Differential Effects of Etomidate and Midazolam on Vascular Adenosine Triphosphate-sensitive Potassium Channels: Isometric Tension and Patch Clamp Studies

Background: The aim of this study was to investigate the effects of two imidazoline-derived intravenous anesthetics, etomidate and midazolam, on vascular adenosine triphosphate-sensitive potassium (KATP) channel activity.

Methods: In isolated rat aorta, isometric tension was recorded to examine the anesthetic effects on vasodilator response to levcromakalim, a selective KATP channel opener. Using the patch clamp method, the anesthetic effects were also examined on the currents through (1) native vascular KATP channels, (2) recombinant KATP channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits, (3) SUR-deficient channels derived from a truncated isoform of Kir6.2 subunit (Kir6.2[DELTA]C36 channels), and (4) mutant Kir6.2[DELTA]C36 channels with reduced sensitivity to adenosine triphosphate (Kir6.2[DELTA]C36-K185Q channels).

Results: Etomidate (>= 10-6 m), but not midazolam (up to 10-6 m), inhibited the levcromakalim-induced vasodilation, which was sensitive to glibenclamide (IC50: 7.21 x 10-8 m; maximum inhibitory concentration: 1.22 x 10-4 m). Etomidate (>= 3 x 10-6 m), but not midazolam (up to 10-4 m), inhibited the native KATP channel activity in both cell-attached and inside-out configurations with IC50 values of 1.68 x 10-5 m and 1.52 x 10-5 m, respectively. Etomidate (10-5 m) also inhibited the activity of various types of recombinant SUR/Kir6.0KATP channels, Kir6.2[DELTA]C36 channels, and Kir6.2[DELTA]C36-K185Q channels with equivalent potency.     

Pharmacologic preconditioning effects: Prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.     

Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts.

OBJECTIVE: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. METHODS: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. RESULTS: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-gamma and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. CONCLUSION: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.     

Sentinel node sampling limits lymphadenectomy in stage I non-small cell lung cancer.

OBJECTIVE: It is controversial whether a systematic mediastinal lymph node dissection (MLND) needs to be performed in all patients with stage I lung cancer. The present study was done to examine the new sentinel lymph nodes hypothesis based on the lobe of the primary tumor. METHODS: In our first study, the lymph node (LN) metastases were assessed in 291 stage I non-small cell lung cancer (NSCLC) patients who had a major lung resection with a systematic mediastinal lymph node dissection. We evaluated the validity of using our new sentinel lymph nodes method based on the lobe of the primary tumor as follows: the pretracheal (#3), tracheobronchial (#4), and hilar nodes (#10) for right upper lobe tumors; #4, subcarinal (#7), and #10 for middle lobe tumors; the subaortic (#5), paraaortic (#6), and #10 for left upper lobe tumors; and the #7, #10, and interlobar nodes (#11) for tumors in either lower lobes. In the second study, we performed a lobectomy with new sentinel node sampling in 64 patients with preoperative complications. If all of the sampling nodes showed no metastases on frozen section diagnosis, systematic node dissections were not performed. RESULTS: Six of 291 patients in the first study had skip metastases that did not involve the new sentinel nodes; 5 of the 6 patients had macroscopic pleural invasion. Thus, we defined pleural invasion as an exclusion criterion for the second study. In the second study, the median follow-up time was 39 months. Metastatic lymph nodes were detected in 11 of 64 patients. Fifty-three patients (83%) had no metastasis in the sampled nodes, and, therefore, a mediastinal lymph node dissection was not done. The morbidity rate in the sampling group was 36%, and there was no mortality. In the sampling group, local recurrences were observed in two patients, distant metastases in eight, and carcinomatous pleuritis in one; the overall 5-year survival rate was 82%. CONCLUSIONS: We found that it is possible to perform a less invasive lymphadenectomy for patients with stage I lung cancer using intra-operative sampling of new sentinel lymph nodes.     

Endogenous bone-marrow-derived stem cells contribute only a small proportion of regenerated myocardium in the acute infarction model.

BACKGROUND: Our recent study showed that granulocyte-colony stimulating factor (G-CSF) promoted bone-marrow cells (BMC) to migrate into the infarcted heart and that they differentiated into cardiomyocytes. However, we still do not know to what degree bone-marrow-derived cardiomyocytes contribute to myocardial regeneration after injury. In this study, we verified the proportional contribution of cells from bone marrow (BM) and from non-bone marrow (n-BM) in regenerating neomyocardium after myocardial infarction. METHODS: Eight C57BL/6 mice were irradiated (900 cGy), and green fluorescent protein (GFP) mouse-derived BMCs (GFP-BMC, 1 x 10(6) cells) were injected. Four weeks later, the left descending coronary artery was ligated. Recombinant human G-CSF (200 microg/kg/day, 8 days) was injected. At 4 weeks after ligation, hearts were fixed for histology. We calculated the proportions of cardiomyocytes derived from BM and n-BM after taking the chimeric rate into consideration. RESULTS: The chimeric rate was 54.6% +/- 5.9%. At the infarcted border area, the total cell number was 1000.3 +/- 56.5/mm(2), and mobilized BM-derived GFP-BMC was 103.3 +/- 13.1/mm(2). After compensation with the chimeric rate, we found BM-derived troponin I-positive cells at 23.9 +/- 4.1/mm(2), nestin-positive cells at 12.9 +/- 2.6/mm(2), and Ki67-positive cells at 18.3 +/- 2.6/mm(2), respectively. We found significant differences in the contribution of troponin I-(6.7% +/- 1.7% vs 93.3% +/- 1.7%), nestin- (2.4 +/- 0.5 vs 97.6 +/- 0.5), and Ki67-positive (3.9 +/- 1.0 vs 96.1 +/- 1.0) cells derived from BM and n-BM. CONCLUSIONS: Bone marrow was one of the origins of regenerated cardiomyocytes; however, the contribution of cells from BM was very small compared with those of n-BM origin in the infarction model.     

A nonspecific colonic ulcer occurring after hepatectomy: Report of a Case

We herein report the case of a 53-year-old man with a nonspecific acute colonic ulcer whose liver function deteriorated after he had undergone hepatectomy. He was referred to our hospital for a hepatoma caused by hepatitis B virus and a right hemihepatectomy was performed. His liver function was poor after the operation, and minor complications such as pleural effusion and biliary fistula developed. A large amount of melena was seen 29 days after the hepatectomy and he developed hemorrhagic shock. Superior mesenteric arteriography revealed pooling of blood in both the hepatic flexure of the ascending colon and the cecum. An emergency right hemicolectomy was performed. There was a 5 x 1-mm ulcer 18 cm distal to the ileocecal valve. Numerous erosions were observed to be scattered throughout the colonic mucosa. The patient recovered slowly and was discharged 6 months after the hepatectomy. This is the first report of an acute colonic ulcer that could have been caused by liver dysfunction.     

Clinical effects of percutaneous cardiopulmonary support in severe heart failure: early results and analysis of complications.

Between January 1993 and December 2001, we employed percutaneous cardiopulmonary support (PCPS) in 35 patients. PCPS was used for postcardiotomy in 25 of these patients who could not be weaned from cardiopulmonary bypass (CPB) because of severe cardiogenic shock. In the other 10 patients, PCPS was used for a non-surgical disease. Twenty-nine patients (82.9%) were weaned from PCPS, and 28 (80.0%) survived. The other 7 patients (20.0%) died due to postoperative complications. The causes of death were multiple organ failure (MOF) due to wound bleeding, low cardiac output syndrome (LOS), myonephropathic metabolic syndrome (MNMS) with severe lower limbs ischemia, cerebrovascular accident (CVA), and sepsis. The first cause for the complications was postoperative sustained severe heart failure. To improve the survival rate, it was necessary to prevent bleeding and begin PCPS at an earlier stage.     

Efficacy of continuous cleansing with teicoplanin on post-CABG methicillin-resistant staphylococcus aureus (MRSA) mediastinitis: report of a case.

The patient was a 48-year-old male who was diagnosed with unstable angina. He had worsening cardiogenic shock during coronary angiography. Emergency coronary artery bypass grafting (CABG) was performed. He had a methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis on day 22 after CABG. Drains were placed in the anterior mediastinum, left thoracic cavity, and abscess cavity, and another drain was placed in the mediastinal space for continuous cleansing with povidone iodine, oxydol. For antibiotics, teicoplanin (TEIC) was administered intravenously and to the local site via the cleansing drain for about one month. No MRSA was detected by culture in discharges from the mediastinal drain. Inflammatory findings were improved, and the patient was discharged and resumed everyday life without recurrence of inflammation as of eight months. Although the number of cases of MRSA mediastinitis is small and accumulation of cases is necessary to investigate therapeutic methods and selection of antibiotics, our department will select closed continuous cleansing and TEIC for antibiotics as the first choice for MRSA mediastinitis, and accumulate cases to investigate its efficacy.