Ketamine Suppresses Platelet Aggregation Possibly by Suppressed Inositol Triphosphate Formation and Subsequent Suppression of Cytosolic Calcium Increase

Background: Ketamine has been shown to suppress platelet aggregation, but its mechanisms of action have not been defined. The purpose of the current study is to clarify the effects of ketamine on human platelet aggregation and to elucidate the underlying mechanisms of its action.

Methods: Platelet aggregation was measured using an eight-channel aggregometer, and cytosolic free calcium concentration was measured in Fura-2/AM-loaded platelets using a fluorometer. Inositol 1,4,5-triphosphate (IP3) was measured with use of a commercially available IP3 assay kit. To estimate thromboxane A2 (TXA2) receptor binding affinity and expression, Scatchard analysis was performed using [3H]S145, a specific TXA2 receptor antagonist. TXA2 agonist binding assay was also performed. The membrane-bound guanosine 5'-triphosphatase activity was determined using [[gamma]-32P]guanosine triphosphate by liquid scintillation analyzer.

Results: Ketamine (500 [mu]m) suppressed aggregation induced by adenosine diphosphate (0.5 [mu]m), epinephrine (1 [mu]m), (+)-9,11-epithia-11,12-methano-TXA2 (STA2) (0.5 [mu]m), and thrombin (0.02 U/ml) to 39.1 +/- 30.9, 46.3 +/- 4.3, -2.0 +/- 16.8, and 86.6 +/- 1.4% of zero-control, respectively. Ketamine (250 [mu]m-1 mm) also suppressed thrombin- and STA2-induced cytosolic free calcium concentration increase dose dependently. Although ketamine (2 mm) had no effect on TXA2 receptor expression and its binding affinity, it (1 mm) suppressed intracellular peak IP3 concentrations induced by thrombin and STA2 from 6.60 +/- 1.82 and 4.39 +/- 2.41 to 2.41 +/- 0.98 and 1.90 +/- 0.86 pmol/109 platelets, respectively, and it suppressed guanosine triphosphate hydrolysis induced by thrombin (0.02 units/ml) and STA2 (0.5 [mu]m) to 50.3 +/- 3.2 and 67.5 +/- 5.5%versus zero-control, respectively.     

Experimental study on the pathogenesis of acute ulceration in obstructive jaundice--with reference to gastric mucosal blood flow

We prepared obstructive jaundice models in rats in order to study the mechanism of acute ulceration in obstructive jaundice centering on impediments to gastric wall blood flow and changes in gastric mucosal NA and PGE2 when the rats were subjected to water immersion restraint stress. The results were: In the obstructive jaundice 2 weeks group, when subjected to water immersion restraint stress, gastric mucosal NA reached a dried up stage from the incipient stage, causing gastric mucosal impediments at the same time, showing a significant decrease of gastric mucosal PGE2. Intragastric pH was at a similar level of excessive acidity in all groups; gastric acid is believed to be a secondary factor promoting ulceration. Gastric mucosal PGE2 showed a significant decrease coinciding with the increase in ulceration index, being a possible factor of ulceration; it is also presumed to regulate gastric wall blood flow alternatively with gastric mucosal NA. Pre-treatment with PGE2 prior to loading stress resulted in a decrease in gastric wall blood flow being significantly controlled. The administration of PGE2 brought about an improvement in gastric wall blood flow and a consequent increase in gastric mucosal NA, being judged effective for acute ulceration in obstructive jaundice.     

HISTOPATHOLOGIGAL STUDY OF HYPERTROPHIC CARDIOMYOPATHY WITH PROGRESSION TO LEFT VENTRICULAR DILATATION

The heart of seven cases of fatal congestive heart failure with dilated left ventricle, developing in 5 patients with symptomatic hypertrophic cardiomyopathy (HCM) and 2 patients with histologically widespread disarray of both ventricles, was morphologically investigated. These 7 cases showed myocardial widespread disarray and massive fibrosis, the mean percent area of fibrosis was 40.6% and 59.4% at upper and lower levels of left ventricles, respectively. Fibrosis was most extentsive in the lateral wall, and followed by anterior, posterior and interventricular walls. The severity of cell infiltration in left ventricle was completely matched to that of fibrosis and was most extensive in subepicardial area followed by middle and subendocardial areas of left ventricle. The intima and medial thickness of intramural small arteries in the fibrotic areas was significantly larger (p<0.05) than that of nonfibrotic areas, which suggested that the effect of intramural small artery was not essential for pathogenesis of massive fibrosis. ACTA PATHOL. JPN. 37: 1041 -1052, 1987.     

The fates of trichothecene mycotoxins, nivalenol and fusarenon-X, in mice

In order to investigate the comparative fates of nivalenol (NIV) and 4-acetyl derivative of NIV (fusarenon-X, FX) in mice, ³H-FX or ³H-NIV was given p.o. to mice. Radioactivity was excreted mainly via the urine in mice given ³H-FX, but mainly via the feces in mice given ³H-NIV. The plasma radioactivity reached a peak at 30 or 60 min after the administration of ³H-FX or ³H-NIV, respectively. The plasma peak level was 5 times higher, and the area under curve (AUC) was 10 times higher, in ³H-FX-administered than ³H-NIV-administered mice. These findings clearly demonstrate that FX is absorbed from the gastrointestinal tract more rapidly and efficiently than NIV. The HPLC profile of radioactivity of acetonitrile extracts of urine and feces indicated that FX is rapidly metabolized to NIV after being absorbed from the gastrointestinal tract. In vitro incubation of tissue homogenates with ³H-FX demonstrated that the liver and kidney are the organs responsible for the FX-to-NIV conversion. Thus this study demonstrated that the higher oral toxicity of FX than NIV that has been observed in mice and rats is due to the efficient absorption of FX than NIV from the gastrointestinal tract, followed by its rapid conversion to NIV by the liver and kidney.     

NEWLY DEVELOPED ULTRASOUND ENDOSCOPE WITH AN ELECTRONIC RADIAL ARRAY TRANSDUCER

A prototype electronic radial scan ultrasound endoscope has been developed by Olympus (Tokyo, Japan) for endoscopic ultrasound (EUS) study. The ultrasound view‐angle of this model is 360° vertical to the scope. Though the diameter of the scanner and the shaft of the scope is bigger than those of the present mechanical radial scan model, clinical manipulation of the new scope is the same as that of the present model. Image quality of the ultrasound picture demonstrated by the electronic radial model was as clear as those provided by the mechanical radial scan model. Ultrasound penetration was better and satisfactory because of less echoic reduction compared to the mechanical radial model. The newly developed electronic radial model can be evaluated as an ultrasound endoscope for the next generation. The advantage of this system is to facilitate the clinical use of color Doppler function and tissue harmonic imaging, and this system can be operated by the same monitor unit as a convex model of ultrasound endoscope.     

Surgical treatment for carcinoma of the papilla of vater

Eighty of 89 patients who underwent radical resection (resectability 89.9%) for carcinoma of the papilla of Vater between 1976 and 1992 were retrospectively reviewed. Seventy-three patients underwent pancreaticoduodenectomy (PD) and 7 underwent pylorus-preserving pancreaticoduodenectomy (PPPD). The postoperative mortality rate was only 3.8% (3 patients). The 3- and 5-year survival rates were 63.6% and 57.4%, respectively. Important factors influencing long-term survival were Stage (clinical stage = Stage), microscopic lymph node metastasis (n), duodenal wall invasion (d), vascular invasion (v), and the epithelium of origin. Early carcinoma of the papilla of Vater is defined as tumor in which invasion is limited within the papilla of Vater; in particular, carcinomatous invasion is within the muscle of Oddi (d₀) with n₀. PD and/or PPPD with radical lymph node dissection should be performed for carcinoma of the papilla of Vater, as these procedures can be performed with low morbidity and mortality.     

Local muscimol disinhibits mesolimbic dopaminergic activity as examined by brain microdialysis and Fos immunohistochemistry

Infusion of muscimol (5×10⁻⁵ M, 60 min) into the nucleus accumbens (NAC) through a dialysis membrane caused a significant increase in extracellular dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). Fos-like immunoreactivity induced by intra-NAC infusion of muscimol was seen ipsilaterally in many accumbofugal target areas, but no Fos-positive neurons were seen in the vicinity of the dialysis membrane in the NAC. Sequential staining of Fos and tyrosine hydroxylase (TH) immunoreactivities revealed that a portion of A10 dopaminergic neurons were double-labelled. These results suggest that muscimol in the NAC disinhibits mesolimbic DA neuronal activity possibly through activity of the accumbofugal GABA neuron system.