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A nitric oxide releasing compound, NOC-18, was injected intrathecally in order to determine the role of NO in spinal nociceptive mechanisms in rats. The nociceptive threshold was evaluated by the radiant heat tail-flick test. The effects of intrathecal injection of N-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor; methylene blue (MB), a soluble guanylate cyclase inhibitor and hemoglobin (Hb), an NO scavenger, on the nociceptive threshold were measured in the presence and absence of 0.1, 1 and 10 microg of NOC-18. The results were compared with a control group of rats which were injected with the same volume of normal saline. NOC-18 caused a dose-dependent curtailment of the tail-flick latency during the period from 15 to 150 min. L-NAME, MB and Hb all produced prolongation of the tail-flick latency during the same time period. The hyperalgesia induced by this concentration range of NOC-18 was completely blocked by Hb, but was not affected by either L-NAME or MB. These findings indicate that NO plays a direct role in thermal hyperalgesia in the spinal cord, and that an another pathway in addition to the NO-cGMP pathway may be involved.

The utility of a new nitric oxide (NO) donor, NOC-18, and the contribution of the neurotransmitter NO to nociception in response to tissue injury in rats, were examined following the subcutaneous injection of formalin into the hindpaw. This model induces biphasic responses in pain-related behavior, such that C-fiber activation during the first phase triggers a state of central sensitization characterized by the second phase. Formalin-induced nociceptive behavior was facilitated by intracerebroventricular administration of NOC-18 in the second phase, but not the first phase. This enhancement was completely abolished by the soluble guanylate cyclase inhibitor, methylene blue. These findings indicate that NO causes nociception via the NO-cGMP pathway in the central nervous system and NOC-18 proved to be a convenient and useful tool for the investigation of nociception-related NO.

We have investigated the effects of ketamine on nitric oxide produced by activated macrophages using a murine macrophage-like cell line, J774. Cells were incubated for 18 h under stimulation with lipopolysaccharide and interferon-gamma or lipoteichoic acid and interferon-gamma, with various concentrations of ketamine (6-600 mumol litre-1). Nitric oxide production was assessed by measuring nitrite, a stable by-product of nitric oxide breakdown, in the medium. Other N-methyl-D-aspartate receptor antagonists, MK-801 (150 mumol litre-1) and dextromethorphan (150 mumol litre-1) were also tested. In addition, we studied the effects of ketamine on production of tumour necrosis factor-alpha by activated macrophages. Ketamine inhibited nitrite production dose-dependently with both lipopolysaccharide- and lipoteichoic acid-activated macrophages by up to approximately 65% at the highest ketamine concentration (600 mumol litre-1). Neither MK-801 nor dextromethorphan had an inhibitory effect. Ketamine also suppressed production of tumour necrosis factor-alpha. The data show that ketamine inhibited nitric oxide production by activated macrophages probably, in part, via inhibition of production of tumour necrosis factor-alpha, an autocrine stimulatory factor for nitric oxide production, but not via the NMDA receptor pathway, which is involved in neuronal nitric oxide production.

The purpose of this study was to examine the effects of xenon and nitrous oxide in equipotent doses of 0.3 MAC on pain threshold and auditory response time in six healthy male volunteers. Compared with 100% oxygen inhalation, xenon and nitrous oxide significantly increased the pain threshold as measured by a radiant heat algometer. There was no significant difference in analgesic effects between xenon and nitrous oxide. Xenon significantly prolonged the response time to auditory stimuli compared with 100% oxygen, but nitrous oxide did not. The inhibitory effect of xenon on the auditory response time was significantly greater than that of nitrous oxide. The same six volunteers were studied to test if naloxone antagonized analgesia induced by xenon or nitrous oxide. The analgesic effects of xenon and nitrous oxide did not differ with or without naloxone.

The ability of exogenous nitric oxide (NO) to induce apoptosis in macrophages was analyzed using NOC, a NO-releasing compound, as a source of NO. Exogenous NO was shown to induce apoptosis in a dose dependent manner. Quantitative analysis revealed that the amount of NO required to induce apoptosis in more than half of macrophages exposed was 100 times larger than that for endogenous NO-induced apoptosis. NOC proved to be a convenient and useful tool for investigation of apoptosis related to NO.

We studied the effects of six inhalation anaesthetics at subanaesthetic concentrations of 0.2 MAC on pain threshold and psychomotor function in six healthy volunteers. When compared with 100% oxygen inhalation, nitrous oxide and methyoxyflurane significantly increased pain threshold as measured by a radiant heat algometer, and prolonged the response time to auditory stimuli. In contrast, halothane, enflurane, isoflurane and sevoflurane produced prolongation of the response time to auditory stimuli but did not influence pain perception. The pain threshold with nitrous oxide remained significantly increased 30 min after its discontinuation, while the response time returned to the preinhalation value. We conclude that nitrous oxide and methoxyflurane possess both analgesic and hypnotic actions but halothane, enflurane, isoflurane and sevoflurane do not have an analgesic action at subanaesthetic concentrations, and the analgesic action of nitrous oxide persists after its elimination.

We used capnometry during high-frequency oscillatory ventilation (HFOV), and compared CO2 measurements at the distal and proximal ends of an endotracheal tube with arterial CO2 values. Ten white rabbits (mean weight, 2.00 +/- 0.2 [SD] kg) underwent tracheostomy under anesthesia with pentobarbital. The trachea was intubated with an endotracheal tube with a second lumen for sampling respiratory gas at the distal tip. Capnometry was performed through the lumen (CO2d) and the proximal end of the endotracheal tube (CO2p). The internal carotid artery was cannulated to sample blood for measuring arterial blood gases. The differences between CO2d, CO2p, and PaCO2 were measured. Only the relation between CO2d and PaCO2 was good (r = 0.915). We concluded that capnometry can be used during HFOV to estimate PaCO2 provided that respiratory gas is sampled from the distal tip of the endotracheal tube.

The effect of prostaglandin E1 (PGE1) on local cerebral blood flow (LCBF) and carbon dioxide reactivity (CO2R) was studied during cerebral aneurysm surgery for subarachnoid haemorrhage in 24 patients under neuroleptanaesthesia. Eleven patients had good neurological status (Hunt and Kosnik grade I: group A) and 13 patients poor status (grades II-IV: group B). Arterial hypotension was induced with PGE1 0.1 micrograms kg-1 min-1 initially and adjusted to maintain mean arterial pressure at about 70 mm Hg. PGE1 was discontinued at the completion of aneurysm clipping. LCBF and CO2R were measured during and after administration of PGE1. LCBF was unchanged and CO2R preserved in both groups. The carbon dioxide response was better in group A than in group B (P less than 0.01). PGE1 may be a suitable agent for hypotensive anaesthesia in these patients.

A modified indicator gas washout method was developed to measure functional residual capacity (FRC) during high-frequency oscillatory ventilation (HFOV) without interruption of HFOV. A hot-wire flowmeter and medical gas analyzer measured the flow rate and argon concentration, respectively, at the expiratory end of the respiratory circuit. Upstream of the hot-wire flowmeter, two heat-and-moisture exchangers for resistance and a rubber balloon for capacitance were placed to convert the oscillating expiratory flow to an almost continuous flow. This made it possible to measure FRC during HFOV without interrupting HFOV. To measure the volume of the entire respiratory circuit, a 10 percent argon in 90 percent oxygen gas mixture was initially used as a bias flow, and after equilibration, the test gas was switched to 100 percent oxygen. By electrical integration of the product of the expiratory flow rate and argon concentration, the total amount of argon equilibrated in the entire respiratory circuit was calculated. The volume of the circuit was calculated by dividing the total amount of argon by the initial argon concentration. Functional residual capacity plus the volume of the respiratory circuit was similarly calculated and the difference was estimated as FRC. The accuracy and reproducibility of our method were evaluated by using a one-compartment lung model. There was a high correlation between the volume setting of the model lung and the estimated FRC. This method can be used to estimate FRC in a one-compartment lung model during HFOV, and it is potentially useful in clinical situations.

Carboxyhemoglobin and methemoglobin levels in 312 units of banked blood and their relationship to the duration of storage were determined. The carboxyhemoglobin level decreased as the storage time increased, and its mean was 1.4% +/- 2.0% (SD) with a range from 0% to 9.6%. Methemoglobin increased during storage, showing a mean level of 1.6% +/- 0.4% and a range from 0.5% to 4.2%. In a separate study, blood drawn from six volunteers who had smoked two cigarettes each was stored as banked blood for 21 days. The mean initial level of carboxyhemoglobin was 4.4% +/- 1.6%, and the mean half-life of carboxyhemoglobin was approximately 47 days. Methemoglobin increased from an initial 1.3% +/- 0.2% to 2.4% +/- 0.6% at the end of storage. The use of banked blood containing high levels of these abnormal hemoglobins could be a potential risk in critically ill patients.

There are many kinds of humidifying devices. We evaluated six humidifiers from the viewpoint of AWLs. The AWL was obtained by calculating the area difference between pressure-volume tracings obtained without and with humidifiers. To examine the effect of pressure monitoring sites on AWL when a humidifier is placed, we measured AWL at three different pressure monitoring sites. The AWL was affected significantly by the pressure monitoring site for the ventilator. When a pressure monitor sensor was placed on the inspiratory limb between the inspiratory valve and humidifiers, the ventilator was not able to compensate for the pressure drop caused by impedance characteristics of the humidifier equipment. This resulted in significant inspiratory AWL on the patient. Thus, humidifying devices should be carefully selected from the viewpoint of not only humidifying capability but also AWL. Furthermore, we must recognize the importance of the pressure monitoring site for the ventilator.

Effects of inhalational anesthetics, methoxyflurane and halothane, on the binding of various opioid ligands were studied. The binding affinity of 3H-methionine enkephalin (delta) was reduced by both anesthetics in the same manner, but the receptor density was not significantly affected. Methoxyflurane decreased the binding affinity but increased the receptor density of 3H-dihydromorphine (mu), while halothane had little effects on both affinity and density. Methoxyflurane also decreased binding affinities of 3H-ethylketocyclazocine (kappa) and 3H-SKF-10047 (sigma), but halothane did not decrease significantly. These effects of the anesthetics were completely disappeared by unsealing and ventilation.

The effects of the d- and l-isomers of pentazocine were compared to that of racemic pentazocine on contractions of the mouse isolated vas deferens. L-pentazocine inhibited electrically evoked contractions of the mouse vas deferens (MVD) in a dose-dependent manner (ID50 0.37 +/- 0.04 microM). In contrast, d-pentazocine augmented field stimulated contractions dose-dependently; per cent increases in contractions at 10 and 30 microM were 57.8 +/- 18.0 and 98.0 +/- 15.1%, respectively. Racemic pentazocine produced an intermediate effect between the two isomers. The effect of 1-pentazocine was antagonized by naloxone, whereas that of d-pentazocine was not. L-pentazocine did not effect the response of the MVD to exogenous norepinephrine at any concentration tested, while d-pentazocine depressed the response of the MVD to exogenous norepinephrine at one dose (0.3 microM). These findings demonstrate that d- and l-pentazocine produce opposite effects on the MVD. The effects of l-pentazocine are opioid mediated, while those of d-pentazocine are not. In the racemic mixture the opposing effects of the two isomers modulate each other, resulting in a diminished effect.

We have developed a new continuous positive airway pressure (CPAP) device that consists of a microcomputer, a pressure transducer, and a pair of electronic interface valves. One of these valves creates the inspiratory demand flow, and the other creates the opposing jet flow by acting as an expiratory valve to maintain a constant CPAP. By controlling the two electronic interface valves, the airway pressure can be kept constant during the entire respiratory cycle. We compared our device with CPAP systems supplied with commercially available ventilators: the Puritan-Bennett 7200a, the Bear 5, the Servo 900C, and the CV 2000. A two-chambered spring loaded model lung was used to simulate inspiration and a piston pump model lung to simulate active exhalation. We compared both the inspiratory triggering work (WWIt) and expiratory flow-resistive work (WE) of each ventilator while in CPAP mode by calculating the corresponding areas of the pressure-volume loops using electrical integration. The WWIt of our apparatus and demand-flow ventilators was much smaller than that of the CV 2000. In our device, WE was also much smaller than those of the others. These results indicate that our device can be used for CPAP without causing airway pressure fluctuation, and therefore, without imposing an extra workload on the patient.

In our study of 14 patients with adult respiratory distress syndrome (ARDS), we measured A-aDO2, VD/VT, arterial-to-end tidal PCO2 ), effective dynamic compliance, and pulmonary vascular resistance on a daily basis. At the onset of ARDS, all patients showed bilateral interstitial edema on the chest X-ray films, P(A-a)O2 of more than 500 mm Hg, marked decrease in effective dynamic compliance, a moderate increase in VD/VT, and a normal value of a-etPCO2. Pulmonary vascular resistance was low. After seven days, all of those who subsequently died and developed persistent elevation of P(A-a)O2, significant increase in VD/VT, a-etPCO2 and pulmonary vascular resistance, and significant decrease in effective dynamic compliance compared to the values at the onset of ARDS. Those abnormalities diverged significantly from the findings in those who survived. By evaluating sequential changes of those parameters, we might be able to predict an accurate prognosis of ARDS.

A fully automated high-performance liquid chromatographic column-switching system is presented for the determination of cyclosporin A in whole blood. After blood proteins were precipitated with acetonitrile, the supernatant was automatically loaded on to a cyanopropyl column for initial separation, and then the fraction containing cyclosporin A was loaded on to a trimethylsilica column for final separation and quantitation. Cyclosporin A was detected by ultraviolet absorption at 205 nm. The minimum detectable concentration of cyclosporin A was 5 ng/ml in 100 microliter of blood. The coefficient of variation of the method was 1.755, 1.748 and 0.655% in whole blood when spiked at the 170, 425 and 850 ng/ml levels, respectively. One assay was completed in 15 min.