Junko Kamiyama

Significant reversal of cardiac upregulated endothelin-1 system in a rat model of sepsis by landiolol hydrochloride.

AIMS Landiolol hydrochloride, an ultra-short-acting highly cardio-selective β-1 blocker, has become useful for various medical problems. Recent studies have demonstrated that co-treatment with landiolol protects against acute lung injury and cardiac dysfunction in rats of lipopolysaccharide (LPS)-induced systemic inflammation, and was also associated with a significant reduction in serum levels of the inflammation mediator HMGB-1 and histological lung damage. Endothelin (ET)-1, a potent vasoconstrictor, has been implicated in pathogenesis of sepsis and sepsis-induced multiple organ dysfunction syndrome. Here, we investigated whether landiolol hydrochloride can play important roles in ameliorating LPS-induced alterations in cardiac ET system of septic rats. MAIN METHODS Eight-week-old male Wistar rats were administered LPS only for 3 h and the rest were treated with LPS as well as with landiolol non-stop for 3 h. KEY FINDINGS At 3 h after LPS (only) administration, circulatory tumor necrosis factor (TNF)-α level, blood lactate concentration and percentage of fractional shortening of heart were significantly increased. In addition, LPS induced a significant expression of various components of cardiac ET-1 system compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized LPS-induced blood lactate levels and cardiac functional compensatory events, without altering levels of plasma TNF-α and ET-1. Most strikingly, landiolol treatment significantly normalized various components of cardiac ET-1 signaling system in septic rat. SIGNIFICANCE Taken together, these data led us to conclude that landiolol may be cardio-protective in septic rats by normalizing the expression of cardiac vasoactive peptide such as ET, without altering the circulatory levels of inflammatory cytokines.

Potential amelioration of upregulated renal HIF-1alpha–endothelin-1 system by landiolol hydrochloride in a rat model of endotoxemia

AIMS Endothelin (ET)-1 is the best known potent vasoconstrictor and has been implicated in pathogenesis of sepsis-associated acute kidney injury (AKI) in human or lipopolysaccharide (LPS)-induced AKI in animal models. We have previously shown that ET-1 is highly up-regulated in renal tissues and in plasma after LPS administration. Here, we investigated whether landiolol hydrochloride, an ultra-short-acting beta-blocker, can play an important role in ameliorating levels of LPS-induced up-regulation of renal HIF-1α-ET-1 system and inflammatory cytokines in a rat model of endotoxemia. MAIN METHODS Male Wistar rats at 8 weeks of age were either administered with: a) lipopolysaccharide (LPS) only for three hours (3 h) or b) LPS, followed by continuous administration of landiolol for 3 h; c) third group was only treated with vehicle. KEY FINDINGS At 3 h after LPS administration there was: a) minimal injury in kidney tissues; b) circulatory levels of creatinine, blood urea nitrogen and NGAL increased and c) expression of inflammatory cytokines, such as TNF-α, IL-6 and iNOS increased at the level of both circulatory and renal tissues. In addition, LPS significantly induced renal expression of ET-1 and HIF-1α compared to control. Finally, treatment of LPS-administered rats with landiolol for 3 h normalized elevated serum markers of renal injury and up-regulated levels of renal HIF-1α-ET-1 system with normalization of TNF-α. SIGNIFICANCE Taken together, these data led us to conclude that landiolol ameliorates the up-regulation of HIF-1α-ET-1 system in minimally morphologically-injured kidney and normalizes biomarkers of renal injury in early hours of endotoxemia of a rat model.

Effects of selective endothelin (ET)-A receptor antagonist versus dual ET-A/B receptor antagonist on hearts of streptozotocin-treated diabetic rats

AIMS The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. MAIN METHODS Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. KEY FINDINGS The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. SIGNIFICANCE Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.

Dual blockade of endothelin action exacerbates up-regulated VEGF angiogenic signaling in the heart of lipopolysaccharide-induced endotoxemic rat model

AIMS Sepsis is a cluster of heterogeneous syndromes associated with progressive endotoxemic developments, ultimately leading to damage of multiple organs, including the heart. However, the pathogenesis of sepsis-induced myocardial dysfunction is still not fully understood. The present study is the first to examine alterations in expression of key angiogenic signaling system mediated by vascular endothelial growth factor (VEGF) in septic heart and the effects of endothelin dual blocker (ETDB) on it. MAIN METHODS Normal Wistar rats were either administered with: a) vehicle only (control group), b) lipopolysaccharide only (LPS: 15 mg/kg) and then sacrificed at different time points (1 h, 3 h, 6 h and 10 h), and c) the last group was co-administered with LPS and ETDB (SB-209670, 1 mg/kg body weight) for 6 h and then sacrificed. KEY FINDINGS Administration of LPS resulted in increases in levels of: a) serum tumor necrosis factor (TNF)-α, b) serum VEGF and c) serum endothelin (ET)-1 levels accompanied by up-regulation of cardiac VEGF and its downstream angiogenic signaling molecules. While cardiac TNF-α level was unchanged among experimental groups, cardiac ET-1 level was significantly higher in LPS-administered group. SIGNIFICANCE We conclude that elevation in VEGF angiogenic signaling may be triggered by diminished oxygenation in the myocardium following LPS administration as a consequence of sepsis-induced microvascular dysfunction. Because of this cardiac dysfunction, oxygen supply may be inadequate at microregional level to support the normal heart metabolism and function. ETDB at 6 h further increased the elevated levels of VEGF angiogenic signaling in endotoxemic heart.

Assessment of circulatory and pulmonary endothelin-1 levels in a lavage-induced surfactant-depleted lung injury rabbit model with repeated open endotracheal suctioning and hyperinflation.

AIMS Endothelin-1 (ET-1) is a mediator of various physiological and pathological processes, including vascular inflammation, cell proliferation and vasoconstriction. Attenuation of ET action using ET-1 antagonists reduces pulmonary vascular leakage and inflammation in several models of lung injuries and experimental acute respiratory distress syndrome (ARDS). Based on these earlier reports, the current study investigates the patterns of ET-1 levels in circulation and pulmonary tissues in an experimental model of lavage-induced surfactant-depleted lung injury. Additionally, we also test the effects of open endotracheal suctioning (OES) and hyperinflation (HI) as recruitment maneuver following OES on ET-1 levels. MAIN METHODS Briefly, 24 Japanese white rabbits were anesthetized and intubated. Normal saline was instilled into the lung and washed mildly. After instillation, rabbits were ventilated at definite settings at a total duration of 3 hours. OES and HI were performed every 15 minutes from the beginning of the protocol. KEY FINDINGS Here, we show that both circulatory and pulmonary ET-1 levels increased in models with lung injury induced by saline lavage compared to healthy control group. No further aggravation in expression of pulmonary ET-1 was seen after OES and HI, although OES and HI worsened arterial hypoxygenation and severity of lung injury. In contrast, circulatory ET-1 levels significantly decreased after OES and HI but were not associated with blood pressure changes. SIGNIFICANCE We conclude that in a saline lavage-induced lung injury model, both circulatory and pulmonary ET-1 levels increased. Further, OES and HI exerted differential effects on ET-1 expression at both circulatory and pulmonary levels.

Effects of Closed Vs. Open Repeated Endotracheal Suctioning During Mechanical Ventilation on the Pulmonary and Circulatory Levels of Endothelin-1 in Lavage-Induced Rabbit ARDS Model

Background: A growing body of evidence demonstrates discretely the difference of open endotracheal suctioning (OES) and closed endotracheal suctioning (CES) on the respiratory and hemodynamic parameters in acute respiratory distress syndrome (ARDS). Endothelin-1 (ET-1), a mediator of vascular inflammation, cell proliferation, and fibrosis in addition to being a potent vasoconstrictor has been potentially implicated in the pathogenesis of ARDS. Here, we investigated the effects of repeated OES vs. CES during mechanical ventilation on circulatory and pulmonary levels of ET-1 in ARDS. Methods: Briefly, 22 Japanese White Rabbits were intubated with a 3.5-mm endotracheal tube. Normal saline was instilled into lung and washed mildly. After instillation, rabbits were ventilated at definite setting; OES and CES duration was for 6 hours and performed every 30 minutes from protocol start. Results: At circulatory level, either OES or CES did not alter plasma ET-1 level compared to the ET-1 level in ARDS before the initiation of endotracheal suctioning (OES 4.7 ± 1.3 pg/ml vs. CES 4.8 ± 1.5 pg/ml, p=0.839). In contrast, pulmonary ET-1 level was significantly higher in CES group compared to OES group after 6 hours of repeated suctioning in ARDS (OES 26.9 ± 2.2 pg/mg vs. CES 29.9 ± 3.3 pg/mg, p=0.018). This change in pulmonary ET-1 level could maintain a parallel relation with PaO2 level. Conclusion: At this moment, we cannot clarify the mechanism and effects of the observed change in ET-1 in a rabbit model of ARDS as well as its clinical impact.

Assessment of Circulatory Levels of Endothelin-1 in Diabetic Subjects Screened Through a Cross Sectional Study from Rural Women in Bangladesh

Aims: Endothelin-1 (ET-1), a potential marker of endothelial dysfunction, has been shown to be elevated in diabetic mellitus (DM) subjects. However, to date, the circulatory profile of ET-1 and its association with DM have not been investigated in any South Asian country, including Bangladesh. The present study assessed circulating levels of ET-1 in subjects with or without DM and further examined the association of ET-1 with clinical and metabolic parameters in Bangladeshi rural women. Main Methods: A total of 2022 rural Bangladeshi women were studied using a cross-sectional survey and then further analysis was performed based on a case control design between DM (n=195) and non-DM (204). Multiple regressions were used to examine the association between circulatory ET-1 level and DM. Key findings: A total of 2022 rural Bangladeshi women aged ≥15 years were studied using a population-based cross-sectional survey (DM prevalence is 9.1%). ET-1 levels were significantly increased in diabetes subjects [DM vs. non-DM: 3.11 ± 0.16 vs. 1.97 ± 0.03, p<0.001]. In multivariable analyses, after adjusting for age, ET-1was found to have significant positive association with waist circumference (p=0.029), fasting plasma glucose levels (p=0.001) and HDL-C (p=0.016). In multiple regression analysis considering ET-1 levels as a dependent variable, we found that plasma glucose levels and HDL-C are the independent determinants for plasma ET-1 levels in Bangladeshi rural women. Through tertile analysis, we found a significant increase in plasma levels of mean ET-1 as levels of blood glucose increased (p for trend<0.001). Significance: A higher circulatory concentration of ET-1 among DM subjects suggests possible endothelial dysfunction in this apparently healthy population. The relation between plasma ET-1 levels and DM needs further investigations aimed at defining the clinical predictive value of ET-1 in DM in the South Asian population.