Toshiteru Ishitani

Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload

1 The present work was carried out in order to determine whether a decrease in cardiac Na+‐Ca2+ exchanger (NCX) activity observed in diabetes is caused by a reduction in NCX protein and mRNA levels and to elucidate the significance of this decrease in alterations in [Ca2+]i homeostasis in diabetic cardiomyocytes. 2 The NCX current was significantly reduced in ventricular myocytes freshly isolated from streptozotocin‐induced diabetic rat hearts, and its current density was about 55 % of age‐matched controls. 3 Diabetes resulted in a 30 % decrease in cardiac protein and mRNA levels of NCX1, a NCX isoform which is expressed at high levels in the heart. 4 The reduced NCX current and the decreased protein and mRNA levels of NCX1 in diabetes were prevented by insulin therapy. 5 Although both diastolic and peak systolic [Ca2+]i were not different between the two groups of myocytes, increasing external Ca2+ concentration to high levels greatly elevated diastolic [Ca2+]i in diabetic myocytes. Inhibition of NCX by reduction in extracellular Na+ by 50 % could produce a marked rise in diastolic [Ca2+]i in control myocytes in response to high Ca2+, as seen in diabetic myocytes. However, cyclopiazonic acid, an inhibitor of sarcoplasmic reticulum Ca2+ pump ATPase, did not modify the high Ca2+‐induced changes in diastolic [Ca2+]i in either control or diabetic myocytes. 6 Only in papillary muscles from diabetic rats did the addition of high Ca2+ cause a marked rise in resting tension signifying a partial contracture that was possibly due to an increase in diastolic [Ca2+]i. 7 In conclusion, the diminished NCX function in diabetic myocytes shown in this study results in part from the decreased levels of cardiac NCX protein and mRNA. We suggest that this impaired NCX function may play an important role in alterations in Ca2+ handling when [Ca2+]i rises to pathological levels.

Imbalances between the levels of tissue factor and tissue factor pathway inhibitor in ARDS patients.

INTRODUCTION To evaluate the pathogenetic role of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and neutrophil elastase in acute respiratory distress syndrome (ARDS), as well as to test the hypothesis that TFPI levels modified by neutrophil activation are not sufficient to prevent TF-dependent intravascular coagulation, leading to sustained systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS), which determine the prognosis of these patients. MATERIALS AND METHODS The study subjects consisted of 55 patients with trauma and sepsis who were divided into three groups according to the Lung Injury Score. Ten normal healthy volunteers served as control. Plasma levels of TF, TFPI, and neutrophil elastase were measured on the day of injury or the day of diagnosis of sepsis (day 0) and days 1 through 4. The number of SIRS criteria that the patient met and the disseminated intravascular coagulation (DIC) score is determined daily. RESULTS Patients (15) developed ARDS, 23 were at risk for but did not develop the syndrome, and 17 patients were without risk for ARDS. TF and neutrophil elastase levels in ARDS patients were persistently higher than those in other two groups and control subjects. However, the TFPI levels showed no difference among the three groups, which retained normal or slightly elevated levels compared to the control subjects. DIC scores did not improve and SIRS continued during the study period in patients with ARDS. The ARDS patients showed higher numbers of dysfunctioning organs and associated with poorer outcome than the other two groups. CONCLUSION Systemic activation of the TF-dependent pathway not adequately balanced by TFPI is one of the aggravating factors of ARDS. High levels of neutrophil elastase released from activated neutrophils may explain the imbalance of TF and TFPI. Persistent DIC and sustained SIRS contribute to MODS, determining the prognosis of ARDS patients.

Tissue factor pathway inhibitor response does not correlate with tissue factor-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome in trauma patients.

ObjectiveTo determine the precise relationship between tissue factor and tissue factor pathway inhibitor (TFPI) after trauma, as well as to test the hypothesis that low TFPI levels are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome (MODS). DesignProspective, observational cohort study. SettingEmergency room and intensive care unit in a university hospital. PatientsThirty-three trauma patients, 18 with disseminated intravascular coagulation (DIC) and 15 without DIC were studied. Ten normal, healthy volunteers served as control subjects. InterventionsNone. Measurements and Main Results Antigen concentration of tissue factor and TFPI, and global parameters of coagulation and fibrinolysis were measured on the day of admission, and on days 1–4 after admission. The number of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined, simultaneously. The results of these measurements, incidence of MODS, and outcome were compared between the DIC patients and those without DIC. In the DIC patients, significantly higher tissue factor levels (p = .0049) and lower platelet counts (p = .0016) were found compared with the non-DIC patients and control subjects. However, the TFPI values remained at normal levels during the study period. No correlation was found between the peak levels of tissue factor and TFPI. The mean duration of SIRS and the maximum number of the SIRS criteria being met by the patients in the DIC group were statistically longer and higher than those in the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the DIC patients compared with those in the non-DIC patients, and the DIC patients had a poor outcome. ConclusionsWe systematically elucidated the relationship between tissue factor and TFPI in post-trauma patients. Highly activated tissue factor-dependent coagulation pathway is not sufficiently prevented by the normal TFPI levels in patients with DIC. The DIC associated with thrombotic and inflammatory responses causes MODS, and leads to poor outcome in post-trauma patients.

Cardiac profile of EGIS-9377, a novel cardiotonic agent as a Ca2+ sensitizer with bradycardiac activity

Abstract. The cardiac profile of EGIS-9377 {2-(1-methylthio)-5-(2-morpholinoethylamino)-8,9-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[1,5-a]pyrimidine dihydrochloride}, a newly synthesized cardiotonic agent, was compared with those of pimobendan and isoprenaline in cardiac preparations isolated from guinea pigs. The positive inotropic potency and efficacy of EGIS-9377 were equal to those of pimobendan in electrically paced papillary muscles, with each agent maximally increasing force of contraction by 30–35% of the maximum effect of isoprenaline. The positive inotropic effects of EGIS-9377 and pimobendan were accompanied by an increase in the relaxation time of the isometric contraction curve, whereas that of isoprenaline was associated with an abbreviation of this parameter. Pimobendan significantly increased the spontaneously beating frequency of right atria, and its positive chronotropic effect amounted to 40% of the maximum effect of isoprenaline. In contrast, EGIS-9377 exerted a significant negative chronotropic action, which resulted in a 30% decrease in the basal frequency. In β-escin-skinned trabecular muscles, both EGIS-9377 and pimobendan substantially enhanced contractions induced by Ca2+. EGIS-9377 at concentrations to cause a significant negative chronotropic action produced a marked prolongation of action potential duration (APD) in guinea pig papillary muscle and greatly inhibited the delayed rectifier potassium current (IK) in guinea pig ventricular single cells. This suggests that the negative chronotropic effect of EGIS-9377 may, at least in part, be due to the prolongation of APD as a result of the IK inhibition. The present results indicate that EGIS-9377 efficiently increases myocardial contractile force possibly due to its Ca2+-sensitizing activity, and yet produces a substantial negative chronotropic action. This cardiac profile of EGIS-9377 is suggested to be a clinically favorable feature compared with the inotropic agents having cyclic AMP generation or phosphodiesterase inhibition as their action mechanisms.