized cats similar measurements were obtained while PPT regions containing NADPH-positive neurons were electrically stimulated. PPT stimulation caused increased ACh release in the FTG and caused respiratory rate depression. Together, these findings are consistent with the hypothesis of a causal relationship between ACh release in the FTG and respiratory depression.

Effect of substance P on respiratory rhythm and pre-inspiratory neurons in the ventrolateral structure of rostral medulla oblongata: an in vitro study

The pre-inspiratory (Pre-I) neurons which fire in the pre- and usually also during the post-inspiratory phase are located in the ventrolateral structures of the rostral medulla. They are suggested as primary rhythm generating neurons for respiration. These have been studied in isolated brainstem-spinal cord preparations from newborn 0–5-day-old rats. We have found that application of substance P (SP) enhanced the respiratory rhythm as measured by C 4 ventral root and pre-I neuronal activities. Furthermore, the effect of SP was dependent on basal respiratory rate. An increase of the Pre-I and C 4 burst rate by SP was clearer when the basal respiratory rhythm was somewhat lower. Moreover, long lasting depression of respiratory rate after the application of the alpha 2-agonist clonidine was reversed by SP. On the other hand, an inhibitory effect appeared in preparations with a higher basal respiratory rate, while the Pre-I burst rate tended to increase during SP perfusion. During chemical synaptic transmission blockade by perfusion with low Ca 2+, high Mg 2+ solution, a pre-I burst retained or completely blocked was found to be enhanced or reactivated by SP perfusion. The results suggest a direct postsynaptic action of SP, which could strongly stimulate burst generating properties of Pre-I neurons.

Site of action of grayanotoxins in mad honey in rats

Grayanotoxins are known to occur in honey produced from the nectar of Rhododendrons of the family Ericaceae. Grayanotoxins extracted from honey sample obtained from a patient who experienced severe bradycardia and hypotension after ingesting two tablespoonfuls corresponded to Rhododendron ponticum tetrades. Anaesthetized albino rats were injected with honey extract intracerebroventricularly or intraperitoneally. The intracerebroventricular dose was equivalent to 50 mg honey and i.p. doses were equivalent to 50 mg, 1 mg kg-1 and 5 g kg-1 honey. Marked bradycardia and respiratory rate depression were observed in rats injected with extract equivalent to 1 and 5 g kg-1 honey i.p. and in rats injected with 50 mg i.c.v., but not in rats given 50 mg i.p. In bilaterally vagotomized animals, grayanotoxin-contaminated honey extract was not bradycardic. These results suggest that the sites of cardiac and respiratory actions are within the central nervous system, and that the bradycardic effect of grayanotoxin is mediated by vagal stimulation at the periphery.

Comparison of several combinations for anesthesia in rabbits

SUMMARY Few safe and effective anesthesia regimens have been described for use in rabbits, partially because of the susceptibility of this species to sometimes fatal respiratory depression. Although inhalant anesthetics are generally safer than injectable anesthetics, their use may be limited by lack of equipment or facilities. This study was conducted to compare effects of several injectable anesthetics in rabbits on response to noxious stimuli, heart rate, respiratory rate, and rectal temperature. Six injectable anesthetic combinations were administered to rabbits: xylazine-ethyl-(l-methyl-propyl) malonyl-thio-urea salt (emtu), ketamine-emtu, xylazine-pentobarbital, xylazine- acepromazine-ketamine (xak), ketamine-chloral hydrate, and ketamine-xylazine. All combinations induced a depression of respiratory rate. Although rectal temperature values were reduced to some degree in each group, the most profound hypothermia was induced by xak. The combination that induced the longest duration of anesthesia was xak. It was concluded that xak was preferable for longer periods of anesthesia (60 to 120 minutes), although it induces severe hypothermia. For short periods of anesthesia, xylazine-pentobarbital, xylazine- emtu, or ketamine-xylazine were deemed adequate; however, xylazine-emtu induced the best survivability and consistency.

Mad Honey Poisoning in Man and Rat

Grayanotoxins are known to occur in the honey produced from the nectar of Rhododendron ponticum growing on the mountains of the eastern Black Sea region of Turkey and also in Japan, Nepal, Brazil, and some parts of North America and Europe. Two cases of honey intoxication are presented here. Both of the patients experienced severe bradycardia and hypotension after ingestion of honey which was brought from Trabzon, Turkey. Microscopical examination showed Rhododendron ponticum pollen tetrades. Anesthetized albino rats were injected intraperitoneally with toxic honey extract doses equivalent to 1 or 5 g honey/kg. Dose-dependent hypotension, bradycardia and respiratory rate depression were observed. When marked bradycardia (approximately 75% of control value) was reached, rats were given atropine sulfate (2 mg/kg, i.p.) or AF-DX 116 (20 mg/kg, i.p.). Atropine sulfate improved both bradycardia and respiratory rate depression. AF-DX 116, which is a selective M2-muscarinic receptor antagonist, restored only heart rate, but not the respiratory rate depression. These results suggest that M2-muscarinic receptors are involved in cardiotoxicity of grayanotoxin.

Does acidosis contribute to stress-induced ulceration in rat stomachs?

The present study examines the involvement of acidosis in stress ulceration in rat stomachs. Cold restraint stress for 2 hr did not affect the blood lactate level; however, it produced respiratory acidosis, as reflected by the depressed respiratory rate which was associated with increased CO 2 tension and a lowered blood pH. Severe hemorrhagic ulceration was found in the glandular mucosa. The effects of stress on blood pH and the stomach were reversed by IV infusion of NaHCO 3. Infusion of HCl IV decreased the blood pH and HCO 3 − level and produced gastric ulceration. It is concluded that respiratory acidosis could be involved in stress ulceration. The metabolic acidosis evoked by HCl also induced gastric damage, but the effect was much less.

Buprenorphine antagonism of ventilatory depression following fentanyl anaesthesia

In order to compare the effect of buprenorphine and naloxone on respiratory depression after fentanyl anaesthesia (25 micrograms/kg), 32 women scheduled for elective abdominal hysterectomy participated in a double-blind randomized investigation. At termination of anaesthesia, after antagonizing residual neuromuscular blockade, 20 normocapnic patients with a respiratory rate of 4 breaths/min or less entered the study, receiving either buprenorphine (0.6 mg in 20 ml NaCl) or naloxone (0.4 mg in 20 ml NaCl) 2 ml/min until 20 ml was given or until the respiratory rate exceeded 8 breaths/min. Respiratory rate, PaCO2, sedation score, and pain intensity were evaluated during a 3-h study period. Fifteen min after beginning the treatment, all the patients in both groups had their ventilatory depression antagonized. There were no statistically significant differences in respiratory rates between groups except at 15 min. On no occasion did either PaCO2 or a sedation score differ statistically significantly between the groups. At 15 min all patients in the buprenorphine group had no or mild pain, compared to the patients in the naloxone group, of whom 50% had moderate to severe pain (P less than 0.05). It seems as if buprenorphine is as effective as naloxone in antagonizing respiratory rate depression following fentanyl anaesthesia.

Development of tolerance to respiratory depression in morphine- and etorphine-pellet-implanted mice

Tolerance to opiate-induced depression of respiratory rate was studied in unanesthetized mice following chronic treatment with morphine or etorphine. Mice implanted subcutaneously (s.c.) with morphine pellets showed development of tolerance to morphine administered both s.c. and intracerebroventricularly (i.c.v.) and to s.c. etorphine and heroin. However, no cross-tolerance to i.c.v. etorphine or heroin was observed. In contrast, mice implanted with etorphine pellets demonstrated development of tolerance to all 3 agents given either s.c, or i.c.v. These findings on development of tolerance to opiate-induced respiratory depression differ from our previous studies measuring analgesia in which mice tolerant to s.c. morphine did not demonstrate development of tolerance to s.c. etorphine or heroin (unidirectional non-cross-tolerance). To investigate a possible mechanism for this difference in development of tolerance, apparent pA2 values for respiratory rate depression were determined for s.c. morphine-naloxone and etorphine-naloxone. The apparent pA2 values for these two opiates were similar, in contrast to the dissimilar apparent pA2 values previously found when analgesia was measured. The apparent pA2 values demonstrated differences between the respiratory depressant and analgesic effects of these opiates, but there was no obvious relationship between apparent pA2 values and the absence of unidirectional non-cross-tolerance observed for respiratory depression.

Effect of chronic intracerebroventricular infusion of cholecystokinin on respiration and sleep.

We investigated the effect of chronic intracerebroventricular infusion of the sulfated cholecystokinin octapeptide (CCK-8S) on sleep pattern and respiratory rate. The results indicate a depression of respiratory rate during Non-REM and REM sleep as well as an increase in the number of REM periods occurring per hour of Non-REM sleep. It is suggested that central release of CCK-8S is capable of modulating the automatic regulation of respiration during sleep and altering the normal sleep-waking pattern.

Seasonal changes in the depression of respiratory rate of rootlets induced by pruning in tea plants.

In an attempt to throw the light on pruning effects in tea cultivation, the relationship between time of pruning and changes in the respiratory rate of rootlets were investigated with a special reference to the content of storage carbohydrates in roots and the growth temperature. One year-old tea plants (Camellia sinensis (L.) O. Kuntze) grown in plastic pots in field were pruned remaining 1/2 or 1/4 of plant height (1/2 pruning or 1/4 pruning). The respiratory rate (oxygen absorption) of rootlets was measured with an electrode. The depression of respiratory rate of rootlets induced by pruning gradually grew stronger from March to July, and then gradually became weaker to November (Fig. 2). The depression was larger in 1/4 pruning plants than in 1/2 pruning plants (Figs. 1 and 2), and was larger in cvs Yabukita and Kurasawa than in cvs Fujimidori and Okumusashi (Table 1). There was no relationship between seasonal changes in the depression of respiratory rate of rootlets induced by pruning and the content of storage carbohydrates in roots (Figs. 3, 4 and 5). On the other hand, seasonal changes in the depression rate of rootlets induced by pruning and temperature at underground of 10 cm were positively related ; correlation coefficients were 0.941 for cv Yabukita and 0.892 for cv Fujimidori (both are siginificant at 1 % level) (Figs. 6 and 7). When the 1/2 pruning was done to the plants grown under two kinds of day-night temperature regimes, 25-20°C and 15-10°C respectively, the depression of respiratory rate of rootlets was larger in 25-20°C than in 15-10°C (Fig. 8 and Table 2). From these results, it was demonstrated that the depression of respiratory rate of rootlets induced by pruning was larger in summer than in other three seasons and the depression was influenced by temperature at the time when pruning was done rather than content of storage carbohydrate in roots.

Absence of a 45 or 60 Hz Electric Field-Induced Respiratory Effect in Physarum polycephalum

Microplasmodia of Physarum polycephalum strain ${\rm M}_{3}{\rm C}$ were exposed to 60 Hz continuous wave electric fields of 0.7 and 70 V/m for more than 13 weeks and to 45 Hz CW fields of the same strengths for nearly 7 weeks. At a particular field strength, duplicate subcultures of sham-exposed and field-exposed microplasmodia were independently maintained and measured to allow comparison of variation between subcultures within an exposure treatment group. Microplasmodial oxygen uptake rates were measured using a Clark-type oxygen electrode system, and respiratory rates were expressed on a unit protein basis. Few consistent respiratory rate differences between sham- and field-exposed subcultures were detected at either 0.7 or 70 V/m. These findings are in contrast to earlier reports of significant microplasmodial respiratory rate depression in response to 45 or 75 Hz, combined 0.7 V/m, 2.0 G electric and magnetic fields and in response to 75 Hz, 0.7 V/m electric field exposure [Greenebaum et al., DHEW R...

Sensory irritation response to inhaled aldehydes after formaldehyde pretreatment

Pretreatment of Fischer-344 (F-344) rats with formaldehyde (HCHO) induces significant cross tolerance to the sensory irritation properties of Cl 2. The purpose of this study was to determine if HCHO pretreatment would cause sensory irritation cross tolerance to other inhaled aldehydes. Male F-344 rats, weighing 190 to 210 g, were pretreated with 15 ppm HCHO, 6 hr/day for 9 days, and challenged on the 10th day with a saturated (acetaldehyde, propionaldehyde, and butyraldehyde), unsaturated (acrolein and crotonaldehyde), or cyclic (cyclohexanecarboxaldehyde, 3-cyclohexene-1-carboxaldehyde, and benzaldehyde) aldehyde. The sensory irritation response in these animals was quantified by measuring respiratory rate depression in a head-only inhalation chamber using plethysmographic techniques. Control animals were challenged identically without prior pretreatment. In naive (nonpretreated) animals, the concentration eliciting a 50% decrease in respiratory rate (RD50) was 23 ppm or less for unsaturated aliphatic aldehydes. For cyclic and saturated aliphatic aldehydes, the RD50 ranged from 600 to 1000 ppm and 3000 to 6800 ppm, respectively. Formaldehyde pretreatment resulted in cross tolerance only with acetaldehyde (RD50 increased 3.5-fold) and acrolein (RD50 increased 5-fold). These results indicate that the development of cross tolerance following HCHO pretreatment is not a general phenomenon. Prediction of acceptable concentrations of occupational exposure for the prevention of sensory irritation in humans has been based primarily on RD50 data for mice. Comparison of the RD50 values obtained for rats in this investigation with previously published results for mice varied by over one-half an order of magnitude, thereby disputing the usefulness of data from F-344 rats in setting threshold limit values for the prevention of sensory irritation.

Ambient temperature modulates the differentiated cardiorespiratory pattern generated by the central noradrenergic system, most likely via alterations of thyrotropin-releasing hormone (TRH) activity

In conscious rabbits with indwelling intracisternal (i.c.) catheters i.c. injections of 600 μg kg −1 6-hydroxydopamine (6-OHDA) elicited with short latencies an increase in metabolic rate followed by cutaneous vasoconstriction and a reduction in renal sympathetic nerve activity; in addition there was depression of respiratory rate, bradycardia and a fall of blood pressure. This differentiated cardiorespiratory activity pattern was fully established about 1 h after i.c. 6-OHDA, when injected at thermoneutrality. At warm ambient temperatures the metabolic and cardiorespiratory responses to i.c. 6-OHDA were considerably diminished and there was tachycardia. Intravenous (i.v.) injection of 4 μg kg −1 bacterial endotoxin (LPS) in intact rabbits evoked with short latency an increase in metabolic rate and the typical cardiorespiratory activity pattern normally seen in cold defense, consisting of cutaneous vasoconstriction, a depression of respiratory rate and, as shown in a previous study, a decrease in renal sympathetic nerve activity while heart rate and arterial blood pressure is little altered. When LPS was i.v. injected 2–3 days after i.c. 6-OHDA, the febrile response was attenuated with lesser cutaneous vasoconstriction and respiratory rate depression. There was no early inhibition in renal sympathetic nerve activity but rather marked excitation, with increases in heart rate and arterial blood pressure. The results indicate that the effects on autonomic system activities being produced by transmitter release at noradrenergic terminals acutely following i.c. 6-OHDA are considerably modulated by ambient temperature. Comparison of autonomic system reactions in fever obtained in the intact animal and after i.c. 6-OHDA reveals the important role of central noradrenergic pathways in preserving blood pressure homeostasis and heat conservation. The appearance of cardiorespiratory responses similar to those obtained after i.c. noradrenaline or i.c. 6-OHDA, when non-thermal activation of thyrotropin-releasing hormone (TRH) neurons occurs (as demonstrated in a previous study), suggests the hypothesis that TRH neurons known to be specifically influenced by changes in body temperature, converge onto the central noradrenergic system producing the typical cardiorespiratory pattern of cold defense.

Sensory irritation tolerance and cross-tolerance in F-344 rats exposed to chlorine or formaldehyde gas

Inhalation of chlorine (Cl 2) or formaldehyde (HCHO) stimulates the trigeminal nerve endings in the nasal mucosa and results in respiratory rate depression in a concentration-dependent manner. To determine tolerance and cross-tolerance, the concentration-response curves of respiratory depression were compared between naive rats and rats pre-exposed to Cl 2 or HCHO. Chlorine tolerance development was time and concentration dependent, being significant following a 1-day (6 hr/day), 10 ppm exposure, and reaching the maximum in 4 days. At 2.5 ppm of Cl 2, tolerance was significant only after 10 days of exposure. Rats tolerant to Cl 2 also showed cross-tolerance to HCHO. Tolerance to HCHO was observed in rats exposed to 28 ppm for 4 days, but not in groups exposed to 15 ppm for 1, 4, or 10 days. However, significant cross-tolerance to Cl 2 was evident following a 1-day exposure to 15 ppm HCHO, with greatest effect seen in the group exposed for 10 days. Tolerance was reduced after a 7-day recovery following a 4-day exposure. Cross-tolerance was reduced also, but to a much lesser extent. These results suggest a common mechanism for tolerance and cross-tolerance development, but different reactive sites may exist for Cl 2 and HCHO at the trigeminal nerve endings.

COMPARISON OF SOME PHARMACOLOGICAL PROPERTIES OF 4-AMINOPYRIDINE AND 3,4-DIAMINOPYRIDINE IN VIVO

4-Aminopyridine and 3,4-diaminopyridine have been compared with respect to their interactions with morphine in the mouse in vivo. In contrast to 4-aminopyridine, 3,4-diaminopyridine was capable of reducing morphine-induced respiratory rate depression in doses which did not produce signs of toxicity.

Respiratory tract lesions induced by sensory irritants at the RD50 concentration

Exposure of mice to airborne sensory irritants causes a concentration-dependent depression of respiratory rate. The RD50 concentration (that concentration which elicits a respiratory rate decrease of 50%) has been predicted to be an unacceptable occupational exposure concentration due to intolerable sensory irritation and possible respiratory tract injury in humans. The purpose of this study was (1) to determine whether lesions occur in the respiratory tract of Swiss-Webster mice after exposure to the RD50 concentrations of tensory irritants and (2) to compare these changes with respect to type and severity. The RD50 values (ppm) of the chemicals studied are as follows: 2,4-toluene diisocyanate (0.4), acrolein (1.7), formaldehyde (3.1), chloropicrin (8.0), chlorine (9.3), sulfur dioxide (117), ammonia (303), hydrogen chloride (309), dimethylamine (511), and epichlorohydrin (687). After exposure of mice for 6 hr/day for 5 days, the respiratory tract was examined for histopathologic changes. All irritants produced lesions in the nasal cavity with a distinct anterior-posterior severity gradient. There was considerable variation in the extent, severity, and nature of the lesions. The lesions ranged from slight epithelial hypertrophy or hyperplasia to epithelial erosion, ulceration, and necrosis with variable inflammation of the subepithelial tissues. Only chlorine, chloropicrin, and epichlorohydrin induced lesions in the lower respiratory tract. These findings give additional support to the potential value of the RD50 model for setting occupational exposure guidelines and predicting the risk of injury to the respiratory tract from exposure to airborne sensory irritants.

Selective cardiorespiratory effects mediated by mu opioid receptors in the nucleus ambiguus

The respiratory and cardiovascular effects of the highly selective mu opioid agonist, d-Ala 2, MePhe 4, Gly-ol 5 enkephalin (DAGO) and the relatively selective delta agonist, D-Ala 2, d-Leu 5 enkephalin (DADL) were compared following injection (0.1 μl) into the nucleus ambiguus (NA) of spontaneously-breathing and artificially-respired, pentobarbital-anesthetized rats. In non-ventilated animals, the opioids elicited dose-related (3 × 10 −11 −3 × 10 −9 M), naloxone-reversible depression of respiratory rate (RR) without altering the tidal volume. Mean arterial pressure (MAP) was unchanged at small doses and decreased at the largest dose; heart rate (HR) was unchanged. In artificially-respired animals, both peptides elicited dose-related, naloxone-reversible increases in mean arterial pressure and heart rate; DAGO was significantly more potent than DADL ( P < 0.01). Given the relative potency and selectivity of the opioids tested, these findings are consistent with the conclusion that mu receptors may selectively mediate the respiratory and cardiovascular actions of opioids in an important brain stem cardiorespiratory center in the rat. Moreover, these data indicate the importance of respiratory effects on the cardiovascular activity of centrally administered opioids.

Effect of dynorphin-(1–13) and related peptides on respiratory rate and morphine-induced respiratory rate depression

Previous studies from our laboratory have shown that the opioid peptide dynorphin-(1–13), although not analgesic when given by itself, can inhibit morphine-induced analgesia in naive mice and potentiate it in morphine tolerant mice. In the present study, we examined the effect of dynorphin-(1–13) with two other dynorphin-like peptides, α-neoendorphin and dynorphin-(1–10) amide, on respiration. Our results show that none of the peptides studied had any significant activity on the respiratory rate in mice when given alone. However, in the presence of morphine, dynorphin-(1–13) antagonized the morphine-induced respiratory rate depression in morphine-tolerant animals; α-neoendorphin enhanced the morphine-induced respiratory rate depression in naive but had no effect in morphine-tolerant animals and dynorphin-(1–10) amide had no modulatory effect on the morphine-induced respiratory rate depression in either group of animals.

Determination of the relative involvement of μ-opioid receptors in opioid-induced depression of respiratory rate by use of β-funaltrexamine

Using a simple method to measure respiratory rate, it was clearly shown that the depression of respiratory rate caused by morphine, ethylketazocine or [D-Ala 2,D-Leu 5]enkephalin was not altered by the highly selective, irreversible μ-antagonists, β-funaltrexamine (β-FNA) at a dose which produced marked antagonism of morphine antinociception. These results indicated that antinociception and depression of respiratory rate are mediated by different receptor interactions. However using a different method to measure respiratory rate (body plythesmograph), β-FNA caused substantial antagonism of morphine-induced respiratory depression indicating that the degree to which μ-receptor interactions contribute to the depression of respiratory rate depends on the methodology. Possible explanations for this difference are discussed. It is concluded that careful consideration of the methodology must be given when one measures respiratory rate and caution must be exercised if measurement of rate alone is used to assess opioid-induced respiratory depression.