Reduction of post-ischemic lung reperfusion injury by fibrinolytic activity suppression

BACKGROUND: Although extensive studies on the detailed mechanisms of ischemia-reperfusion injury have been conducted, the implication of the fibrinolytic system has not been known. To determine the role of the fibrinolytic system in ischemia-reperfusion injury, we used tranexamic acid, a synthetic specific plasmin and tissue-type plasminogen activator inhibitor, to suppress fibrinolytic activity in a rabbit lung ischemia-reperfusion model. METHODS: New Zealand White rabbits were randomly divided into two groups: a simple ischemia group and a group injected with tranexamic acid before left hilar occlusion. After 2 hours of warm ischemia, plasma was collected from pulmonary vessels. Fibrin zymography was used to ascertain fibrinolytic activity, and enzyme-linked immunosorbent assay was used to determine soluble thrombomodulin levels as a marker for endothelial cells damage. Changes in left pulmonary function including arterial oxygen tension, peak airway pressure, and pulmonary vascular resistance were recorded during reperfusion after the 2 hours of warm ischemia. RESULTS: Fibrinolytic activity and soluble thrombomodulin levels increased in the vessels of the ischemic lung, indicating endothelial cell injury. The increased fibrinolytic activity and the rise in soluble thrombomodulin were suppressed by the preadministration of tranexamic acid, resulting in remarkably improved pulmonary function during reperfusion. After 2 hours of reperfusion, the wet-to-dry weight ratios and histological studies showed reduced pulmonary edema in the group that had received tranexamic acid. CONCLUSION: These findings suggest that the fibrinolytic system is involved in the onset mechanism of ischemia-reperfusion injury through induced endothelial cell damage and increased vascular permeability.     

A longitudinal study on social support and life satisfaction among Japanese elderly]

The purpose of this study was to examine the impact of social support on life satisfaction among Japanese elderly aged 60 and over (N = 1,285), using the longitudinal data of a national representative sample. An initial survey was carried out in 1987, and a follow-up was conducted in 1990. We measured life satisfaction by the Life Satisfaction Index A. Social support was measured from two aspects, providing support and receiving support. The impact of social support and changes in support during a period of three years on life satisfaction were assessed by sex after controlling for influences of socioeconomic status, physical functioning, and initial life satisfaction. Providing support predicted a high life satisfaction three years later only in females. Receiving support was not significantly associated with life satisfaction for either males or females. However changes in providing and receiving support had a significant impact on life satisfaction of the elderly. The findings of this study suggest that the effects of social support on life satisfaction differ by sex and the impacts of changes in support are strong determinant predicting life satisfaction of the elderly.     

Development of the local medical service network system. Integration of medical service with the network system between university hospital and other medical institutions.

Although every medical institution always make efforts to provide best services for the patients, it tends to be insufficient to send the patient's information and share them with other medical institutions. It is partly because in the Japanese medical care system there is no obligation to inform patients' medical information to other medical institutions. To provide effective and cost-effective medical service, we made a local network system between university hospital and other medical institutions. The system contributes to clarify the role of medical institutions and the continuity of medical service. For the next step, we must construct the home-care information service network towards the total service for the patients.     

Potentiation of the hypotensive effect of adrenomedullin in pregnant rats

The hypotensive effect of adrenomedullin, a potent vasodilator peptide, was examined in conscious pregnant (6, 13 and 20 days of pregnancy) and non-pregnant rats. The intravenous administration of adrenomedullin (0.01-3.0 nmol/kg) produced a dose-dependent depressor response in pregnant and non-pregnant rats. At low doses (0.01-0.1 nmol/kg), the maximum decrease in blood pressure was significantly higher in pregnant rats (20 days pregnant) than in non-pregnant rats. At high doses, no significant difference was observed between the two groups. Furthermore, the administration of adrenomedullin did not significantly affect the basal mean blood pressure (MBP) at any dose when compared to the non-pregnant group at 6 and 13 days of pregnancy. In the ovariectomized rats, the depressor responses in 17beta-estradiol-treated, progesterone-treated and 17beta-estradiol+progesterone-treated rats were not significantly different from that in the control rats, suggesting that the augmented effect on the depressor response to adrenomedullin in pregnant rats may not be due to hormonal changes during pregnancy. The adrenomedullin receptor mRNA level of the descending thoracic aorta was significantly higher in the late-pregnancy rats (20 days of pregnancy). However, the levels did not show any difference between the early-pregnant rats (6 and 13 days of pregnancy) and the non-pregnant rats. These findings suggested that the changes in the depressor response to adrenomedullin which occur at term in pregnant rats may be mediated by changes of adrenomedullin receptor gene expression rather than by sex hormones.     

Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.     

Influence of glycerol-induced acute renal failure on the pharmacokinetics of cyclosporin in rats.

Although it is widely believed that renal dysfunction has no effect on the pharmacokinetics of cyclosporin, many clinical reports suggest that renal dysfunction after renal transplantation is closely related to the pharmacokinetics of cyclosporin. To clarify the relationship between renal dysfunction and the pharmacokinetics of cyclosporin, we examined the influence of acute renal failure (ARF) on its pharmacokinetics in glycerol-induced ARF rats. The values of indicators of renal function (serum creatinine, blood urea nitrogen), but not those of indicators of hepatic function, were significantly increased in ARF rats that received glycerol compared with values for control rats. The area under the blood cyclosporin concentration-time curve after oral administration (AUCpo) were 4.976+/-0.847 mghL(-1) for ARF rats and 9.684+/-1.100 mghL(-1) for control rats; AUCpo in ARF was significantly reduced in a manner dependent on renal function. The oral clearance of cyclosporin in ARF and control rats was 1.172+/-0.207 and 0.544+/-0.062Lh(-1) kg(-1), respectively, whereas total body clearance in ARF and control rats was 0.151+/-0.008 and 0.183+/-0.010Lh(-1)kg(-1), respectively. The relative bioavailability of cyclosporin in ARF and control rats was 0.118 and 0.336, respectively. In an in-vitro study using everted sac and liver-slice methods, the apparent first-order rate constants for cyclosporin uptake (k(uptake)) and metabolism (k(metab)) in gut tissues were reduced, whereas k(uptake) and k(metab) in liver were increased. Gastric emptying, measured by use of paracetamol, was significantly reduced in ARF rats. These results suggest that glycerol-induced ARF results in several changes in the pharmacokinetics of cyclosporin in rats. From these results, we conclude that reduction of the absorbed fraction of cyclosporin strongly contributes to the decrease in AUCpo in the presence of ARF.     

Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes.

Troglitazone, a new oral antidiabetic drug, is reported to be mostly metabolized to its conjugates and not to be oxidized by cytochrome P-450 (P-450) enzymes. Of fourteen cDNA-expressed human P-450 enzymes examined, CYP1A1, CYP2C8, CYP2C19, and CYP3A4 were active in catalyzing formation of a quinone-type metabolite at a concentration of 10 microM troglitazone, whereas CYP3A4 had the highest catalytic activity at 100 microM substrate. In human liver microsomes, rates of the quinone-type metabolite formation (at 100 microM) were correlated well with rates of testosterone 6beta-hydroxylation (r = 0.98), but those at 10 microM troglitazone were not correlated with any of several marker activities of P-450 enzymes. Quercetin efficiently inhibited quinone-type metabolite formation (at 10 microM troglitazone) in human samples that contained relatively high levels of CYP2C, whereas ketoconazole affected these activities in liver microsomes in which CYP3A4 levels were relatively high. Anti-CYP2C antibodies strongly inhibited quinone-type metabolite formation (at 10 microM troglitazone) in CYP2C-rich human liver microsomes (by approximately 85%); the intensity of this effect depended on the human samples and their P-450 status. The results suggest that in human liver both CYP2C8 and CYP3A4 have major roles in quinone-type metabolite formation and that the hepatic contents of these two P-450 forms determine which P-450 enzymes play major roles in individual humans. CYP3A4 may be expected to play a role in formation of quinone-type metabolite from troglitazone even at a low concentration in humans.     

On the regulation of tryptophan metabolism "via" kynurenine.

The tryptophan leads to nicotinic acid pathway is inhibited in the nicotinic acid administered rats; in this case tryptophan chiefly metabolizes "via" serotonin. The serotonin pathway is inhibited in the excess phenylalanine administered rats, especially due to the inhibition of the tryptophan-5-hydroxylase reaction. Xanthurenic acid inhibits kynurenine-3-hydroxylase in vitro, which is a very important regulatory enzyme for xanthurenic acid and nicotinic acid production.     

Detection of pre-C and core region mutants of hepatitis B virus in chronic hepatitis B virus carriers.

We analyzed the pre-C and core region of hepatitis B virus (HBV) DNA by a polymerase chain reaction in 22 chronic carriers. In 9 hepatitis B e antigen-positive asymptomatic carriers, a single DNA band was detected at the expected size, whereas additional shorter DNA bands were observed in 7 out of 11 patients with chronic hepatitis. The smaller-sized DNAs from one chronic hepatitis patient had various lengths of deletions spanning from 105 to 183 bp in the middle of the core gene, and all deletions included common nucleotide sequences. All of the smaller-sized DNAs from the other patients proved to be variant core genes. They were deleted in similar regions by Southern analysis using oligonucleotide probes. A follow-up study revealed that four out of seven chronic hepatitis patients with a short core gene seroconverted to antibody to hepatitis B e antigen, but those with only a "wild type" did not. In another set of sequence studies, clones isolated from two chronic carriers displayed heterogeneity of the pre-C and core gene which was more often present in sera with normal alanine aminotransferase levels than with abnormal levels. These results suggest that mutant HBV alters the host immune response, and may modulate the clinical course of HBV infection. An alternative possibility is that chronic hepatitis selects for mutant forms.