Fukuichiro Okumura

Detection of air embolism by transesophageal echocardiography.

In this study transesophageal echocardiography was utilized for detecting air embolism in dogs in the supine position and in patients undergoing neurosurgery in the sitting position. In dogs, the threshold dose of venous air for detection was determined using either a bolus injection or continuous infusion of air via the jugular vein for up to three minutes. The ability to detect air in the aorta also was determined by a bolus injection into the left ventricle via an arterial catheter. For venous injection of air, the threshold dose by bolus was 0.02 ml/kg. When given by infusion, air could be detected in all cases by both contrast echocardiogram and Doppler sound changes at the rate of 0.05 ml·kg-1. min-1. When air was injected into the left ventricle, the threshold dose was 0.001 ml/kg using contrast echocardiogram. In the clinical evaluation, air was clearly demonstrated in five of six patients by transesophageal echocardiogram along with appropriate changes in Doppler sounds, pulmonary artery pressure, and end-tidal carbon dioxide concentration. Our results suggest that transesophageal echocardiography may be a more sensitive and accurate method for detecting venous air embolism than other commonly used monitors for patients undergoing neurosurgical procedures in the sitting position. This device may also be able to detect air in the aorta in patients experiencing paradoxical air embolism during surgery due to intracardiac or pulmonary shunts.

The Effect of Pentoxifylline on Acid-induced Alveolar Epithelial Injury

Background Acid instillation into one lung is known to cause an increase in the permeability of the endothelium to protein in both the instilled and the contralateral lungs. Activated neutrophils are believed to be involved in causing this increased permeability. Pentoxifylline, a drug used in clinical practice, has multiple effects on neutrophils, including inhibition of phagocytosis, degranulation, and superoxide generation. This study investigated whether pretreatment with pentoxifylline would protect the alveolar epithelium or lung endothelium from injury. Methods The effect of acid instillation into one lung of anesthetized rabbits using several quantitative parameters was investigated. The quantification of the bidirectional movement of the alveolar (sup 125 Iodine‐albumin) and the circulating protein tracers (sup 131 Iodine‐albumin) was used as a measurement of the permeabilities of the lung epithelium and the lung endothelium in the acid‐instilled lung. Bronchoalveolar lavage and measurement of the entry of the circulating protein tracer were used to assess the permeabilities of these barriers in the noninstilled lung. Results The instillation of HCl (pH 1.25, 1.2 ml/kg) into the right lung resulted in an increase in the protein permeability of the right lungs alveolar epithelium and endothelium as well as an increase in the permeability to protein of the left lungs endothelium. Pentoxifylline pretreatment attenuated the increase in the endothelial permeability of both lungs by 50% and restored the PaO2 /FI sub O2 to normal in the pretreated animals exposed to acid injury. Conclusions Acid aspiration causes a dramatic increase in the alveolar epithelial permeability of the acid‐instilled lung, but the permeability of the alveolar epithelium of the contralateral lung remains normal. In contrast, unilateral acid instillation causes an increase in the permeability of the endothelium of both lungs. The increase in endothelial permeability can be attenuated by pretreatment with pentoxifylline administration, and this leads to restoration of normal gas exchange.

Age‐related modifications of effects of ketamine and propofol on rat hippocampal acetylcholine release studied by in vivo brain microdialysis

Background: We sometimes encounter impairment of learning and memory after general anesthesia in elderly patients. The aim of this study was to examine age‐related modifications of the effects of ketamine and propofol on rat hippocampal acetylcholine (ACh) release because hippocampal cholinergic neurons are supposed to be involved in learning and memory.

Differential effects of thiopental on neuronal nicotinic acetylcholine receptors and P2X purinergic receptors in PC12 cells

Background: PC12 cells, derived from rat pheochromocytoma, express neuronal nicotinic acetylcholine receptors (nAchRs) and P2X purinergic receptors, both of which resemble the receptors in postganglionic sympathetic neurons. The former is the established and the latter is the putative receptor to mediate fast synaptic transmission. The authors investigated effects of thiopental on these two ligand‐gated ion channels. Methods: Whole cell currents were recorded in PC12 cells without treatment of nerve growth factor, using conventional whole cell patch clamp technique. Nicotine or adenosine tri‐phosphate (ATP) 30 micro Meter was applied for 4–5 s in the absence or presence of thiopental 3–300 micro Meter. Results: Nicotine induced the rapidly decaying inward current at ‐60 mV, which exhibited the characteristics of the neuronal nAchR‐mediated current. Thiopental inhibited the nicotine‐induced inward current and accelerated the current decay in a dose‐dependent manner, resulting in the greater effects on the steady current than the peak current. IC50s for the peak and steady current were 56.7 and 7.4 micro Meter, when the anesthetic was coapplied with nicotine. Thiopentals inhibition was not associated with a change in the reversal potential and was voltage‐independent at membrane potential of ‐30 to ‐70 mV. Most of thiopentals effects seemed to require channel opening. In contrast to the nicotine‐induced current, thiopental had little effect on the current elicited by ATP. Conclusions: Thiopental, whose reported EC50 for general anesthesia is 25 micro Meter, inhibited the neuronal nAchR‐mediated current but not the P2X receptor‐mediated response in PC12 cells at clinically relevant concentrations. Inhibition may result in suppression of synaptic transmission in sympathetic ganglia.

L-DOPA inhibits spontaneous acetylcholine release from the striatum of experimental Parkinson's model rats

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM L-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The L-DOPA-induced decrease was not affected by (-)-sulpiride which completely blocked D2- and D3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM D-DOPA nor 100 nM dopamine caused by any change in ACh release. These findings suggest that L-DOPA-sensitive mechanisms are supersensitized in Parkinsons disease model rats.

Comparison of the effects of convulsant and depressant barbiturate stereoisomers on AMPA-type glutamate receptors.

BACKGROUND Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system. Although barbiturates have been shown to suppress the AMPA receptor-mediated responses, it is unclear whether this effect contributes to the anesthetic action of barbiturates. The authors compared the effects of depressant [R(-)] and convulsant [S(+)] stereoisomers of 1-methyl-5-phenyl-5-propyl barbituric acid (MPPB) on the AMPA and gamma-aminobutyric acid type A (GABA(A)) receptor-mediated currents to determine if the inhibitory effects on AMPA receptors correlate to the in vivo effects of the isomers. METHOD The authors measured whole-cell currents in the rat cultured cortical neuron at holding potential of -60 mV. Kainate 500 microM was applied as the agonist for AMPA receptors. Thiopental (3-300 microM), R(-)-MPPB or S(+)-MPPB (100-1,000 microM) was coapplied with kainate under the condition in which the GABA(A) receptor-mediated current was blocked. Effects of MPPB isomers on the current elicited by GABA 1 microM were studied in the separate experiments. RESULTS Thiopental inhibited the kainate-induced current reversibly and in a dose-dependent manner, with a concentration for 50% inhibition of 49.3 microM. Both R(-)-MPPB and S(+)-MPPB inhibited the kainate-induced current with a little stereoselectivity. R(-)-MPPB was slightly but significantly more potent than S(+)-MPPB. In contrast, R(-)-MPPB enhanced but S(+)-MPPB reduced the GABA-induced current. CONCLUSIONS Both convulsant and depressant stereoisomers of the barbiturate inhibited the AMPA receptor-mediated current despite of their opposite effects on the central nervous system in vivo. Although thiopental exhibited a considerable inhibition of AMPA receptors, the results suggest that the inhibition of AMPA receptors contributes little to the hypnotic action of the barbiturates.

Neutrophil Elastase Inhibitor, ONO-5046, Modulates Acid-induced Lung and Systemic Injury in Rabbits

Background Acid instillation leads to direct lung and to secondary systemic organ injury, probably via activated macrophages and neutrophils. This study investigated the effects of neutrophil elastase on organ injury after unilateral lung acid instillation by administrating a specific neutrophil elastase inhibitor, ONO-5046, before acid instillation. Methods Three groups of anesthetized rabbits (n = 12 in each group) underwent tracheostomies, and instillations were made into their right lower lobe airspaces with either phosphate buffered saline (pH, 7.4; volume, 1.2 ml/kg; n = 12) or HCl (pH, 1.25; volume, 1.2 ml/kg; n = 24). In half of the acid-instilled rabbits, ONO-5046,10 mg/kg, was given intravenously 15 min before the HCl instillation, and then 10 mg [center dot] kg sup -1 [center dot] h sup -1 of the drug was continuously infused throughout the experiment. The other groups of animals received the vehicle intravenously. Anesthesia and mechanical ventilation was continued for 8 h, whereas arterial blood gases were sampled intermittently. Eight hours after saline or acid instillation, the animals were killed, and their lungs, heart, kidneys, liver, and small intestines were harvested. Wet-to-dry weight ratios (W/D) and myeloperoxidase (MPO) assays of these organs were done, and elastase assays on the bronchoalveolar lavage fluids (BALF) obtained from each lung also were performed. Results Pretreatment with ONO-5046 attenuated the physiologic changes seen in the vehicle-treated animals. Significant decreases in W/D of the noninstilled lungs and of the small intestine and normalization of the oxygenation of the experimental animals occurred. The ONO-5046 pretreatment did not affect the neutrophil sequestration in the lungs or in the other organs as determined by neutrophil counts in BALF and by the MPO assays. Conclusions A neutrophil elastase inhibitor, ONO-5046, administered immediately before acid instillation attenuated the physiologic changes seen in the vehicle-treated animals. The drug blocked neutrophil elastase but did not block neutrophil sequestration in the lungs, although the drug improved measurements of lung injury.

6-OHDA-induced lesion of the nigrostriatal dopaminergic neurons potentiates the inhibitory effect of 7-OHDPAT, a selective D3 agonist, on acetylcholine release during striatal microdialysis in conscious rats

Using striatal microdialysis, we attempted to clarify whether or not locally infused 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OHDPAT), a selective D3 agonist, modulates the basal acetylcholine (ACh) release in conscious rats sham-operated and lesioned with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. In the sham-operated rats, 7-OHDPAT at 1 microM decreased ACh release by 19% of control. In the 6-OHDA-lesioned rats, 7-OHDPAT (0.1-10 microM) decreased ACh release in a concentration-dependent manner. The decrease of 37% of control was seen at 1 microM 2 weeks after the lesion. The 7-OHDPAT (1 microM)-induced decrease was completely antagonized by 1 microM (-)-sulpiride, a D2 and D3 antagonist, while (-)-sulpiride at 1 microM alone failed to alter ACh release. There may exist intrastriatal D3 receptors to inhibit ACh release, and supersensitization is evident in a 6-OHDA-lesioned rat Parkinsons model.

Nonstereospecific actions of ketamine isomers on the force of contraction, spontaneous beating rate, and Ca2+ current in the guinea pig heart.

Ketamine possesses stereospecific actions of anesthesia with the S(+)-isomer being three to four times as potent an anesthetic as the R(-)-isomer. We investigated the mechanical and electrophysiologic effects of ketamine isomers in guinea pig cardiac preparations. Both isomers decreased the contractile force of electrically driven papillary muscles and the spontaneously beating rate of the right atria in a concentration-dependent manner. There were no significant differences between the S(+)- and R(-)-isomers for these measured variables. Consistent with the results from mechanical experiments, electrophysiologic experiments using whole cell voltage clamp techniques revealed that both isomers suppressed identically the transsarcolemmal Ca2+ current (I (Ca)), which plays a role in the generation of the force of contraction and the spontaneous firing of sinoatrial node cells. In conclusion, the optical isomers of ketamine have equipotent cardiodepressant effects in the guinea pig. Inasmuch as the S(+)-isomer is the more potent anesthetic, it could offer significant clinical advantage over the R(-)-isomer or the racemate, in terms of impairment of cardiac functions, if the present results could be extrapolated to the clinical setting. (Anesth Analg 1996;83:75-80)

Supersensitization of intrastriatal dopamine receptors involved in opposite regulation of acetylcholine release in Parkinson's model rats

Using striatal microdialysis, we studied effects of SKF 38393, a D1 agonist, and quinpirole, a D2 agonist, on the acetylcholine (ACh) release from the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats by local infusion into the striatum. The present experiments clearly demonstrated evidence for the existence of intrastriatal D1 and D2 receptors regulating ACh release and for supersensitization of the striatal stimulatory D1 and inhibitory D2 receptor mechanisms in 6-OHDA lesioned rats.