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Giant left atrium due to mitral stenosis with massive atelectasis: A successful case with perioperative approach☆ Atsushi Tanita , Yusuke Hosokawa ⁎, Takeshi Tomiyama , Maiko Kato , Junya Matsuda , Keisuke Sawai , Yoshie Arita , Toshiyuki Aokage , Hiroomi Suzuki , Hiroshige Murata , Hideki Miyachi , Toshiyuki Shibui , Takahito Nei , Koichi Akutsu , Takeshi Yamamoto , Shinhiro Takeda , Takashi Nitta , Kunio Tanaka , Kyoichi Mizuno , Keiji Tanaka a

¶Background. There have been some reports that radiation necrosis can be controlled conservatively. There are rare cases showing progressive space-occupying radiation necrosis (PSORN). It is very difficult to control PSORN by conservative treatment. The purpose of this study was to evaluate the early diagnosis of those cases and the timing of surgery for patients with PSORN. Method. We have experienced some cases where quality of life was improved by the removal of PSORN after stereotactic radiosurgery (SRS) for brain metastases. Therefore, we evaluated retrospectively the diagnosis and treatment of six cases of symptomatic PSORN at approximately 6–12 months after SRS for metastatic brain tumours. Findings. In all six cases, on Magnetic Resonance Imaging with Gd contrast material (Gd-MRI), PSORN was revealed as a ring-like enhanced mass with large perifocal oedema coupled with the appearance of neurological deficit. Proton Magnetic Resonance Spectroscopy (1H-MRS) enabled us to differentiate PSORN from recurrence of metastases in all six cases. Single Photon Emission Computed Tomography with thallium-201 chloride (201TlCl-SPECT) enabled us to do this in four cases of the six. In four cases of the six, lesionectomy of the ring-like enhanced mass (PSORN) was performed, and in two of these cases the removal was performed within 4 weeks from the time when conservative treatment became ineffective, and the neurological deficit and perifocal oedema was improved as was the quality of life. However, in the other two patients who were left for more than 16 weeks, the deficit was gradually progressive. The two patients who did not receive lesionectomy were treated by conservative means with steroids and/or heparin and warfarin and they had progressive neurological symptoms. Interpretation. Although, the number of patients is small in this study, and more data will be needed, it is recommended that lesionectomy is performed at an early stage, if possible, when conservative management has failed.

A transient (lasting for 15 min) bilateral carotid artery occlusion model was created by using male Mongolian gerbils ( n=20, weight 50-60 g). The animals were divided into a group with mild hypothermia (34 degrees C, n=10) and a normothermic group (37 degrees C, n=10). High-energy phosphate metabolism (ATP, PCr, Pi) and intracellular pH were sequentially measured using (31)P-MRS during ischemia and after reperfusion for 1 week. The same animals were also subjected to a histopathological evaluation. During ischemia, there were no statistically significant differences between the two groups in the quantities of the metabolites. However, after reperfusion the rate of metabolic recovery by the mildly hypothermic (MH) group was significantly higher (by 10-20%) than the normothermic (NT) group. The intracellular pH decreased about 0.4 in both groups after ischemia; and after reperfusion the intracellular pH of the MH group returned to baseline levels faster than in the NT group. One week after ischemia, energy metabolism gradually decreased about 10-20% in both groups. In the histopathological evaluation, pyramidal cell damage in the hippocampus was 33% on average in the MH group and 79% in the NT group. The neuronal damage to the cerebral cortex was 26% in the MH group and 61% in the NT group. Astrocyte reactivity in the hippocampus and cerebral cortex was 2.9% and 1.1% in the MH group and 9.7% and 5.2% in the NT group. The results of this experiment indicate that the protective effect of mild hypothermia is due to the high recovery rate of ATP and PCr and the prevention of a secondary decline in high phosphate energy.

Renovascular hypertension occasionally manifests clinically as electrolyte disorders and albuminuria in addition to elevated blood pressure. A 49-year-old man who had renovascular hypertension also had severe hypokalemia, hyponatremia, polyuria and polydipsia that were treated by an angiotensin-converting enzyme inhibitor and resection of an atrophic kidney with a compromised blood supply. This is a case of hyponatremic-hypertensive syndrome related to renovascular hypertension and occurring as an additional abnormality.

Emergency triage and therapeutic decisions using the recently developed whole blood rapid troponin T test were evaluated and compared with conventional electrocardiographic (ECG) diagnosis in a total of 155 patients with chest pain who visited 16 emergency outpatient clinics in the Tokyo metropolitan area. Thirty-seven patients (23.9%) had a final diagnosis of acute myocardial infarction or high-risk unstable angina requiring emergency coronary intervention and these events were defined as acute coronary syndrome. Diagnostic values using the second-generation rapid troponin T test were evaluated according to 3 time-windows in 85 patients. The sensitivity of the test was 10% for patients assessed within 3 h after the onset, 62.5% for 3-6 h after, and 75% for more than 6h, whereas conventional ECG diagnosis had 100% sensitivity at any time-window. In contrast, the specificity of the rapid troponin T test was 100%, 100%, and 97.4%, whereas that of conventional ECG diagnosis was 25%, 57.1%, and 42.2%, respectively for the 3 time-windows. The positive predictive value of ECG diagnosis was inferior to the rapid troponin T test, which reflected the prudent attitude of physicians taking ECG decisions as positive when myocardial ischemia was suspected. The diagnostic efficacy of the rapid troponin T test was remarkable in patients with the non-ST elevation type of acute coronary syndrome. A questionnaire survey on therapeutic decisions revealed that only 10% of Tokyo outpatient institutes performed prehospital thrombolytic therapy, 30-33% administered aspirin or nitrate, and 16.7% gave heparin. The rapid troponin T test is extremely useful for cardiac emergency triage and therapeutic decision making. There is a requirement for practical guidelines for the primary therapeutic decisions for patients with suspicious acute coronary syndrome.

It is often difficult to make a correct diagnosis of ring-like enhanced lesions on Gd-enhanced MR brain images. To differentiate these lesions using proton MR spectroscopy (1H-MRS), we retrospectively evaluated the correlation between the 1H-MR spectra and histopathological findings. We evaluated proton MR spectra obtained from the lesions in 45 patients, including metastasis (n = 19), glioblastoma (n = 10), radiation necrosis (n = 7), brain abscess (n = 5), and cerebral infarction (n = 4). The rate of misdiagnosis was found to be lowest at the threshold level of 2.48 for the (choline containing compounds)/(creatine and phosphocreatine) ratio (Cho/Cr) obtained from the whole lesions, which include the enhanced rim and the non-enhanced inner region. That is, the positively predictive values of a Cho/Cr greater than 2.48 for diagnosing metastasis or glioblastoma was 88.9 and 60.0%, respectively, and the positively predictive value of a Cho/Cr less than 2.48 for diagnosing radiation necrosis or cerebral infarction was 71.4 and 100%, respectively. For further differentiating between metastasis and glioblastoma, information about the presence and absence of an N-acetyl-aspartate (NAA) peak and lipid- or lactate-dominant peak was found to be useful. In 73.7% of metastasis cases a lipid-dominant peak was observed in the whole lesion without an NAA peak in the inner region, whereas the same pattern was observed in only 10% of the glioblastoma cases. Correlation with the histopathological findings showed that a high Cho signal is suggestive of neoplasm. Lipid signal in the non-enhanced central region was correlated to necrosis. Lactate signals were often observed in glioblastoma, abscess and sometimes metastasis, presumably reflecting the anaerobic glycolysis by the living cells in the ring-like enhanced rim. Single-voxel proton MR spectroscopy may serve as a potential tool to provide useful information of differentiation of ring-like enhanced lesions that cannot be diagnosed correctly using enhanced MR images alone.

In patients with paraneoplastic cerebellar degeneration (PCD) due to gynecologic malignancies, a high titer of anti-Purkinje cell antibody (anti-Yo) has been found. Most patients, however, have limited oncologic disease at the time of onset of neurologic symptoms. We describe 2 cases of PCD due to tubal cancer with anti-Yo antibody. The onset of PCD occurred 4 and 14 months before the detection of cancer, respectively, and the presence of anti-Yo antibody facilitated early laparotomy in both cases. These patients, whose neurologic symptoms have not progressed, have survived without evidence of disease for 81 and 30 months since surgery, respectively. The presence of the anti-Yo antibody in patients with PCD warrants an aggressive approach to diagnosis and treatment of the underlying gynecologic cancer.

Dibutyryl cAMP (DBcAMP) has a high membrane permeability, and maintenance of the intracellular cAMP concentration may improve the viability of organs. In this study, the effect of DBcAMP pretreatment on warm ischemic injury of rat livers was evaluated. Warm ischemic liver injury was induced in adult Wistar rats weighing 250-280 g by leaving them at room temperature (22-25 degrees C) after cardiac arrest. The hepatic cAMP concentration, %ATP, and trypan blue-positive nuclear ratio were determined after different durations of warm ischemia. In addition, transaminase and endothelin-1 (ET-1) release into the perfusate were examined during 60 min of isolated liver perfusion with Krebs-Henseleit solution. The optimal dose and time of DBcAMP pretreatment were determined to be 15 mg/kg and 60 min prior to warm ischemia, respectively. Data on the trypan blue-positive nuclear ratio and the release of transaminases and ET-1 revealed that warm ischemia first damaged the endothelial cells and then the hepatocytes. DBcAMP pretreatment appeared to protect the liver from warm ischemic injury by increasing the intracellular cAMP concentration and stabilizing the cell membranes of endothelial cells and hepatocytes.

The aim of the present study was to investigate whether percutaneous coronary intervention–related periprocedural myocardial infarction (MI) can be suppressed more significantly with high- compared with low-dose rosuvastatin. A total of 232 patients scheduled to undergo elective percutaneous coronary intervention within 5 to 7 days were assigned to groups that would receive either 2.5 or 20 mg/day of rosuvastatin (n = 116 each). The incidence of periprocedural MI did not significantly differ between the high and low-dose groups (8.7% vs 18.7%, p = 0.052). In patients who were not taking statins at the time of enrollment, high-dose rosuvastatin significantly suppressed periprocedural MI compared with the low dose (10.5% vs 30.0%, p = 0.037). The difference was not significant in patients who were already taking statins (high vs low dose 7.6% vs 10.6%, p = 0.582). In conclusion, the incidence of percutaneous coronary intervention–related periprocedural MI was reduced more effectively by high-dose than by low-dose rosuvastatin in statin-naive patients. However, low-dose rosuvastatin is sufficient for patients who are already taking statins.

Uveitis was induced in rats by endotoxin administration. The temporal correlation between ocular inflammatory reaction and lens metabolic change was examined. The levels of lens phosphate compounds, adenosine triphosphate (ATP), choline phosphate (CP), and inorganic phosphate (Pi), were measured using 31P-nuclear magnetic resonance (NMR) spectroscopy. Anterior chamber inflammation reaction appeared 12 h after administration, peaked at 24 h, and disappeared by 72 h. Concurrent with the active inflammation, lens Pi increased significantly 22 +/- 17% (p < 0.05) and 23 +/- 15% (p < 0.05), 12 and 24 h after administration, respectively, and returned to normal while the inflammation abated. No significant changes were observed in CP and ATP levels in the lens during the course of inflammation. The time course of the inflammation appeared closely related to the change in Pi level, which may be part of the protective mechanism of the lens against inflammation.

Rat carrageenin-induced pleurisy was used as an acute exudative inflammatory model. The crude ethanol extract of the pleural fluid at 5 hr after carrageenin injection caused the very slow contraction of guinea-pig ileum, which was antagonized by FPL 55712 (1 microgram/ml). The ethanol extract was cleaned by LH-20 and was rendered for separation of LTC4 and LTD4 by reversed-phase high-performance liquid chromatography (HPLC). Two peaks which showed the same retention time on HPLC as those of LTC4 and LTD4 had the contractile activity of guinea-pig ileum and the ratios of the contractile activity to the height on HPLC agreed with those of synthetic LTC4 and LTD4. Two peaks of delta 6-trans-LTB4, 5S, 12R-(E, E, E, Z)-diHETE and 5S, 12S-(E, E, E, Z)-diHETE, were detected, but the appreciable amount of LTB4 was smaller than that of each delta 6-trans-LTB4 in the pleural fluid at 5 hr.

The actions of leukotriene (LT) C 4 and D 4 on the systemic arterial pressure and the insufflation pressure in guinea pigs and rabbits were examined. In guinea pigs, 0.3 – 3 nmole/kg of LTC 4 and 0.1 – 1.0 nmole/kg of LTD 4 administrated from left jugular vein caused dose-dependent increase of the airway resistance measured by the Konzett-Rossler method and a triphasic blood pressure response; an initial hypotension, a secondary hypertension and a third long-lasting hypotension. All of the hypertensive phase and 100 – 150% of the increase of the airway resistance by LTC 4 and LTD 4 were inhibited by a selective thromboxane synthetase inhibitor, OKY-1581 (10 mg/kg, i.v.) and only the hypertension was observed. Indomethacin (10 mg/kg, i.p.) also inhibited not only the airway resistance increase, but also the prolonged hypotension by LTC 4 and shortened the duration of the hypotension by LTD 4 . It is suggested that thromboxane might be involved in bronchoconstriction and hypertensive effects by LTC 4 and LTD 4 and that hypotensive prostaglandin might be involved in the hypotensive phase after LTC 4 and LTD 4 . In rabbits, the increse of the airway resistance by LTC 4 and LTD 4 (upto 100 nmole/kg, i.v.) was negligible and only the hypotension was observed.

A single platelet thrombus was formed in an arteriole of the hamster cheek pouch by electrical stimulation followed by topical application of ADP. The sizes of the thrombi were continuously recorded with a photocell placed on a TV monitor screen and quantified by areas on the record. Repeated application of small doses of ADP (5–15 nmol/10 μl) resulted in very reproducible formation of the thrombi, and the size of the thrombi was reduced dose-dependently by topical application of PGI2. Three drugs were tested in this model. Cycloxygenase inhibitor (indomethacin 10 mg/kg, i.p.) increased the formatiion of thrombi, while a smaller dose (3 mg/kg) did not have any significant effect. This could be explained by inhibition of the generation of endogemous PGI2, since aggregation of hamster platelets by ADP was not inhibited by indomethacin in vitro . EG-626 (phthalazinol, a phosphodiesterase inhibitor) (300 mg/kg, i.p.) decreased the size of thrombus. AI-122 (1.0 mg/kg, i.p.) which has been proven to enhance PGI2 biosynthesis from isolated rat aortae, also decreased the formation. Thus, drugs such as EG-626 or AI-122 are quite promising as anti-thrombic drugs.

A lithium and carbamazepine combination was reported in five patients with bipolar disorder (DSM-III), who had not received benefits from conventional treatments. Patients 1, 2 and 4 showed favorable antimanic responses to carbamazepine used in combination with lithium carbonate. Patient 3 did not respond well to either lithium or carbamazepine alone, but improved dramatically on the simultaneous administration of the two drugs. The prophylactic benefit was observed in two patients. These clinical results suggest that a lithium and carbamazepine combination may be more efficacious in the treatment of acute manic episode and the prevention of affective recurrences than each drug alone.

Injection of γ-carrageenin into t he pleural cavity of rats caused the accumulation of the pleural exudate. When levels of prostaglandins (PGs) and thromboxane (TX) B 2 were quantified by gas chromatography-mass spectrometry as their methyl ester (ME)-dimethyllisopropylsilyl (DMiPS) ether or ME-methoxine-DMiPS ether derivatives, 6-keto-PGF 1α reached the maximum at 1 hr after carrageenin, then PGE 2 and TXB 2 showed peaks at 3 hr and waned off before 9 hr. he PGF 2α level was kept low, but PGD 2 , PGE 1 and PGF 1α were not detected. Aspirin (100 mg/kg, i.p.) significantly decreased the PG and TXB 2 levels and suppressed the rate of plasma exudation until 5 hr, but did not at 7 hr, when it was measured by the amount of exuded pontamine sky blue injected intravenously. OKY-025 (300 mg/kg, i.p.), a selective TXA synthetase inhibitor, and tranylcypromine (20 mg/kg, i.p.), a PGI synthetase inhibitor, could not extensively inhibit the accumulation of the exudate. These results suggest that the cyclooxygenase products of arachidonic acid, particularly PGE 2 , definitely play an important role in the exudation during the first 5 hr.

Rat pleurisy was induced by intrapleural injection of lambda-carrageenin. The pleural exudate began to be accumulated 1-3 h after carrageenin administration and showed a peak at 19 h. The levels of prekallikrein and high-molecular-weight (HMW), but not low-molecular-weight (LMW), kininogen in the pleural fluid were markedly decreased when compared with those in plasma. Prekallikrein in rat plasma was activated by incubation with carrageenin in vitro. Captopril increased the plasma exudation significantly at 1-5 h. Depletion of prekallikrein and HMW kininogen in rat plasma by preadministration of bromelain caused marked inhibition of the plasma exudation at 1-24 h. The rest of the plasma exudation after bromelain was further decreased by simultaneous pretreatment of rats with both bromelain and aspirin. These results clearly indicate that plasma prekallikrein was activated in the pleural cavity and bradykinin released was responsible for plasma exudation during the entire course of this pleurisy.

A 70-year-old female was treated surgically for an extracerebral cavernous hemangioma of the middle fossa. The literature contains reports of one autopsy and 20 operative cases of cavernous hemangioma of the middle fossa. We compared these cases with cerebral cavernous hemangiomas and found that the incidence is high in Japanese females and in individuals over 20 years of age (average age, 43 years). Signs and symptoms are usually disturbed visual acuity or ocular movement rather than manifestations of increased intracranial pressure. Plain x-rays showed destruction of the sella without hyperostotic changes of the sella or the middle cranial fossa. CT scans showed isodensity/high-density areas of a dumbbell configuration, with the smaller part in the sella and the larger part in the middle fossa. Other CT features were contrast enhancement and evidence of atrophic processes in the surrounding brain. Conventional angiography showed an avascular mass lesion, but tumor staining was demonstrated only by prolonged injection, selective angiography, or subtraction. A review of the literature and our own operative findings suggest that the origin of this tumor is the cavernous sinus. Total removal of such tumors is difficult because of profuse intraoperative bleeding, and operative mortality is high (38%). It should be stressed that correct preoperative diagnosis is very important in decreasing operative deaths.

Rat IgE pleurisy was induced by the injection of dinitrophenol-conjugated bovine serum albumin (DNP-BSA) 48 hours after the intrapleural injection of rat anti-DNP-IgE serum. IgG-BSA complex pleurisy was also induced by the intrapleural injection of IgG-BSA complexes produced at the optimum ratio in vitro . Plasma exudation was markedly increased in the first 20 minutes, but not observed thereafter, in IgE pleurisy, whereas marked plasma exudation in the first 20 minutes was followed by weak exudation at three and five hours in IgG-BSA complex pleurisy. Leukotrienes (LTs) E4 (100 ng/rat), D4 (32) and B4 (16) were detected on HPLC in the pleural exudate in the first 20 minutes of IgG-BSA complex pleurisy, but less (9 ng/rat) LTE4 alone was detected in the five-hour exudate. The first 20-minute pleural exudate contained 13 ng/rat of LTE4 in IgE pleurisy. The plasma exudation for the initial 20 minutes in IgE pleurisy was completely inhibited by simultaneous treatment of rats with pyrilamine (2.5 mg/kg, i.p.) and methysergide (3 mg/kg, i.p.), as it was in compound 48/80-induced pleurisy. In IgG-BSA complex pleurisy, 90% of the pleural exudate for the first 20 minutes was inhibited by the same treatment, and the rest was completely suppressed by simultaneous treatment with an intrapleural injection of AA-1777, a selective 5-lipoxygenase inhibitor. AA-1777 alone did not reduce the plasma exudation significantly. The 5-lipoxygenase inhibitor was also very effective in reducing the migrating numbers of polymorphonuclear and mononuclear leukocytes to half, without affecting the eosinophils or mast cells.

We studied the effects of positive end-expiratory pressure (PEEP) ventilation in ten patients with acute myocardial infarction (nine in Killip class III, one in Killip class IV; pulmonary capillary wedge pressure greater than 24 mmHg) and of extracorporeal ultrafiltration method (ECUM) in seven patients with refractory heart failure due to acute myocardial infarction and others. Application of PEEP resulted in significant increases in PaO2 and SaO2 and decrease in PaCO2. Significant reduction in mean pulmonary arterial and pulmonary capillary wedge pressures and heart rate was observed, while stroke work index increased significantly. There was a significant correlation between changes in stroke work index and PaO2 after the application of PEEP. The use of ECUM removed fluid of 1416 +/- 662 ml (680-2800 ml) with the ultrafiltration flux rate being 478 +/- 223 ml/hour. Significant decreases in mean pulmonary arterial, pulmonary capillary wedge and central venous pressures were observed, while PaO2 increased significantly. BUN and serum creatinine levels increased significantly, and total protein and serum albumin tended to increase. There was a significant correlation between fluid removed and change in PaO2 after the use of ECUM. Thus, PEEP and ECUM are beneficial for patients with refractory heart failure. The mechanism(s) are: reduction in preload due to an increased intrathoracic pressure and a decreased systemic venous return with PEEP, or due to removal of excess fluid with ECUM, and improvement of the oxygenation of the blood.

Intrapleural injection of 2% λ-carrageenin caused the accumulation of exudate up to 19 hr. The rate of plasma exudation, measured by the exuded dye amounts for 20 min in the pleural cavity after intravenous injection of pontamine sky blue, showed a peak at 5 hr. Aspirin (100 mg/kg, i. p.) suppressed the dye exudation up to 5 hr, but did not at 7 hr. This inhibition coincided with the decrease of the PG and TXB2 levels, which were measured by gas chromatography-mass spectrometry, in the pleural exudate. In vitro experiments, MK-447, a phenolic compound, stimulates PG endoperoxide biosynthesis at lower doses and inhibits it at higher doses, acting as a tryptophan-like cofactor required by PG endoperoxide synthetase. This drug (0.3, 1.0 and 3.0 mg/kg, i. p.) suppressed the dye exudation dose-dependently up to 5 hr, but did not at 7 hr even at a higher dose, in combination with the dose-dependent decrease of the pleural level of PGE2, which was reported to be a major PG among PGs and TXB2 in the exudate in inducing the plasma exudation (Harada et al ; Prostaglandins, 23 : 881, 1982). Thus, the anti-inflammatory action of MK-447 can be explained by inhibition of PGE2 generation, giving no consideration to the role of oxygen-derived free radicals as a prime mediator in inflammation.

The metabolism of leukotrienes (LTs) in the cell-containing inflammatory exudate of rat pleurisy was studied in vitro . The exudates of both nonallergic carrageenin-induced pleurisy and IgG immune complex-mediated pleurisy converted 3H-LTB4 to 20-OH LTB4, but virtually did not metaboized 3H-LTC4 or 3H-LTE4 up to 2 hrs. 3H-LTD4 was changed to LTC4 by the exudated of nonallergic pleurisy, whereas 3H-LTD4 was metabolized to LTE4 by that allergic pleurisy. Reflecting on the different metabolism, the γ-glutamyl transpeptidase activity in the exudate of carrageenin-induced pleurisy was significantly higher than that in IgG immune complex mediated pleurisy. The enzyme activity was not derived from the blood itself, but from the infiltrated polymorphonuclear leukocytes. The activity of the cell homogenate in both exudates was not significantly different. Thus, it could be concluded that the difference in the metabolism of LTD4 between the nonallergic and allergic pleural exudates in vitro was mainly attributable to the enhanced activity of the γ-glutamyl transpeptidase released in the exudate.

Pleurisy was induced in rats after intrapleural injection of 2% λ-carrageenin. The volume of the pleural exudate increased rapidly between 1 and 3 h, continuing to increase until 7 h. The dye amounts exuded into the pleural cavity for 20 min after 5% pontamine sky blue (60 mg/kg, i.v.) increased markedly at 1 to 3 h, then they kept constant until 6 h, decreasing thereafter. The PGE level in the pleural fluid increased rapidly during the period from 1 to 3 h, when the exudate commenced to accumulate, and then decreased slightly until 7 h. The main PG in the pleural fluid was recognized as PGE2 on thin-layer chromatography. The pretreatment of rats with a PG synthetase inhibitor, indomethacin (5 mg/kg, i.p.), 30 min before carrageenin administration resulted in the significant reduction of dye leakage at 1 h and of the pleural fluid exudation at 1 to 3 h. The intravenous injection into rats of stem bromelain (10 mg/kg, i.v.), a SH-protease from pineapples, caused the depletion of high molecular weight kininogen in plasma without effect on the content of low molecular weight kininogen. The pretreatment of rats with bromelain 30 min before carrageenin caused a marked reduction in the dye exudation during the periods from 1 to 3 h and 5 to 6 h. The accumulation of the exudate was strongly suppressed at the same periods. Although each treatment by itself did not completely abolish the dye and fluid exudation, the treatment of rats simultaneously with indomethacin and bromelain resulted in suppression of dye leakage from 1 to 6 h and practically no fluid accumulation was observed until 4 h. These results strongly indicate that prostaglandin is released in combination with bradykinin at the period when the pleural exudate commences to accumulate.

A mode of interaction of bradykinin with prostaglandins (PGs) in pain were compared with that in acute inflammation. When pain production was measured as an increase in reflex hypertensive response of the lightly anesthetized dogs after intrasplenic injection of bradykinin, the response was dependent to the doses (0.3-5 nmol) of bradykinin and that by the small doses (0.1-1 nmol) was blocked by intrasplenic infusion of indomethacin (0.54 mumol/min). The response to the threshold dose of bradykinin (0.3 nmol), which was suppressed during the indomethacin infusion, was potentiated by simultaneous injection of exogenous PGs. Order of the potency was PGI2 greater than PGH2 greater than PGE2 = TXA2 much greater than PGD2. Thus, it is clear that bradykinin induced pain through the generation of one of prostaglandins. On the other hand, the activity of bradykinin in plasma leakage was potentiated by simultaneous injection of PGE2, when tested in rabbit skin. In rat carrageenin-induced pleurisy, plasma prekallikrein was activated and high molecular weight (HMW) kininogen, not low molecular weight (LMW) kininogen, was consumed in the pleural cavity in the entire course of the pleurisy. Bradykinin played a role in plasma exudation in the pleurisy, because the plasma leakage was markedly inhibited in the rats, in which prekallikrein and HMW kininogen in plasma were depleted by intravenous bromelain. PGE2 was found in the pleural exudate, but the contribution of PGE2 itself to the plasma exudation seems to be only 10%. On the basis of the bradykinin release in the pleural cavity, once the PGE2 release was superimposed, the maximal plasma leakage was observed, indicating that PGE2 was released independently from bradykinin, and potentiated the plasma leakage by bradykinin.

Experimental pleurisy in rats was induced by intra-pleural injection of 0.1 ml 2%-λ-carrageenin, as previously reported (1, 2) . The accumulation of pleural fluid continued until the peak volume of 4 ml at 19 hrs after carrageenin injection, involvemen of plasma kallikrein-kinin system in the early phase of the pleurisy was proved with the following series of experiments.(1) The levels of prekallikrein, HMW-and LMW-kininogens in plasma and pleural fluid were measured at 1, 3 and 5 hrs after carrageenin injection. The level of HMW-kininogen in pleural fluid was extremely low, whereas LMW-kininogen level was not reduced. The level of prekallikrein was also low in the pleural fluid, about 1/10 of that in plasma. As the plasma levels of these components in pleurisy rats were not significantly different from those in control rats, the above results suggest that plasma kallikrein-kinin system could be activated at the inflammatory site, but not in circulating blood.(2) Pretreatment with 10 mg/kg intraperitoneal captopril enhanced significantly the accumution of pleural fluid as well as dye exudation.(3) Pretretament with bromelain, 10 mg/kg intravenously, which was shown to exhaust HMW-kininogen and prekallikrein, suppressed the accumulation of pleural fluid and dye exudation, significantly at 1, 3 and hrs after crageenin.

Pleurisy was induced by intrapleural injection of 0.1ml of 2% λ-carrageenin in male rats(SD strain, SPF, 8-9weeks). Complement titers were measured by Lachmann’s method(50% hemolysis, CH50), using EAC142, which was made by preincubation of erythrocytes with zymosan-treated serum. Complement titers in pleural exudate, expressed in terms of mg protein, were lower than those in serum during the whole course. Considering the in vitro complement activation of rat serum with carrageenin, it could be concluded that complement was activated in pleural cavity. Pleural exudate accumulation began rapidly 1-3 hr after carrageenin injection. Polymorphonuclear leucocytes (PMN) increased their numbers rapidly up to 5 hr and stayed at the same level thereafter, whereas mononuclear leucocyte (Mono) numbers increased gradually up to 24 hr. Using dexamethasone(arachidonic acid(AA) release inhibitor), benoxapro-fen(a lipoxygenase inhibitor with a weak cyclooxygenase inhibition) and K-76COONa(an inhibitor of complement activation), it could be concluded that PMN migration was induced by arachidonic acid metabolites and activated complements. Mono migration particularly in the late phase might be induced by lipoxygenase products.

As an inflammatory model, rat carrageenin-induced pleurisy was used. The pleural exudate was collected 5 hr after the injection of the 2% λ-carrageenin solution to the right pleural cavity. After measurement of the exudate volume, the extraction of leukotriene (LT) and HETE was performed by addition of 4-fold volumes of ethanol. This crude extract caused the very slow contraction of the guinea-pig (GP) ileum, which was similar to that of LTC4 and was inhibited by FPL55712(1 μg/ml). For further puriflication, LTC4 and LTD4 in the sample were separated as 80% ethanol eluate with Sepahdex LH-20 and LTB4, and HETEs were extracted with diethylether. After evaporation, the purified samples dissolved in methanol were applied to high perfomance liquid chromatography. The peaks, coinciding to the retention time of LTC4 and LTD4, respectively, were collected for examination of the contraction on GP ileum. The contraction by the sample was also inhibited by FPL55712. When the ratios of the contractile activity over the peak height on HPLC were compared, the values of the two peaks of the sample were similar to those of LTC4 and LTD4, respectively. LTB4 in the pleural fluid at 5 hr was smaller than 5,12-diHETE. Several mono-HETEs were also found. These results show the presence of LTC4 and LTD4 in the pleural fluid at 5 hr. As LTC4 and LTD4 are potent in plasma exudation, they might play a role in the carrageenin-induced pleurisy at 5 hr.