Involvement of nitric oxide in parasympathetic and antidromic vasodilatations in cat lower lip.

The involvement of nitric oxide (NO) in the lower lip vasodilatations mediated via parasympathetic and antidromic mechanisms was examined in alpha-chloralose/urethane-anesthetized cats, with the two types of blood flow responses being recorded separately (by laser Doppler flowmeter) from the two sides of the lower lip. The central cut end of the lingual nerve (LN) or the peripheral cut end of the inferior alveolar nerve (IAN) was electrically stimulated to elicit parasympathetic or antidromic vasodilatation, respectively, in the lower lip. N(G)-nitro-L-arginine methyl ester (L-NAME), but not N(G)-nitro-D-arginine methyl ester (D-NAME) (each at 30 mg/kg), markedly reduced the increases in lip blood flow evoked by stimulation, the reduction being to a similar degree irrespective of whether LN or IAN was stimulated. Pretreatment with L-arginine did not prevent the L-NAME-induced attenuation of either type of vasodilatation. In conclusion, these results suggest that synthesized NO may have a common site of action in antidromic and parasympathetic vasodilator pathways to the cat lower lip.

Suppression of parasympathetic reflex vasodilatation in the lower lip of the cat by isoflurane, propofol, ketamine and pentobarbital: implications for mechanisms underlying the production of anaesthesia.

We have compared the effects of isoflurane, propofol, ketamine and pentobarbital on parasympathetic reflex vasodilatation to investigate their involvement in GABA-mediated synaptic inhibition, enhancement of which is thought to underlie the action of many anaesthetic agents. In cats anaesthetized with urethane-alpha-chloralose, parasympathetic reflex vasodilation in the ipsilateral lower lip was elicited by electrical stimulation of the central cut end of the lingual nerve. Isoflurane and pentobarbital both produced marked dose-dependent inhibition of this vasodilator response. In contrast, propofol and ketamine had no effect on parasympathetic reflex vasodilation. Administration of a GABA antagonist (picrotoxin) reversed the inhibition produced by isoflurane (previous results) and pentobarbital (present study). Our results suggest that isoflurane and pentobarbitone inhibit parasympathetic reflex vasodilatation via a GABA-mediated mechanism, but that propofol and ketamine have no such effect. Our results with propofol cast doubt on its presumed mechanism of action as an anaesthetic.

Effects of inhalation anesthetics on parasympathetic reflex vasodilation in the lower lip and palate of the cat.

The present experiments were designed to examine the effects of inhalation anesthetics (isoflurane, halothane, and sevoflurane) on the parasympathetic reflex vasodilation in the lower lip and palate elicited by electrical stimulation of the central cut end of the lingual nerve in vagosympathectomized cats. Isoflurane (1.5%), halothane (1.0%), and sevoflurane (2.5%), each at a concentration of 1.0 minimum alveolar concentration, markedly suppressed the evoked blood flow increases in the lower lip, whereas nitrous oxide (70% in 30% oxygen) and morphine (2 mg/kg iv) did not. Prior administration of picrotoxin, a gamma-aminobutyric acid (GABA) antagonist (2 mg/kg iv), reversed the inhibitory effect of isoflurane on the parasympathetic reflex response. Decerebration had no significant effect on the isoflurane-induced inhibition. These findings suggest that there is a GABA-mediated suppressive mechanism acting on this parasympathetic reflex response; the sites at which inhalation anesthetics exert such an inhibitory action could be in the midbrain, pons, or medulla, but not in the hypothalamus or higher structure.

Comparative effects of lingual and facial nerve stimulation on intracranial and extracranial vasomotor responses in anesthetized cats.

Electrical stimulation of the central cut end of the lingual nerve (as reflex activation of parasympathetic nerve) or of the peripheral cut end of the facial (VIIth cranial) nerve (as direct activation of parasympathetic nerve) elicited the ipsilateral blood flow increases in lower lip, palate and common carotid artery (CCA) but not in frontal cerebral cortex in alpha-chloralose-urethane anesthetized, vago-sympathectomized cats. No significant difference, in terms of the vasomotor changes examined, was found between lingual nerve and facial nerve stimulation. The results suggest that there is no somato-parasympathetic reflex vasodilator mechanism serving the frontal cerebral cortex, and that changes in CCA blood flow should not be taken to be indicative of blood flow changes in cerebrocortical blood flow. However, we cannot entirely rule out the possibility of a neurogenic vasodilator influence of the facial pathway, since small blood flow increases in the frontal cerebral cortex were sometimes observed on facial nerve stimulation.

Blood flow increases in common carotid artery, lower lip and palate elicited by lingual nerve stimulation in anesthetized cats.

The purpose of the present study was to examine whether changes in blood flow in the common carotid artery (CCA) reflect those in individual extracranial tissues (lower lip and palate). Changes were evoked at the three sites simultaneously using a somato-parasympathetic reflex activation method in urethane-alpha-chloralose anesthetized, vago-sympathectomized cats. Somato-parasympathetic reflex activation was induced by electrical stimulation of the central cut end of the ipsilateral lingual nerve. The blood flow changes evoked in CCA, lower lip and palate changed in parallel when the stimulus to the blood vessels was changed (by changing the stimulus applied to the afferents or by blocking the efferent pathway). However, when drugs were given intravenously which would act directly on receptors in the blood vessels (including the endothelium) or alter the systemic blood pressure level, the evoked responses in CCA reacted in a quantitatively different manner from those evoked in lower lip and palate. These results suggest that evoked changes in CCA blood flow cannot be regarded as an accurate reflection of changes occurring simultaneously in individual extracranial tissues, at least when examining the effect of such drugs on parasympathetic mediated vasodilation.

Effects of stellate ganglion block on cardiac coronary circulation.

Since the stellate ganglion contains cardiac sympathetic nerves, stellate ganglion block (SGB) may influence cardiac and coronary hemodynamics. We investigated this influence of SGB by measuring the heart rate (HR), the left circumflex coronary artery blood flow (CBF), the maximum rate of increase of the left ventricular pressure (LV max dP/dt), the cardiac output (CO), the myocardial oxygen consumption (MVO2), and the myocardial oxygen extraction ratio (MOER) in nine dogs before and after performing SGB by means of injection of 2 ml 1% mepivacaine. Left SGB resulted in a decrease of 10% in CBF and a decrease of 15% in LV max dP/dt, but HR, CO, and MVO2 remained unchanged. On the other hand, right SGB resulted in a decrease of 30% in CBF and a decrease of 25% in LV max dP/dt, as well as a decrease of 20% in HR, 15% in CO, and 25% in MVO2. SGB on either side resulted in an increase in MOER that was slight but nonetheless significant (P<0.05) in that it suggested a relative deficit in CBF with respect to MVO2. Inhalation of 100% oxygen decreased MOER to the pre-SGB level in either side, thus improving the myocardial oxygen supply-demand relationship. This study suggests the possibility that SGB has deteriorative effects on the myocardial oxygen supply-demand relationship. Those effects were counteracted by the inhalation of 100% oxygen.

Hyperbaric oxygen combined with nicardipine administration accelerates neurologic recovery after cerebral ischemia in a canine model.

OBJECTIVE: To evaluate the efficacy of combined therapy--hyperbaric oxygenation with nicardipine administration--for neurologic recovery after complete cerebral ischemia. DESIGN: Randomized, prospective, controlled, unblinded, study, with 14-day postischemic observation. SETTING: Laboratory of the Department of Anesthesiology, Tohoku University School of Medicine. SUBJECTS: Nineteen healthy mongrel dogs (mean weight 10.4 kg) divided randomly into two groups-ten dogs in the untreated group and nine dogs in the treated group. INTERVENTIONS: Fifteen minutes of complete global cerebral ischemia was achieved by occlusion of the ascending aorta and the caval veins. Dogs in the treated group each received a 0.01-mg/kg bolus injection of nicardipine immediately after the reestablishment of circulation, followed by a 0.03-microgram/kg/min continuous infusion of nicardipine for 3 days and hyperbaric oxygen therapy with 3 atmospheres absolute pressures in an FIO2 of 1.0 for 1 hr at 3, 24, and 29 hrs after ischemia. Neurologic recovery was evaluated based on the survival time and rate, the Electroencephalogram (EEG) Score (1 = normal, 5 = isoelectric), and the Neurologic Recovery Score (100 = normal, 0 = brain dead) over a 14-day postischemic period. MEASUREMENTS AND MAIN RESULTS: Neurologic Recovery Scores of the treated group were always higher than those scores of the untreated group throughout the 14-day period. The best Neurologic Recovery Score was 83.1 +/- 5.3 in the treated group and 46.9 +/- 5.2 in the untreated group (p < .01). The numbers of dogs that recovered to a Neurologic Recovery Score of > 85 (assessed as almost normal) was five of nine in the treated group and none of ten in the untreated group (p < .01). Recovery of EEG over 14-day period was better in the treated group. The survival rate and the predicted survival rate were 78% and 13.6 days in the treated group and 30% and 9.0 days in the untreated group, respectively (p < .04 for the survival rate and p < .05 for the survival time). CONCLUSION: Combined therapy, using hyperbaric oxygenation with nicardipine administration, given after 15 mins of complete global cerebral ischemia, accelerates neurologic recovery in dogs.

Flecainide is effective against premature supraventricular and ventricular contractions during general anesthesia.

The effect of intravenously administered flecainide on premature supraventricular (PSCs) and ventricular contractions (PVCs) which developed under general anesthesia was evaluated. Flecainide was infused intravenously at a rate of 0.2 mg/kg/min until the efficacy of this drug appeared or for 10 min; thus, the maximum dose was determined to be 2 mg/kg. Flecainide was administered to 10 patients who experienced more than 5 supraventricular and/or ventricular contractions/min for a period of more than 5 min (PVCs, 4 patients; PSCs, 6 patients). PVCs in 4/4 cases and PSCs in 5/6 cases disappeared following administration of flecainide. The average dose of flecainide was 1.08±0.17 mg/kg (SE). This dose of flecainide did not affect the heart rate and QRS interval, but caused a transient decrease in systolic blood pressure from 127±6 mmHg (SE) to 114±6 mmHg, a 14% increase in the PQ interval, and a 6.3% increase in the QT interval. These results suggest that flecainide is a promising drug for the treatment of PSCs and PVCs which develop during general anesthesia. Transient hypotension and cardiac conduction disturbances immediately after injection may occur when flecainide is used intravenously.

Elevation of the extracellular glutamate concentration in the hippocampus after total cerebral ischemia related to the deterioration of the recovery in EEG and evoked potentials in dogs.

The concentrations of extracellular glutamate (Glu), aspartate (Asp) and glycine (Gly) were measured by microdialysis method in the cortex and hippocampus before, during and after 15 min of total cerebral ischemia in dogs. The correlations between the concentrations of amino acids and the changes in EEG and evoked potentials (EP) after ischemia were evaluated. Total cerebral ischemia was achieved by occluding the ascending aorta and the caval veins. The concentrations of Glu in the hippocampus significantly increased from 1.73 +/- 0.59 (mean +/- SEM) nmol.ml(-1) at pre-ischemia to 5.46 +/- 1.34 (P < 0.05) during ischemia and 14.37 +/- 3.70 (P < 0.01) 0-15 min after ischemia, and returned to the pre-ischemic level 30 min after ischemia. The concentration of hippocampal Glu 0-15 min after ischemia had significant negative correlations with the EEG-EP scores (0 = serious deterioration of electrical function and 6 = normal electrical function) 30 min, 3 hr and 5 hr after ischemia (r = -0.69, P < 0.05 : r = -0.67, P < 0.05 : r = -0.70, P < 0.05, respectively). The increase of the extracellular Glu concentration in the hippocampus immediately after ischemia may aggravate the neurological outcome after total cerebral ischemia.

Hyperbaric oxygen therapy accelerates neurologic recovery after 15-minute complete global cerebral ischemia in dogs.

BACKGROUND AND METHODS: Although hyperbaric oxygen therapy is clinically used for the treatment of several types of ischemic brain injury, few basic animal studies are available that provide a rationale for this therapy for complete global brain ischemia. Therefore, we investigated the effect of hyperbaric oxygen therapy on neurologic recovery after 15-min complete global cerebral ischemia in a canine model. Complete global ischemia was induced in 19 dogs by occlusion of the ascending aorta and the caval veins. Nine dogs were randomized to treatment with hyperbaric oxygenation (3 atmospheres absolute, 100% oxygen for 1 hr) at 3, 24, and 29 hrs after ischemia under spontaneous respiration, while the other ten dogs served as the control group without hyperbaric oxygen therapy (group C). Neurologic recovery was evaluated based on the electroencephalogram (EEG) activity score (1 = normal; 5 = isoelectric) and the neurologic recovery score (100 = normal; 0 = brain death) over a 14-day postischemic period. RESULTS: The survival rates were 3/10 (30%) in the control group vs. 7/9 (78%) in the group treated with hyperbaric oxygen (p < .05). Over the 14-day postischemic period, the best (lowest) EEG scores of each dog were significantly (1.7 +/- 0.2 vs. 2.9 +/- 0.3; mean +/- SE, p < .01) lower in the hyperbaric oxygen-treated group. The best neurologic recovery scores of each dog were significantly (69 +/- 6 vs. 48 +/- 5; mean +/- SE, p < .05) higher in the treated animals. The number of dogs that recovered to a neurologic recovery score of > 65 (assessed as a slight disability) were 1/10 in the control group and 6/9 in the group treated with hyperbaric oxygen (p < .02). CONCLUSIONS: Hyperbaric oxygen therapy performed in the early postischemic period accelerated neurologic recovery and improved the survival rate in dogs after 15-mins of complete global cerebral ischemia.

Comparison of the relaxant effects of diazepam, flunitrazepam and midazolam on airway smooth muscle.

The mechanisms by which benzodiazepines produce muscle relaxation and respiratory depression are not known, but they may include actions on peripheral benzodiazepine receptors or central GABA receptors, or a direct action on airway smooth muscle may also be involved. We have compared, therefore, the effects of diazepam, flunitrazepam and midazolam on airway tone by measuring isometric tension of guineapig trachealis muscle. Cumulative concentrations of diazepam, flunitrazepam and midazolam caused concentration-dependent relaxation of resting tone in the tracheal smooth muscle with no significant differences in pD2 values (-log EC50--an index of potency) or intrinsic activities (% of maximum response) for relaxations for the three compounds. Pretreatment with propranolol 10(-6) mol litre-1, flumazenil 10(-7) and 10(-6) mol litre-1 or PK11195 10(-6) mol litre-1 had no effect on diazepam- or midazolam-induced relaxation. Diazepam 3 x 10(-6) mol litre-1 pretreatment shifted the concentration-response curves for acetylcholine, histamine and serotonin (5-HT) to the right by a factor of approximately 2. Flunitrazepam 3 x 10(-6) mol litre-1 pretreatment also shifted the curves for histamine and 5-HT similarly to the right, whereas midazolam pretreatment did not inhibit any agonist-induced contractions. These results suggest that benzodiazepines relax airway smooth muscle, not via neural pathways or central and peripheral benzodiazepine receptors, but by a direct action on airway smooth muscle.

Preventative effect of PGE1 for postoperative liver damage.

The efficacy of a low dose of PGE(1)-use on the postoperative liver damage was evaluated. PGE(1) was infused in with the mean rate of 0.026 microg.kg(-1).min(-1) during surgical procedure to 93 patients under GO-enflurane anesthesia (the PG). Serum GOT, GPT and total bilirubin (TBIL) values measured before, at the end of (End) and 3 days (3d) after the operation were compared to those obtained from 43 patients without PGE(1) administration (the control). This dose of PGE(1) did not change blood pressure and heart rate, but slightly decreased Pa(O)(2). In patients with preoperative normal values of GOT, GPT and TBIL, increases in GOT, GPT and TBIL observed at End in the PG were significantly lower than those in the control (31.9 vs 72.2 IU, 25.9 vs 61.9 IU, 0.68 vs 0.83 mg.dl(-1), respectively). GOT, GPT and TBIL at 3d significantly increased in both groups, and these levels were identical between the two groups. In patients with preoperative abnormal values, only GOT at End increased in both groups, while no significant difference between the PG and the control group was noted. GOT at 3d and GPT at End and 3d did not significantly changed in either group. These results suggest that the low dose of PGE(1) administered during an operation prevents the development of postoperative liver damage, but does not treat the damaged hepatic cells.

Effects of neostigmine and edrophonium on human erythrocyte acetylcholinesterase activity.

Erythrocyte acetylcholinesterase (AChE) activities in vivo were measured over 60 min using a spectrophotometric method after administration of neostigmine or edrophonium for antagonism of pancuronium-induced neuromuscular block in 31 patients. Erythrocyte AChE activities decreased to 11.3 (SD 1.2)% and 11.4 (0.8)% of baseline values (P less than 0.001) within 2 min, then recovered slowly and were 43.2 (6.2)% and 27.9 (2.9)% (P less than 0.001) 60 min after administration of neostigmine 0.036 mg kg-1 and 0.071 mg kg-1, respectively. However, the enzyme activity after edrophonium 1.43 mg kg-1 did not change significantly over 60 min. The results suggest that mechanisms other than AChE inhibition may be responsible for the anti-curare effect of edrophonium.

Partial Purification and Characterization of Polyphenol Oxidase Isozymes in Banana Bud.

Polyphenol oxidase was extracted from banana buds in the presences of Triton X-100, isoascorbate, and Polyclar AT, and two isozymes I and II have been separated and partially purified by chromatographies on Butyl Toyopearl 650 and DEAE-cellulose. I and II had different mobility in polyacrylamide gel electrophoresis with optimum pHs of 6.8 and 5.5, respectively. Both enzymes showed the apparent Km values of 0.5 mM for dopamine with substrate inhibitions at its higher concentrations. I and II were inhibited competitively by NaCI with the Ki values of 140 mM and 40 mM, respectively. I and II have a high heat stability, and 88 and 95% of the initial activities were retained after 1-hr incubation at 70°C, respectively.

The effects of calcium antagonists on EEG, evoked potentials and neurologic recovery after complete global brain ischemia for 15 minutes in dogs.

The effects of three calcium antagonists on the recovery from neurologic damages after complete global brain ischemia were examined by evaluating the change of a electroencephalogram (EEG), evoked potentials (EP) and a neurologic recovery score (NRS) in dogs. Fifteen minutes global brain ischemia was achieved by occluding the ascending aorta and the caval veins. Nicardipine (NC), flunarizine (FL) and diltiazem (DL) were administered with continuous infusions for three days after the ischemia. The EEG-EP scores (0 : no response - 6 : normal) 3 hr after the ischemia were 1.4 +/- 0.4 (mean +/- SE) in the control, 2.2 +/- 0.3 in the NC, 2.2 +/- 0.4 in the FL and 2.1 +/- 0.2 in the DL. There were no significant differences between the 4 groups. The survival rates on the 7th day after the ischemia were 67% (6/9) in the control, 78% (7/9) in the NC, 56% (5/9) in the FL and 89% (8/9) in the DL. No significant differences were presented between the 4 groups. The NRSs (0 : death - 100 : normal) on the 7th day were 40.3 +/- 7.3 in the control, 59.0 +/- 8.5 in the NC, 63.2 +/- 9.7 in the FL and 55.7 +/- 3.3 in the DL. Each treated group showed a tendency to have a higher NRS than that in the untreated control group. The NRS in all dogs treated by the Ca(++) antagonists on the 7th day was 58.7 +/- 4.1, which was significantly higher than that in the control group ( P < 0.05). We conclude that the continuous administration of calcium antagonists for three days after the global brain ischemia would be beneficial for the neurologic recovery.

[The effect of surfactant therapy associated with high frequency jet ventilation on oxygenation in canine lavaged lungs].

The effects of exogenous surfactant (SF) replacement therapy associated with high frequency jet ventilation (HFJV) on blood gas changes, pulmonary and hemodynamic variables were studied in canine lavaged lungs. The lungs were lavaged repeatedly with physiological saline until PaO2 decreased to 100 mmHg under intravenous pentobarbital anesthesia with 100% oxygen. SF (50 mg.kg-1) in the experimental group (n = 12) and saline in the control group (n = 8) were administered to the trachea using HFJV with a duration of 10 min. HFJV was further continued for 1 hour to make surfactant distribute evenly. Then respiration was controlled by the conventional mechanical ventilator for 3 hrs. During the administration of SF (10 min). PaCO2 was not altered. In the surfactant group, PaO2 improved significantly (200 mmHg) at the end of HFJV and was maintained for the next 3 hrs at this level, but it did not improve in the saline group. Therefore, we suggest that HFJV can be used safely for the treatment of acute respiratory failure and is an effective method for the administration of the pulmonary surfactant into the alveoli.

The effects of a thromboxane A2 receptor antagonist on neurologic recovery after 15 min complete global brain ischemia in dogs.

The effects of a thromboxane A(2) receptor antagonist (anti-TXA(2); ONO-3708) on the neurologic recovery after 15 min complete cerebral ischemia were investigated in dogs. Complete cerebral ischemia was achieved by occlusion of the trunk of the aorta, the superior and the inferior caval vein. Seventeen dogs were divided into 2 groups; 1) control group (no drug, n = 9), 2) Anti-TXA(2) group (anti-TXA(2) 200 mcg.kg(-1) in iv bolus soon after recirculation followed by continuous infusion at a rate of 10 mcg.kg(-1).min(-1) for 3 days, n = 8). EEG, auditory brainstem response (ABR), middle latency response (MLR), and somatosensory evoked potential (SEP) recordings were obtained before ischemia, 120 min after re-circulation and on the 7th day after ischemia. The neurologic recovery score (NRS) were determined on the 3rd and the 7th day. Impaired EEG score was significantly higher in the anti-TXA(2) group on 7th day after ischemia ( P < 0.05). Anti-TXA(2) increased the reappearance rates of the ABR-Vth ( P < 0.05) and the SEP-N(3) waves ( P < 0.01) at 120 min after ischemia. The survival rate tended to be higher in the anti-TXA(2) group. However, NRS did not significantly differ in the groups.

The antiarrhythmic effect of flecainide on halothane-epinephrine induced arrhythmias in dogs.

The antiarrhythmic effect of flecainide acetate (FCN), a newly developed class I antiarrhythmic drug, was evaluated on epinephrine (E)-halothane induced arrhythmias in dogs. The arrhythmogenic dose of E (ADE) under 1% of halothane was significantly increased from 0.71 +/- 0.08 to 1.08 +/- 0.11 and 1.84 +/- 0.23 micro g.kg(-1).min(-1) by the administration of 2 and 4 mg.kg(-1) of FCN, respectively. The arrhythmias induced by ADE in the absence of FCN were stopped by 1.78 +/- 0.29 mg.kg(-1) of FCN in bolus injections. These results suggest that FCN can be used for the treatment of arrhythmias that E contributes to under halothane anesthesia.

The effects of nicardipine given after 10-minutes complete global cerebral ischemia on neurologic recovery in dogs.

The effect of nicardipine (NC) on neurologic recovery from ischemic insult after 10-minutes complete global cerebral ischemia was evaluated in dogs by examination of neurologic recovery score (NRS: complete recovery = 100, death = 0). Ischemia was achieved by occlusion of ascending aorta, and NC, 10 microg.kg(-1) in bolus followed by infusion of 0.33 microg.kg(-1).min(-1) for 2 hours, was administered immediately after re-establishment of circulation. The mortality at 7th day was 2/9 in the control Copyright and 1/9 in the NC group (ns). NRS on 2nd day was 52.3 +/- 6.8 in the C and 70.6 +/- 6.5 in the NC ( P < 0.05), but that on 7th day did not differ between the two groups. The numbers of dogs recovered to over 80 in NRS on the 2nd day was 1/9 in the C and 5/9 in the NC ( P < 0.05), but that on the 7th day increased to 3/9 in the C and remained at 5/9 in the NC (ns). These results suggest that NC accelerates the early neurologic recovery from ischemic damage, but influences little the final outcome.